Cancers

27 pages, 15911 KiB

Open AccessEditor’s ChoiceArticle

Pro-Inflammatory Cytokines Transactivate Glycosylated Cytokine Receptors on Cancer Cells to Induce Epithelial–Mesenchymal Transition to the Metastatic Phenotype

by Leili Baghaie, David A. Bunsick, Emilyn B. Aucoin, Elizabeth Skapinker, Abdulrahman M. Yaish, Yunfan Li, William W. Harless and Myron R. Szewczuk

Cancers 2025, 17(7), 1234; https://doi.org/10.3390/cancers17071234 - 5 Apr 2025

Cited by 1 | Viewed by 608

Abstract

Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of [...] Read more.

Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of primary breast, colorectal, and prostate cancer. We also investigated the regulation of their cognate receptors. Methods: All experiments were conducted using the PANC-1, SW620, and MCF-7 cell lines, treated with three different cytokines (TGF-β1, HGF, and IL-6). The effect of these cytokines on the expression of epithelial–mesenchymal transition (EMT) cell surface markers and neuraminidase-1 activity was measured via fluorescent microscopy and image analysis software. Results: The findings show that these cytokines increase the expression of mesenchymal markers while reducing epithelial markers, corresponding to the EMT process. A strong link between cytokine receptor signaling and the Neu-1-MMP-9-GPCR crosstalk was identified, suggesting that cytokine receptor binding leads to increased Neu-1 activity and subsequent signaling pathway activation. Oseltamivir phosphate (OP) prevented sialic acid hydrolysis by neuraminidase-1 (Neu-1), leading to the downregulation of these signaling cascades. Conclusions: In concert with the previous work revealing the role of Neu-1 in regulating other glycosylated receptors implicated in cancer cell proliferation and EMT, targeting Neu-1 may provide effective treatment against a variety of malignancies. Most significantly, the treatment of patients with specific inhibitors of Neu-1 soon after primary cancer surgery may improve our ability to cure early-stage cancer by inhibiting the EMT process and disrupting the ability of any residual cancer cell population to metastasize. Full article

(This article belongs to the Special Issue Role of Cytokines in Cancer)

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15 pages, 735 KiB

Open AccessEditor’s ChoiceReview

Revolutionizing MASLD: How Artificial Intelligence Is Shaping the Future of Liver Care

by Nicola Pugliese, Arianna Bertazzoni, Cesare Hassan, Jörn M. Schattenberg and Alessio Aghemo

Cancers 2025, 17(5), 722; https://doi.org/10.3390/cancers17050722 - 20 Feb 2025

Cited by 3 | Viewed by 1166

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as a leading cause of chronic liver disease. In recent years, artificial intelligence (AI) has attracted significant attention in healthcare, particularly in diagnostics, patient management, and drug development, demonstrating immense potential for application and implementation. [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as a leading cause of chronic liver disease. In recent years, artificial intelligence (AI) has attracted significant attention in healthcare, particularly in diagnostics, patient management, and drug development, demonstrating immense potential for application and implementation. In the field of MASLD, substantial research has explored the application of AI in various areas, including patient counseling, improved patient stratification, enhanced diagnostic accuracy, drug development, and prognosis prediction. However, the integration of AI in hepatology is not without challenges. Key issues include data management and privacy, algorithmic bias, and the risk of AI-generated inaccuracies, commonly referred to as “hallucinations”. This review aims to provide a comprehensive overview of the applications of AI in hepatology, with a focus on MASLD, highlighting both its transformative potential and its inherent limitations. Full article

(This article belongs to the Special Issue The Applications of Artificial Intelligence in Gastroenterology)

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32 pages, 2615 KiB

Open AccessEditor’s ChoiceReview

The Role of the Gut Microbiota in Modulating Signaling Pathways and Oxidative Stress in Glioma Therapies

by Aleksandra Krawczyk, Gabriela Elzbieta Sladowska and Barbara Strzalka-Mrozik

Cancers 2025, 17(5), 719; https://doi.org/10.3390/cancers17050719 - 20 Feb 2025

Cited by 1 | Viewed by 1257

Abstract

Tumors of the central nervous system (CNS), especially gliomas, pose a significant clinical challenge due to their aggressive nature and limited therapeutic options. Emerging research highlights the critical role of the gut microbiota in regulating CNS health and disease. The composition of the [...] Read more.

Tumors of the central nervous system (CNS), especially gliomas, pose a significant clinical challenge due to their aggressive nature and limited therapeutic options. Emerging research highlights the critical role of the gut microbiota in regulating CNS health and disease. The composition of the gut microbiota is essential for maintaining CNS homeostasis, as it modulates immune responses, oxidative status, and neuroinflammation. The microbiota–gut–brain axis, a bidirectional communication network, plays a pivotal role in cancer and CNS disease treatment, exerting its influence through neural, endocrine, immunological, and metabolic pathways. Recent studies suggest that the gut microbiota influences the solidification of the tumor microenvironment and that dysbiosis may promote glioma development by modulating systemic inflammation and oxidative stress, which contributes to tumorigenesis and CNS tumor progression. This review interrogates the impact of the gut microbiota on glioma, focusing on critical pathways such as NF-κB, MAPK, PI3K/Akt/mTOR, and Kynurenine/AhR that drive tumor proliferation, immune evasion, and therapy resistance. Furthermore, we explore emerging therapeutic strategies, including probiotics and microbiota-based interventions, which show potential in modulating these pathways and enhancing immunotherapies such as checkpoint inhibitors. By focusing on the multifaceted interactions between the gut microbiota, oxidative stress, and CNS tumors, this review highlights the potential of microbiota-targeted therapies and their manipulation to complement and enhance current treatments. Full article

(This article belongs to the Section Molecular Cancer Biology)

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17 pages, 3414 KiB

Open AccessEditor’s ChoiceArticle

TLR2-Bound Cancer-Secreted Hsp70 Induces MerTK-Mediated Immunosuppression and Tumorigenesis in Solid Tumors

by Ahmet Kaynak, Subrahmanya D. Vallabhapurapu, Harold W. Davis, Eric P. Smith, Petr Muller, Borek Vojtesek, Robert S. Franco, Wen-Hai Shao and Xiaoyang Qi

Cancers 2025, 17(3), 450; https://doi.org/10.3390/cancers17030450 - 28 Jan 2025

Cited by 2 | Viewed by 1257

Abstract

Background: A hallmark of cancer is the presence of an immunosuppressive tumor microenvironment (TME). Immunosuppressive M2 macrophages (MΦs) in the TME facilitate escape from immune surveillance and promote tumor growth; therefore, TME-induced immunosuppression is a potent immunotherapeutic approach to treating cancer. Methods [...] Read more.

Background: A hallmark of cancer is the presence of an immunosuppressive tumor microenvironment (TME). Immunosuppressive M2 macrophages (MΦs) in the TME facilitate escape from immune surveillance and promote tumor growth; therefore, TME-induced immunosuppression is a potent immunotherapeutic approach to treating cancer. Methods: Cancer cell-secreted proteins were detected by using liquid chromatography–mass spectrometry (LC-MS). Neutralizing antibodies (nAbs) were used to assess which proteins were involved in MΦs polarization and differentiation. The protein–protein interaction was characterized using co-immunoprecipitation and immunofluorescence assays. Cancer-secreted heat shock protein 70 (Hsp70) protein was quantified using an enzyme-linked immunosorbent assay (ELISA). MΦ polarization and tumor growth were assessed in vivo with subcutaneous LLC-GFP tumor models and toll-like receptor 2 (TLR2) knockout mice; in vitro assessments were conducted using TLR2 knockout and both LLC-GFP and LN227 lentiviral-mediated knockdown (KD) cells. Results: Cancer cells released a secreted form of Hsp70 that acted on MΦ TLR2 to upregulate Mer receptor tyrosine kinase (MerTK) and induce MΦ M2 polarization. Hsp70 nAbs led to a reduction in CD14 expression by 75% in THP-1 cells in response to Gli36 EMD-CM. In addition, neutralizing TLR2 nAbs resulted in a 30% and 50% reduction in CD14 expression on THP-1 cells in response to MiaPaCa-2 and Gli36 exosome/microparticle-depleted conditioned media (EMD-CMs), respectively. Hsp70, TLR2, and MerTK formed a protein complex. Tumor growth and intra-tumor M2 MΦs were significantly reduced upon cancer cell Hsp70 knockdown and in TLR2 knockout mice. Conclusions: Cancer-secreted Hsp70 interacts with TLR2, upregulates MerTK on MΦs, and induces immunosuppressive MΦ M2 polarization. This previously unreported action of secreted Hsp70 suggests that disrupting the Hsp70-TLR2-MerTK interaction could serve as a promising immunotherapeutic approach to mitigate TME immunosuppression in solid cancers. Full article

(This article belongs to the Special Issue Heat Shock Proteins in Cancers)

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34 pages, 1418 KiB

Open AccessEditor’s ChoiceReview

Advances in the Repurposing and Blood–Brain Barrier Penetrance of Drugs in Pediatric Brain Tumors

by Julian S. Rechberger, Stephanie A. Toll, Subhasree Biswas, Hyo Bin You, William D. Chow, Nicholas Kendall, Pournima Navalkele and Soumen Khatua

Cancers 2025, 17(3), 439; https://doi.org/10.3390/cancers17030439 - 27 Jan 2025

Cited by 1 | Viewed by 2286

Abstract

Central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with prognosis remaining dismal for some of these malignancies. Though the past two decades have seen advancements in surgery, radiation, and targeted therapy, major unresolved hurdles continue to undermine [...] Read more.

Central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with prognosis remaining dismal for some of these malignancies. Though the past two decades have seen advancements in surgery, radiation, and targeted therapy, major unresolved hurdles continue to undermine the therapeutic efficacy. These include challenges in suboptimal drug delivery through the blood–brain barrier (BBB), marked intra-tumoral molecular heterogeneity, and the elusive tumor microenvironment. Drug repurposing or re-tasking FDA-approved drugs with evidence of penetration into the CNS, using newer methods of intracranial drug delivery facilitating optimal drug exposure, has been an area of intense research. This could be a valuable tool, as most of these agents have already gone through the lengthy process of drug development and the evaluation of safety risks and the optimal pharmacokinetic profile. They can now be used and tested in clinics with an accelerated and different approach. Conclusions: The next-generation therapeutic strategy should prioritize repurposing oncologic and non-oncologic drugs that have been used for other indication, and have demonstrated robust preclinical activity against pediatric brain tumors. In combination with novel drug delivery techniques, these drugs could hold significant therapeutic promise in pediatric neurooncology. Full article

(This article belongs to the Special Issue Advances in Drug Repurposing to Overcome Cancers)

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21 pages, 1715 KiB

Open AccessEditor’s ChoiceReview

Exploring Artificial Intelligence Biases in Predictive Models for Cancer Diagnosis

by Aref Smiley, C. Mahony Reategui-Rivera, David Villarreal-Zegarra, Stefan Escobar-Agreda and Joseph Finkelstein

Cancers 2025, 17(3), 407; https://doi.org/10.3390/cancers17030407 - 26 Jan 2025

Cited by 4 | Viewed by 1465

Abstract

The American Society of Clinical Oncology (ASCO) has released the principles for the responsible use of artificial intelligence (AI) in oncology emphasizing fairness, accountability, oversight, equity, and transparency. However, the extent to which these principles are followed is unknown. The goal of this [...] Read more.

The American Society of Clinical Oncology (ASCO) has released the principles for the responsible use of artificial intelligence (AI) in oncology emphasizing fairness, accountability, oversight, equity, and transparency. However, the extent to which these principles are followed is unknown. The goal of this study was to assess the presence of biases and the quality of studies on AI models according to the ASCO principles and examine their potential impact through citation analysis and subsequent research applications. A review of original research articles centered on the evaluation of predictive models for cancer diagnosis published in the ASCO journal dedicated to informatics and data science in clinical oncology was conducted. Seventeen potential bias criteria were used to evaluate the sources of bias in the studies, aligned with the ASCO’s principles for responsible AI use in oncology. The CREMLS checklist was applied to assess the study quality, focusing on the reporting standards, and the performance metrics along with citation counts of the included studies were analyzed. Nine studies were included. The most common biases were environmental and life-course bias, contextual bias, provider expertise bias, and implicit bias. Among the ASCO principles, the least adhered to were transparency, oversight and privacy, and human-centered AI application. Only 22% of the studies provided access to their data. The CREMLS checklist revealed the deficiencies in methodology and evaluation reporting. Most studies reported performance metrics within moderate to high ranges. Additionally, two studies were replicated in the subsequent research. In conclusion, most studies exhibited various types of bias, reporting deficiencies, and failure to adhere to the principles for responsible AI use in oncology, limiting their applicability and reproducibility. Greater transparency, data accessibility, and compliance with international guidelines are recommended to improve the reliability of AI-based research in oncology. Full article

(This article belongs to the Section Methods and Technologies Development)

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20 pages, 2817 KiB

Open AccessEditor’s ChoiceSystematic Review

Fluorescence-Guided Surgery to Detect Microscopic Disease in Ovarian Cancer: A Systematic Review with Meta-Analysis

by Evrim Erdemoglu, Carrie L. Langstraat, Amanika Kumar, Stuart A. Ostby, Marlene E. Girardo, Andrea Giannini and Kristina A. Butler

Cancers 2025, 17(3), 410; https://doi.org/10.3390/cancers17030410 - 26 Jan 2025

Cited by 1 | Viewed by 1210

Abstract

Background: The objective in epithelial ovarian cancer is to reach maximal cytoreduction with no visible residual tumor. Tumor detection during cytoreductive surgery depends on visual inspection, palpation, or blind biopsy, methods that lack reliability for identifying microscopic disease. Although the importance of [...] Read more.

Background: The objective in epithelial ovarian cancer is to reach maximal cytoreduction with no visible residual tumor. Tumor detection during cytoreductive surgery depends on visual inspection, palpation, or blind biopsy, methods that lack reliability for identifying microscopic disease. Although the importance of microscopic disease in epithelial ovarian cancer is controversial, it may harbor chemoresistant cells and explain the high recurrence rates. Fluorescence-guided surgery (FGS) is an emerging approach. However, the potential in ovarian cancer remains underexplored; the majority of the existing evidence pertains to gastrointestinal tumors and a limited group of ovarian cancer patients. Their comparative effectiveness is still uncertain. Objective: To systematically review and evaluate the role of fluorescence-guided surgical techniques in detecting microscopic disease in ovarian cancer and compare their efficacy to total peritonectomy. Data Sources: A systematic search was made in three databases (PubMed, Web of Science, and Embase). The search was conducted from 1975 to 2024, including randomized controlled trials, observational studies, and conference abstracts in the last 25 years. Study Selection: Clinical studies published in English involving ovarian cancer patients undergoing FGS or total peritonectomy were included. Case reports, reviews, animal studies, and studies involving mixed cancer populations without ovarian cancer-specific data were excluded. Two independent reviewers screened 631 studies, yielding 12 eligible studies for final analysis. Data Extraction and Synthesis: Data were extracted and synthesized in accordance with PRISMA and MOOSE guidelines, using random-effects models for independent analysis. Sensitivity, specificity, positive predictive value (PPV), and odds ratios (ORs) were grouped, accompanied by subgroup analyses based on the fluorescence agent employed. For quality assessment, we utilized the NIH quality tool. Main Outcome(s) and Measure(s): The primary outcome was the rate of change in surgical management due to fluorescence guidance or total peritonectomy. Secondary outcomes comprised lesion-level sensitivity, specificity, and PPV. Safety outcomes included adverse events associated with fluorescence agents. Results: There were 12 studies involving 429 ovarian cancer patients. FGS improved the detection of microscopic disease compared to standard visualization methods, with a pooled sensitivity of 0.77. Folate receptor-targeted agents had high sensitivity (84%) but low specificity (26%). Aminolevulinic acid (5-ALA) showed superior diagnostic accuracy with a sensitivity of 84% and a specificity of 96%. Total peritonectomy showed no significant advantage over FGS for detecting microscopic disease. The adverse events were mild, with no serious events reported. We observed a high heterogeneity across studies and methodologies. Conclusions and Relevance: Fluorescence-guided surgery utilizing fluorescence tracers demonstrates potential in improving the detection of microscopic disease and may change surgical management in epithelial ovarian cancer, particularly with 5-ALA. Variability in performance and limited data on survival outcomes necessitates additional research. Total peritonectomy does not offer further advantage in the detection of microscopic disease. Future trials should focus on standardizing methodology and evaluating the effects of microscopic disease removal on survival outcomes. Registration: The study was registered to PROSPERO as CRD42024578274. Full article

(This article belongs to the Special Issue Paradigm Shifts in Gynaecological Oncology Surgery)

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38 pages, 2883 KiB

Open AccessEditor’s ChoiceReview

Hepatic Iron Overload and Hepatocellular Carcinoma: New Insights into Pathophysiological Mechanisms and Therapeutic Approaches

by Elena Chatzikalil, Konstantinos Arvanitakis, Georgios Kalopitas, Matilda Florentin, Georgios Germanidis, Theocharis Koufakis and Elena E. Solomou

Cancers 2025, 17(3), 392; https://doi.org/10.3390/cancers17030392 - 24 Jan 2025

Cited by 2 | Viewed by 2546

Abstract

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is rising in global incidence and mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disease, is strongly linked to metabolic conditions that can progress to [...] Read more.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is rising in global incidence and mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disease, is strongly linked to metabolic conditions that can progress to liver cirrhosis and HCC. Iron overload (IO), whether inherited or acquired, results in abnormal iron hepatic deposition, significantly impacting MASLD development and progression to HCC. While the pathophysiological connections between hepatic IO, MASLD, and HCC are not fully understood, dysregulation of glucose and lipid metabolism and IO-induced oxidative stress are being investigated as the primary drivers. Genomic analyses of inherited IO conditions reveal inconsistencies in the association of certain mutations with liver malignancies. Moreover, hepatic IO is also associated with hepcidin dysregulation and activation of ferroptosis, representing promising targets for HCC risk assessment and therapeutic intervention. Understanding the relationship between hepatic IO, MASLD, and HCC is essential for advancing clinical strategies against liver disease progression, particularly with recent IO-targeted therapies showing potential at improving liver biochemistry and insulin sensitivity. In this review, we summarize the current evidence on the pathophysiological association between hepatic IO and the progression of MASLD to HCC, underscoring the importance of early diagnosis, risk stratification, and targeted treatment for these interconnected conditions. Full article

(This article belongs to the Special Issue Advanced Research in Oncology in 2024)

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15 pages, 1392 KiB

Open AccessEditor’s ChoiceReview

Unraveling the Role of Fusobacterium nucleatum in Colorectal Cancer: Molecular Mechanisms and Pathogenic Insights

by Linda Galasso, Fabrizio Termite, Irene Mignini, Giorgio Esposto, Raffaele Borriello, Federica Vitale, Alberto Nicoletti, Mattia Paratore, Maria Elena Ainora, Antonio Gasbarrini and Maria Assunta Zocco

Cancers 2025, 17(3), 368; https://doi.org/10.3390/cancers17030368 - 23 Jan 2025

Cited by 4 | Viewed by 3100

Abstract

Fusobacterium nucleatum, a gram-negative anaerobic bacterium, has emerged as a significant player in colorectal cancer (CRC) pathogenesis. The bacterium causes a persistent inflammatory reaction in the colorectal mucosa by stimulating the release of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α, creating an [...] Read more.

Fusobacterium nucleatum, a gram-negative anaerobic bacterium, has emerged as a significant player in colorectal cancer (CRC) pathogenesis. The bacterium causes a persistent inflammatory reaction in the colorectal mucosa by stimulating the release of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α, creating an environment conducive to cancer progression. F. nucleatum binds to and penetrates epithelial cells through adhesins such as FadA, impairing cell junctions and encouraging epithelial-to-mesenchymal transition (EMT), which is associated with cancer advancement. Additionally, the bacterium modulates the host immune system, suppressing immune cell activity and creating conditions favorable for tumor growth. Its interactions with the gut microbiome contribute to dysbiosis, further influencing carcinogenic pathways. Evidence indicates that F. nucleatum can inflict DNA damage either directly via reactive oxygen species or indirectly by creating a pro-inflammatory environment. Additionally, it triggers oncogenic pathways, especially the Wnt/β-catenin signaling pathway, which promotes tumor cell growth and longevity. Moreover, F. nucleatum alters the tumor microenvironment, impacting cancer cell behavior, metastasis, and therapeutic responses. The purpose of this review is to elucidate the molecular mechanisms by which F. nucleatum contributes to CRC. Understanding these mechanisms is crucial for the development of targeted therapies and diagnostic strategies for CRC associated with F. nucleatum. Full article

(This article belongs to the Special Issue Novel Approaches and Advances in Interventional Oncology)

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12 pages, 1306 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Molecular Profiling of Metastatic Pancreatic Adenocarcinomas

by Vijay Antony, Tong Sun, Darin Dolezal and Guoping Cai

Cancers 2025, 17(3), 335; https://doi.org/10.3390/cancers17030335 - 21 Jan 2025

Cited by 1 | Viewed by 1228

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed late, with an extremely poor prognosis. Treatment options like surgery, radiation, and chemotherapy are rarely curative. Tumor progression from primary to metastatic PDAC remains poorly understood at the molecular level. Methods: In the current study, [...] Read more.

Background: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed late, with an extremely poor prognosis. Treatment options like surgery, radiation, and chemotherapy are rarely curative. Tumor progression from primary to metastatic PDAC remains poorly understood at the molecular level. Methods: In the current study, we analyzed the molecular profiles of metastatic PDAC obtained via the Oncomine Comprehensive Assay in comparison to primary PDAC. Results: The current study cohort consisted of 115 metastatic PDAC cases, of which 71 (62%) cases succeeded in molecular testing while the remaining 44 (38%) cases contained insufficient tumor cells. Molecular profiling of 71 cases revealed a total of 239 molecular alterations, 3.4 alterations per case on average, predominantly in the form of gene mutations. The most common gene mutations included KRAS (86%) and TP53 (83%) mutations. Gene copy number alterations were also detected in 19 (27%) cases involving genes such as CCNE1 and ERBB2. Compared to the molecular profiles of primary PDAC reported in our prior study and TCGA database, there seemed to be increased rates of TP53, ARID1A, BRAF, and PIK3CA mutations in the metastatic diseases. Conclusions: These findings suggest that metastatic PDAC possesses unique genetic characteristics, offering potential therapeutic targets in advanced-stage pancreatic cancer. Full article

(This article belongs to the Special Issue Histology and Pathology of Pancreatic Cancer)

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37 pages, 2321 KiB

Open AccessEditor’s ChoiceReview

Triple-Negative Breast Cancer Progression and Drug Resistance in the Context of Epithelial–Mesenchymal Transition

by Ewa Błaszczak, Paulina Miziak, Adrian Odrzywolski, Marzena Baran, Ewelina Gumbarewicz and Andrzej Stepulak

Cancers 2025, 17(2), 228; https://doi.org/10.3390/cancers17020228 - 12 Jan 2025

Cited by 2 | Viewed by 3593

Abstract

Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to [...] Read more.

Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to other breast cancer subtypes. Despite advancements in targeted therapies, traditional chemotherapy (primarily using platinum compounds and taxanes) continues to be the standard treatment for TNBC, often with limited long-term efficacy. TNBC tumors are heterogeneous, displaying a diverse mutation profile and considerable chromosomal instability, which complicates therapeutic interventions. The development of chemoresistance in TNBC is frequently associated with the process of epithelial–mesenchymal transition (EMT), during which epithelial tumor cells acquire a mesenchymal-like phenotype. This shift enhances metastatic potential, while simultaneously reducing the effectiveness of standard chemotherapeutics. It has also been suggested that EMT plays a central role in the development of cancer stem cells. Hence, there is growing interest in exploring small-molecule inhibitors that target the EMT process as a future strategy for overcoming resistance and improving outcomes for patients with TNBC. This review focuses on the progression and drug resistance of TNBC with an emphasis on the role of EMT in these processes. We present TNBC-specific and EMT-related molecular features, key EMT protein markers, and various signaling pathways involved. We also discuss other important mechanisms and factors related to chemoresistance in TNBC within the context of EMT, highlighting treatment advancements to improve patients’ outcomes. Full article

(This article belongs to the Special Issue Triple Negative Breast Cancer Therapy Resistance and Metastasis)

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29 pages, 1367 KiB

Open AccessEditor’s ChoiceReview

Current Paradigm and Future Directions in the Management of Nodal Disease in Locally Advanced Cervical Cancer

by Elki Sze-Nga Cheung and Philip Yuguang Wu

Cancers 2025, 17(2), 202; https://doi.org/10.3390/cancers17020202 - 9 Jan 2025

Cited by 2 | Viewed by 1317

Abstract

Approximately 36% of patients with cervical cancer present with regional nodal metastasis at diagnosis, which is associated with adverse survival outcomes after definitive treatment. In the modern era of chemoradiotherapy (CRT) and image-guided adaptive brachytherapy (IGABT), where excellent local control is achieved for [...] Read more.

Approximately 36% of patients with cervical cancer present with regional nodal metastasis at diagnosis, which is associated with adverse survival outcomes after definitive treatment. In the modern era of chemoradiotherapy (CRT) and image-guided adaptive brachytherapy (IGABT), where excellent local control is achieved for patients with locally advanced cervical cancer (LACC), nodal failure remains a major challenge to cure. To optimize treatment outcomes for node-positive LACC and reduce the incidence of nodal failure, various treatment approaches have been explored, including methods of surgical nodal staging or dissection, RT dose escalation strategies, such as intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) to involved nodes, and elective treatment of subclinical para-aortic (PAO) disease. Additionally, there is growing interest in emerging precision RT techniques, such as magnetic resonance-guided radiotherapy (MRgRT) and proton therapy, which may allow for further improvement in the therapeutic ratio. This review outlines the various methods of detection of nodal metastasis, treatment options for node-positive LACC, techniques of nodal radiotherapy and their clinical evidence in efficacy and toxicity profiles. Furthermore, recent advances in systemic therapy and promising novel therapeutic directions that may shape the management of node-positive LACC are discussed. Full article

(This article belongs to the Special Issue Advanced Research in Oncology in 2024)

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32 pages, 370 KiB

Open AccessEditor’s ChoiceReview

Management of Patients with Vulvar Cancers: A Systematic Comparison of International Guidelines (NCCN–ASCO–ESGO–BGCS–IGCS–FIGO–French Guidelines–RCOG)

by Stefano Restaino, Giulia Pellecchia, Martina Arcieri, Giorgio Bogani, Cristina Taliento, Pantaleo Greco, Lorenza Driul, Vito Chiantera, Rosa Pasqualina De Vincenzo, Giorgia Garganese, Francesco Sopracordevole, Violante Di Donato, Andrea Ciavattini, Paolo Scollo, Giovanni Scambia, Giuseppe Vizzielli and Gynecologic Oncology Group

Cancers 2025, 17(2), 186; https://doi.org/10.3390/cancers17020186 - 8 Jan 2025

Cited by 4 | Viewed by 2732

Abstract

Background: Vulvar carcinoma is an uncommon gynecological tumor primarily affecting older women. Its treatment significantly impacts the quality of life and, not least, aesthetics because of the mutilating surgery it requires. Objectives: The management requires a multidisciplinary team of specialists who know how [...] Read more.

Background: Vulvar carcinoma is an uncommon gynecological tumor primarily affecting older women. Its treatment significantly impacts the quality of life and, not least, aesthetics because of the mutilating surgery it requires. Objectives: The management requires a multidisciplinary team of specialists who know how to care for the patient in her entirety, not neglecting psychological aspects and reconstructive surgery. How do the guidelines address multidisciplinarity, team surgical management, passing through preoperative diagnosis, and follow-up in such a challenging rare tumor to treat? Methods: To answer these questions, we compared the main scientific recommendations to identify similarities and differences in diagnostic and therapeutic management to provide an overview of the gaps that there are currently in European and American international recommendations in providing management guidance in a cancer that is both among the rarest and most difficult to manage. In this way, we aim to encourage an update in practices based on the latest scientific evidence. Results: A review of various international guidelines, some dating back to 2014, shows significant variation in approaches, ranging from initial diagnostic procedures to managing relapses. The most recent guidelines also lacked references to the latest literature, indicating that more robust scientific evidence is needed before new treatments, such as electrochemotherapy for palliation and reconstructive surgery post exenteration, can be widely adopted. Conclusions: From the systematic comparison of the main international guidelines, a strong heterogeneity emerged in the diagnostic and therapeutic recommendations as well as for the multidisciplinary approach that today is essential. Our work certainly stimulated an update of the main guidelines. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

19 pages, 792 KiB

Open AccessEditor’s ChoiceReview

Recurrent and Metastatic Head and Neck Cancer: Mechanisms of Treatment Failure, Treatment Paradigms, and New Horizons

by William T. Barham, Marshall Patrick Stagg, Rula Mualla, Michael DiLeo and Sagar Kansara

Cancers 2025, 17(1), 144; https://doi.org/10.3390/cancers17010144 - 5 Jan 2025

Cited by 2 | Viewed by 1723

Abstract

Background: Head and neck cancer is a deadly disease with over 500,000 cases annually worldwide. Metastatic head and neck cancer accounts for a large proportion of the mortality associated with this disease. Many advances have been made in our understanding of the mechanisms [...] Read more.

Background: Head and neck cancer is a deadly disease with over 500,000 cases annually worldwide. Metastatic head and neck cancer accounts for a large proportion of the mortality associated with this disease. Many advances have been made in our understanding of the mechanisms of metastasis. The application of immunotherapy to locally recurrent or metastatic head and neck cancer has not only improved oncologic outcomes but has also provided valuable insights into the mechanisms of immune evasion and ultimately treatment failure. Objectives: This review paper will review our current understanding of biological mechanisms of treatment failure and metastasis. Published and ongoing clinical trials in the management of metastatic head and neck cancer will also be summarized. Methods: A narrative review was conducted to address the current understanding of the mechanisms of treatment failure and current treatment paradigms in recurrent and metastatic head and neck carcinoma. Conclusions: Our understanding of treatment failure in this disease is rapidly evolving. Immunotherapy represents a valuable new tool in the fight against recurrent and metastatic head and neck squamous cell carcinoma. Integrating patient and tumor specific data via artificial intelligence and deep learning will allow for a precision oncology approach, thereby achieving better prognostication and management of patients with this deadly disease. Full article

(This article belongs to the Collection Advances in Diagnostics and Treatment of Head and Neck Cancer)

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20 pages, 2716 KiB

Open AccessEditor’s ChoiceArticle

Machine Learning and Computed Tomography Radiomics to Predict Disease Progression to Upfront Pembrolizumab Monotherapy in Advanced Non-Small-Cell Lung Cancer: A Pilot Study

by Ian Janzen, Cheryl Ho, Barbara Melosky, Qian Ye, Jessica Li, Gang Wang, Stephen Lam, Calum MacAulay and Ren Yuan

Cancers 2025, 17(1), 58; https://doi.org/10.3390/cancers17010058 - 28 Dec 2024

Cited by 1 | Viewed by 1998

Abstract

Background/Objectives: Pembrolizumab monotherapy is approved in Canada for first-line treatment of advanced NSCLC with PD-L1 ≥ 50% and no EGFR/ALK aberrations. However, approximately 55% of these patients do not respond to pembrolizumab, underscoring the need for the early intervention of non-responders to optimize [...] Read more.

Background/Objectives: Pembrolizumab monotherapy is approved in Canada for first-line treatment of advanced NSCLC with PD-L1 ≥ 50% and no EGFR/ALK aberrations. However, approximately 55% of these patients do not respond to pembrolizumab, underscoring the need for the early intervention of non-responders to optimize treatment strategies. Distinguishing the 55% sub-cohort prior to treatment is a real-world dilemma. Methods: In this retrospective study, we analyzed two patient cohorts treated with pembrolizumab monotherapy (training set: n = 97; test set: n = 17). The treatment response was assessed using baseline and follow-up CT scans via RECIST 1.1 criteria. Results: A logistic regression model, incorporating pre-treatment CT radiomic features of lung tumors and clinical variables, achieved high predictive accuracy (AUC: 0.85 in training; 0.81 in testing, 95% CI: 0.63–0.99). Notably, radiomic features from the peritumoral region were found to be independent predictors, complementing the standard CT evaluations and other clinical characteristics. Conclusions: This pragmatic model offers a valuable tool to guide first-line treatment decisions in NSCLC patients with high PD-L1 expression and has the potential to advance personalized oncology and improve timely disease management. Full article

(This article belongs to the Special Issue Advances in Oncological Imaging)

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24 pages, 1923 KiB

Open AccessEditor’s ChoiceArticle

Predictive Mortality and Gastric Cancer Risk Using Clinical and Socio-Economic Data: A Nationwide Multicenter Cohort Study

by Seong Uk Kang, Seung-Joo Nam, Oh Beom Kwon, Inhyeok Yim, Tae-Hoon Kim, Na Young Yeo, Myoung Nam Lim, Woo Jin Kim and Sang Won Park

Cancers 2025, 17(1), 30; https://doi.org/10.3390/cancers17010030 - 25 Dec 2024

Cited by 1 | Viewed by 1128

Abstract

Background/Objectives: Gastric cancer is a leading cause of cancer-related mortality, particularly in East Asia, with a notable burden in Republic of Korea. This study aimed to construct and develop machine learning models for the prediction of gastric cancer mortality and the identification of [...] Read more.

Background/Objectives: Gastric cancer is a leading cause of cancer-related mortality, particularly in East Asia, with a notable burden in Republic of Korea. This study aimed to construct and develop machine learning models for the prediction of gastric cancer mortality and the identification of risk factors. Methods: All data were acquired from the Korean Clinical Data Utilization for Research Excellence by multiple medical centers in South Korea. A total of 23,717 gastric cancer patients were divided into two groups by cause of mortality (all-cause of 2664 and disease-specific of 1620) and investigated. We used comprehensive data integrating clinical, pathological, lifestyle, and socio-economic factors. Cox proportional hazards analysis was conducted to estimate hazard ratios for mortality. Five machine learning models (random forest, gradient boosting machine, XGBoost, light GBM, and cat boosting) were developed to predict mortality. The models were interpreted by SHAP, one of the explainable AI techniques. Results: For all-cause mortality, the gradient-boosting machine learning model demonstrated the highest performance with an AUC-ROC of 0.795. For disease-specific mortality, the light GBM model outperformed others, achieving an AUC-ROC of 0.867. Significant predictors included the AJCC7 stage, tumor size, lymph node count, and lifestyle factors such as smoking, drinking, and diabetes. Conclusions: This study underscores the importance of integrating both clinical and lifestyle data to enhance mortality prediction accuracy in gastric cancer patients. The findings highlight the need for personalized treatment approaches in the Korean population and emphasize the role of demographic-specific data in predictive modeling. Full article

(This article belongs to the Section Clinical Research of Cancer)

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21 pages, 911 KiB

Open AccessEditor’s ChoiceReview

Insights into the Relationship Between the Gut Microbiome and Immune Checkpoint Inhibitors in Solid Tumors

by Sona Ciernikova, Aneta Sevcikova, Maria Novisedlakova and Michal Mego

Cancers 2024, 16(24), 4271; https://doi.org/10.3390/cancers16244271 - 23 Dec 2024

Cited by 2 | Viewed by 2129

Abstract

Immunotherapy with immune checkpoint inhibitors represents a revolutionary approach to the treatment of solid tumors, including malignant melanoma, lung cancer, and gastrointestinal malignancies. Anti-CTLA-4 and anti-PD-1/PDL-1 therapies provide prolonged survival for cancer patients, but their efficacy and safety are highly variable. This review [...] Read more.

Immunotherapy with immune checkpoint inhibitors represents a revolutionary approach to the treatment of solid tumors, including malignant melanoma, lung cancer, and gastrointestinal malignancies. Anti-CTLA-4 and anti-PD-1/PDL-1 therapies provide prolonged survival for cancer patients, but their efficacy and safety are highly variable. This review focuses on the crucial role of the gut microbiome in modulating the efficacy and toxicity of immune checkpoint blockade. Studies suggest that the composition of the gut microbiome may influence the response to immunotherapy, with specific bacterial strains able to promote an anti-tumor immune response. On the other hand, dysbiosis may increase the risk of adverse effects, such as immune-mediated colitis. Interventions aimed at modulating the microbiome, including the use of probiotics, prebiotics, fecal microbial transplantation, or dietary modifications, represent promising strategies to increase treatment efficacy and reduce toxicity. The combination of immunotherapy with the microbiome-based strategy opens up new possibilities for personalized treatment. In addition, factors such as physical activity and nutritional supplementation may indirectly influence the gut ecosystem and consequently improve treatment outcomes in refractory patients, leading to enhanced patient responses and prolonged survival. Full article

(This article belongs to the Special Issue Immunotherapy of Solid Tumors and New Ideas of Anti-tumor Metastasis)

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24 pages, 4058 KiB

Open AccessEditor’s ChoiceReview

Targeting of Non-Classical Human Leukocyte Antigens as Novel Therapeutic Strategies in Cancer

by Javier David Benitez Fuentes, Jorge Bartolome Arcilla, Kauzar Mohamed Mohamed, Alfonso Lopez de Sa, Alicia de Luna Aguilar, Kissy Guevara-Hoyer, Pablo Ballestin Martinez, Antonio David Lazaro Sanchez, Edgardo D. Carosella, Alberto Ocaña and Silvia Sánchez-Ramon

Cancers 2024, 16(24), 4266; https://doi.org/10.3390/cancers16244266 - 22 Dec 2024

Cited by 2 | Viewed by 1817

Abstract

Human leukocyte antigens (HLAs) are essential regulators of immune responses against cancer, with classical HLAs well-documented for their role in tumor recognition and immune surveillance. In recent years, non-classical HLAs—including HLA-E, HLA-F, HLA-G, and HLA-H—have emerged as critical players in the immune landscape [...] Read more.

Human leukocyte antigens (HLAs) are essential regulators of immune responses against cancer, with classical HLAs well-documented for their role in tumor recognition and immune surveillance. In recent years, non-classical HLAs—including HLA-E, HLA-F, HLA-G, and HLA-H—have emerged as critical players in the immune landscape of cancer due to their diverse and less conventional functions in immune modulation. These molecules exhibit unique mechanisms that enable tumors to escape immune detection, promote tumor progression, and contribute to therapeutic resistance. This review provides a comprehensive examination of the current understanding of non-classical HLAs in solid cancers, focusing on their specific roles in shaping the tumor microenvironment and influencing immune responses. By analyzing how HLA-E, HLA-F, HLA-G, and HLA-H modulate interactions with immune cells, such as T cells, natural killer cells, and antigen-presenting cells, we highlight key pathways through which these molecules contribute to immune evasion and metastasis. Additionally, we review promising therapeutic strategies aimed at targeting non-classical HLAs, including emerging immunotherapies that could potentially enhance cancer treatment outcomes by reversing immune suppression within tumors. Understanding the influence of these non-classical HLAs in solid cancers may offer new insights into cancer immunology and may lead to the development of innovative and more effective immunotherapeutic approaches. This review underscores the importance of non-classical HLAs as potential therapeutic targets, providing a necessary foundation for future studies in the evolving field of cancer immunotherapy. Full article

(This article belongs to the Special Issue Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors (2nd Edition))

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20 pages, 1081 KiB

Open AccessEditor’s ChoiceReview

Implication of the Extracellular Matrix in Metastatic Tumor Cell Dormancy

by Chloe Redoute-Timonnier and Patrick Auguste

Cancers 2024, 16(23), 4076; https://doi.org/10.3390/cancers16234076 - 5 Dec 2024

Cited by 1 | Viewed by 1336

Abstract

Metastasis is the main cause of cancer-related deaths. The formation and growth of metastasis is a multistep process. Tumor cells extravasating in the secondary organ are in contact with a new microenvironment and a new extracellular matrix (ECM), called the metastatic niche. Some [...] Read more.

Metastasis is the main cause of cancer-related deaths. The formation and growth of metastasis is a multistep process. Tumor cells extravasating in the secondary organ are in contact with a new microenvironment and a new extracellular matrix (ECM), called the metastatic niche. Some components of the ECM, such as periostin, can induce tumor cell growth in macrometastasis. In contrast, other components, such as Thrombospondin 1 (TSP-1), can maintain isolated cells in a dormant state. During dormancy, intracellular signaling activation, such as p38, maintains tumor cells arrested in the cell-cycle G0 phase for years. At any moment, stress can induce ECM modifications and binding to their specific receptors (mainly integrins) and reactivate dormant tumor cell growth in macrometastasis. In this review, we describe the tumor microenvironment of the different niches implicated in tumor cell dormancy. The role of ECM components and their associated receptors and intracellular signaling in the reactivation of dormant tumor cells in macrometastasis will be emphasized. We also present the different methodologies and experimental approaches used to study tumor cell dormancy. Finally, we discuss the current and future treatment strategies to avoid late metastasis relapse in patients. Full article

(This article belongs to the Special Issue Extracellular Matrix Proteins in Cancer)

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19 pages, 2052 KiB

Open AccessEditor’s ChoiceArticle

Uterine Carcinosarcoma (UCS): A Literature Review and Survival Analysis from a Retrospective Cohort Study

by Mauro Francesco Pio Maiorano, Gennaro Cormio, Brigida Anna Maiorano and Vera Loizzi

Cancers 2024, 16(23), 3905; https://doi.org/10.3390/cancers16233905 - 21 Nov 2024

Cited by 3 | Viewed by 1733

Abstract

Background/Objectives: Uterine carcinosarcomas (UCSs) are rare and aggressive malignancies with limited epidemiological data. This study aims to evaluate the clinical and pathological features and prognostic factors of UCS in a retrospective cohort of 80 patients, contributing to improved management strategies. Methods: We conducted [...] Read more.

Background/Objectives: Uterine carcinosarcomas (UCSs) are rare and aggressive malignancies with limited epidemiological data. This study aims to evaluate the clinical and pathological features and prognostic factors of UCS in a retrospective cohort of 80 patients, contributing to improved management strategies. Methods: We conducted a retrospective analysis of UCS cases treated from 1995 to 2024 at three institutions. Data on demographics, clinical features, histopathology, treatment, and outcomes were collected. Overall survival (OS) and prognostic factors were assessed using Kaplan–Meier and Cox proportional hazards regression analyses. Results: The median age of patients was 66 years, with a median overall survival of 34.5 months. Disease recurrence occurred in 32.5% of cases, with a median disease-free interval of 17.92 months. Age, tumour stage, and size emerged as significant predictors of survival. Stage I–II patients had a significantly better prognosis than those with Stage III–IV (HR = 0.438, p = 0.008). Tumour size >4 cm was associated with increased mortality (HR = 2.154, p = 0.019). Lymphadenectomy was not independently associated with improved survival. Adjuvant chemotherapy, mainly carboplatin and paclitaxel, was administered to 67.5% of patients, achieving a complete response in 66.67%. Conclusions: Tumour stage and age are significant independent predictors of survival in UCS, underscoring the need for early diagnosis and intervention. Tumour size is also crucial in determining prognosis. The role of lymphadenectomy remains uncertain, emphasizing the importance of individualized treatment approaches. Future research should explore molecular profiling to further refine prognostication and therapeutic strategies for this challenging malignancy. Full article

(This article belongs to the Section Molecular Cancer Biology)

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14 pages, 2192 KiB

Open AccessEditor’s ChoiceSystematic Review

Prostate-Specific Membrane Antigen (PSMA) PET/CT in the Detection and Diagnosis of Hepatocellular Carcinoma (HCC): A Systematic Review and Meta-Analysis

by Nicholas Hannah, Catherine Yu, Leya Nedumannil, James Haridy, Grace Kong, Alex Boussioutas and Siddharth Sood

Cancers 2024, 16(22), 3865; https://doi.org/10.3390/cancers16223865 - 19 Nov 2024

Cited by 2 | Viewed by 1629

Abstract

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is widely used in prostate cancer. Recent studies indicate hepatocellular carcinoma (HCC) demonstrates PSMA PET uptake. The diagnostic accuracy of PSMA PET for HCC is not known. We conducted a systematic review and meta-analysis of [...] Read more.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is widely used in prostate cancer. Recent studies indicate hepatocellular carcinoma (HCC) demonstrates PSMA PET uptake. The diagnostic accuracy of PSMA PET for HCC is not known. We conducted a systematic review and meta-analysis of studies assessing ⁶⁸Ga-PSMA-11 in HCC. Nine studies were included, with 196 patients and a total of 491 HCC lesions. Per-patient analysis yielded a pooled sensitivity of 89.8% (95% CI 78.5–95.5). Specificity was poorly reported, with insufficient data. When per-lesion level analysis was performed on seven studies, the pooled sensitivity was 94.5% (95% CI 82.9–98.4), and specificity was again poorly reported with insufficient data. Among the three studies with adequate data for full per-lesion meta-analysis, 115 lesions in 41 patients demonstrated sensitivity of 97.1% (95% CI 87.8–99.4), while specificity was 42.2% (95% CI 0.3–99.4). Two studies provided sufficient data for meta-analysis on a per-patient level (n = 50 patients), demonstrating a sensitivity of 92.5% (95% CI 64.0–98.9) and specificity of 72.4% (95% CI 1.3–99.8). PSMA PET demonstrates a high sensitivity for HCC and shows promise as an imaging modality for diagnosis and staging of HCC. However, the existing literature does not provide enough data to confidently evaluate its specificity and, therefore, accuracy. Further prospective studies are necessary, with a focus on the accurate reporting of benign lesions and inclusion of patients with an intermediate probability of HCC. Full article

(This article belongs to the Special Issue New Approaches in Radiotherapy for Cancer)

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21 pages, 1704 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Landscape of FOXM1 in Triple-Negative Breast Cancer and Aggressive Solid Cancers

by Sayra Dilmac, Zuhal Hamurcu and Bulent Ozpolat

Cancers 2024, 16(22), 3823; https://doi.org/10.3390/cancers16223823 - 14 Nov 2024

Cited by 2 | Viewed by 2608

Abstract

Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer, lacking common treatment targets such as estrogen (ER), progesterone (PR), and HER2 receptors. This subtype is associated with significant heterogeneity, chemoresistance, early recurrence, metastasis, and poor patient survival. FOXM1 [...] Read more.

Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer, lacking common treatment targets such as estrogen (ER), progesterone (PR), and HER2 receptors. This subtype is associated with significant heterogeneity, chemoresistance, early recurrence, metastasis, and poor patient survival. FOXM1 is a cancer-promoting transcription factor that plays a critical role in TNBC and other highly aggressive cancers by driving cell proliferation, invasion, metastasis, and drug resistance. In TNBC, mutations in the TP53 gene—detected in approximately 80% of patients—lead to the overexpression of FOXM1, making it a promising therapeutic target. Beyond TNBC, FOXM1 is implicated in other solid cancers, such as brain (glioblastoma), lung, and pancreatic cancers, and is considered an Achilles’ heel of aggressive cancers. Despite its potential as a therapeutic target, there are currently no FDA-approved FOXM1 inhibitors, and none have advanced to clinical trials. This review explores the role of FOXM1 in cancer progression and highlights the current status of efforts to develop effective FOXM1 inhibitors. Full article

(This article belongs to the Collection Targeting Solid Tumors)

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17 pages, 2527 KiB

Open AccessEditor’s ChoiceReview

Tracing Quiescent Cancer Cells In Vivo

by Moon Jong Kim

Cancers 2024, 16(22), 3822; https://doi.org/10.3390/cancers16223822 - 14 Nov 2024

Cited by 3 | Viewed by 1846

Abstract

QCCs have long gained significant interest as potential “seeds” for recurrent cancers. Clinical evidence suggests that a subset of cancer cells exits the cell cycle and enters a quiescent state following anti-cancer treatment. These microscopic-residual QCCs are extremely challenging to trace and detect [...] Read more.

QCCs have long gained significant interest as potential “seeds” for recurrent cancers. Clinical evidence suggests that a subset of cancer cells exits the cell cycle and enters a quiescent state following anti-cancer treatment. These microscopic-residual QCCs are extremely challenging to trace and detect within patients. Additionally, QCCs resist conventional anti-cancer therapies due to the lack of cell activity. Notably, upon the unknown environmental cues in unknown time points, sometimes decades later, QCCs can reactivate, triggering cancer relapse at primary or secondary sites. Currently, no targeted therapies or diagnostic tools exist for QCCs, and their molecular regulatory mechanisms remain largely unknown. The major challenge in understanding QCCs lies in the limited availability of human-relevant pre-clinical models that trace and collect QCCs in vivo. This review provides an overview of existing QCC tracing systems and analyzes their limitations. It also cautiously proposes potential improvements for tracing QCCs in vivo based on recent advancements in QCC studies and lineage-tracing techniques. Developing human-relevant and easily accessible in vivo tracing systems will be a crucial step in advancing QCC diagnostics and therapeutic strategies. Full article

(This article belongs to the Special Issue Cancer Cells Fostered Microenvironment in Metastasis)

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24 pages, 2009 KiB

Open AccessEditor’s ChoiceReview

Harnessing Bacterial Agents to Modulate the Tumor Microenvironment and Enhance Cancer Immunotherapy

by Christina James Thomas, Kaylee Delgado, Kamlesh Sawant, Jacob Roy, Udit Gupta, Carly Shaw Song, Rayansh Poojary, Paul de Figueiredo and Jianxun Song

Cancers 2024, 16(22), 3810; https://doi.org/10.3390/cancers16223810 - 13 Nov 2024

Cited by 6 | Viewed by 3096

Abstract

Cancer immunotherapy has revolutionized cancer treatment by leveraging the immune system to attack tumors. However, its effectiveness is often hindered by the immunosuppressive tumor microenvironment (TME), where a complex interplay of tumor, stromal, and immune cells undermines antitumor responses and allows tumors to [...] Read more.

Cancer immunotherapy has revolutionized cancer treatment by leveraging the immune system to attack tumors. However, its effectiveness is often hindered by the immunosuppressive tumor microenvironment (TME), where a complex interplay of tumor, stromal, and immune cells undermines antitumor responses and allows tumors to evade immune detection. This review explores innovative strategies to modify the TME and enhance immunotherapy outcomes, focusing on the therapeutic potential of engineered bacteria. These bacteria exploit the unique characteristics of the TME, such as abnormal vasculature and immune suppression, to selectively accumulate in tumors. Genetically modified bacteria can deliver therapeutic agents, including immune checkpoint inhibitors and cytokines, directly to tumor sites. This review highlights how bacterial therapeutics can target critical immune cells within the TME, such as myeloid-derived suppressor cells and tumor-associated macrophages, thereby promoting antitumor immunity. The combination of bacterial therapies with immune checkpoint inhibitors or adoptive cell transfer presents a promising strategy to counteract immune suppression. Continued research in this area could position bacterial agents as a powerful new modality to reshape the TME and enhance the efficacy of cancer immunotherapy, particularly for tumors resistant to conventional treatments. Full article

(This article belongs to the Topic Gut Microbiota and Cancer)

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15 pages, 1325 KiB

Open AccessEditor’s ChoiceReview

Unlocking Intracellular Oncology Targets: The Unique Role of Antibody-Based T-Cell Receptor Mimic (TCRm) Therapeutics in T-Cell Engagers (TCEs) and Antibody-Drug Conjugates (ADCs)

by Jeffrey Molldrem and Dongxing Zha

Cancers 2024, 16(22), 3776; https://doi.org/10.3390/cancers16223776 - 8 Nov 2024

Cited by 1 | Viewed by 3825

Abstract

Effectively targeting intracellular tumor-associated proteins presents a formidable challenge in oncology, as they are traditionally considered inaccessible to conventional antibody-based therapies and CAR-T cell therapies. However, recent advancements in antibody engineering have revolutionized this field, offering promising new strategies to combat cancer. This [...] Read more.

Effectively targeting intracellular tumor-associated proteins presents a formidable challenge in oncology, as they are traditionally considered inaccessible to conventional antibody-based therapies and CAR-T cell therapies. However, recent advancements in antibody engineering have revolutionized this field, offering promising new strategies to combat cancer. This review focuses on the innovative use of T-cell receptor mimic (TCRm) antibodies within the therapeutic frameworks of T-cell engagers (TCE) and antibody-drug conjugates (ADCs). TCRm antibodies, designed to recognize peptide-MHC complexes rather than cell surface proteins, integrate the capacity of T-cells to reach intracellular targets with the unique strengths of antibodies. When incorporated into T-cell engaging therapeutics, TCRms redirect T cells to cancer cells, facilitating direct cytotoxicity. In ADCs, TCRm antibodies deliver cytotoxic agents with highly specific targeting to cancer cells, sparing healthy tissues. Together, these antibody-based strategies represent a significant leap forward in oncology, opening new avenues for the treatment of cancers previously deemed untreatable, with other potential applications in autoimmune diseases. This review discusses the mechanisms, clinical advancements, and future prospects of these cutting-edge therapies, highlighting their potential to transform the landscape of cancer treatment. Full article

(This article belongs to the Collection The Development of Anti-cancer Agents)

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16 pages, 21457 KiB

Open AccessEditor’s ChoiceArticle

Virtual Tumor Mapping: A New Standard for Surgeon–Pathologist Collaboration in Treating Oral Squamous Cell Carcinoma

by Adam Michcik, Maksym Jopek, Rafał Pęksa, Piotr Choma, Łukasz Garbacewicz, Adam Polcyn, Tomasz Wach, Maciej Sikora and Barbara Drogoszewska

Cancers 2024, 16(22), 3761; https://doi.org/10.3390/cancers16223761 - 7 Nov 2024

Cited by 1 | Viewed by 1170

Abstract

Background: The histopathological assessment is critical in the comprehensive treatment process for patients diagnosed with oral squamous cell carcinoma (OSCC). A detailed and precise specimen characterization is essential to facilitate effective surgeon–pathologist communication. Methods: In response to this need, a user-friendly virtual communication [...] Read more.

Background: The histopathological assessment is critical in the comprehensive treatment process for patients diagnosed with oral squamous cell carcinoma (OSCC). A detailed and precise specimen characterization is essential to facilitate effective surgeon–pathologist communication. Methods: In response to this need, a user-friendly virtual communication protocol utilizing a 3D scanner has been developed. This study involved 50 patients with OSCC, whose resected tumors were directly scanned in the operating room and subsequently annotated and characterized using available software. Results: The direct application of annotations and descriptions onto the virtual tumor specimens significantly enhanced the quantity and accuracy of information conveyed to the pathologist. Conclusions: The proposed solution’s repeatability and standardized approach make integration into routine clinical practice feasible, thereby establishing a potential new standard in the field. Full article

(This article belongs to the Special Issue Recent Studies on Oral Cancer: Diagnostic Technologies, Pathology, and Surgery)

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18 pages, 1512 KiB

Open AccessEditor’s ChoiceReview

Targeting Menin in Acute Myeloid Leukemia: Therapeutic Advances and Future Directions

by Sandhya Dhiman, Vikram Dhillon and Suresh Kumar Balasubramanian

Cancers 2024, 16(22), 3743; https://doi.org/10.3390/cancers16223743 - 6 Nov 2024

Cited by 1 | Viewed by 3222

Abstract

Germline mutations in the MEN1 gene encoding menin protein cause multiple endocrine neoplasia type 1 (MEN1) syndrome. Recent evidence suggests that inhibiting the interaction of menin with its crucial oncogenic protein partners represents a promising therapeutic strategy to AML. Menin plays a critical [...] Read more.

Germline mutations in the MEN1 gene encoding menin protein cause multiple endocrine neoplasia type 1 (MEN1) syndrome. Recent evidence suggests that inhibiting the interaction of menin with its crucial oncogenic protein partners represents a promising therapeutic strategy to AML. Menin plays a critical role in lysine methyltransferase 2A (KMT2A)-gene-rearranged and NPM1-m acute leukemias, both associated with adverse outcomes with current standard therapies, especially in the relapsed/refractory setting. Disrupting the menin–KMT2A interaction affects the proleukemogenic HOX/MEIS transcription program. This disruption leads to the differentiation of KMT2Ar and NPM1-m AML cells. Small molecular inhibitors of the menin–KMT2A interaction target the central cavity of MEN1 to inhibit the MEN1-KMT2A interaction and could target a similar transcriptional dependency in other leukemia subsets, broadening their therapeutic potential. These agents, both as monotherapies and in combination with synergistic drugs, are undergoing preclinical and clinical evaluation with promising early results. With the growing literature around menin inhibitors in AML, we discussed the biology of menin, its mechanism of action, its interacting partners in leukemia, possible inhibitors, their implications, synergistic drugs, and future therapeutic strategies in this review. Full article

(This article belongs to the Section Cancer Therapy)

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15 pages, 646 KiB

Open AccessEditor’s ChoiceReview

Copper and Colorectal Cancer

by Maciej Małyszko and Adam Przybyłkowski

Cancers 2024, 16(21), 3691; https://doi.org/10.3390/cancers16213691 - 31 Oct 2024

Cited by 1 | Viewed by 2214

Abstract

Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30–40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is [...] Read more.

Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30–40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is crucial for mitochondrial respiration, pigmentation, iron transport, antioxidant defense, hormone production, and extracellular matrix biosynthesis. Copper deficiency, often caused by mutations in the ATP7A gene, results in Menkes disease, an X-linked recessive disorder. On the contrary, Wilson disease is characterized by toxic copper accumulation. Cuproptosis, a unique form of cell death regulated by copper, is a subtype of necrosis induced by enhanced mitochondrial metabolism and intracellular copper accumulation. This process can reduce the malignant potential of tumor cells by inhibiting glucose metabolism. Therapeutically, copper and its complexes have shown efficacy in malignancy treatments. The disruption of copper homeostasis and excessive cuproplasia are significant in colorectal cancer development and metastasis. Therefore, manipulating copper status presents a potential therapeutic target for colorectal cancer, using copper chelators to inhibit copper formation or copper ion carriers to promote cuproptosis. This review highlights the role of copper in human physiology and pathology, emphasizing its impact on colorectal cancer and potential therapeutic strategies. Future AI-based approaches are anticipated to accelerate the development of new compounds targeting cuproptosis and copper disruption in colorectal cancer. Full article

(This article belongs to the Special Issue Advancing Horizons in Colorectal Surgery: Innovative Approaches and Outcomes)

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17 pages, 9029 KiB

Open AccessEditor’s ChoiceArticle

Genome-Wide CRISPR Screen Identifies Genes Involved in Metastasis of Pancreatic Ductal Adenocarcinoma

by Risky Oktriani, Anna Chiara Pirona, Lili Kalmár, Ariani S. Rahadian, Beiping Miao, Andrea S. Bauer, Jörg D. Hoheisel, Michael Boettcher and Haoqi Du

Cancers 2024, 16(21), 3684; https://doi.org/10.3390/cancers16213684 - 31 Oct 2024

Cited by 2 | Viewed by 1872

Abstract

Background/Objectives: Early and aggressive metastasis is a major feature of pancreatic ductal adenocarcinoma. Understanding the processes underlying metastasis is crucial for making a difference to disease outcome. Towards these ends, we looked in a comprehensive manner for genes that are metastasis-specific. Methods [...] Read more.

Background/Objectives: Early and aggressive metastasis is a major feature of pancreatic ductal adenocarcinoma. Understanding the processes underlying metastasis is crucial for making a difference to disease outcome. Towards these ends, we looked in a comprehensive manner for genes that are metastasis-specific. Methods: A genome-wide CRISPR-Cas9 gene knockout screen with 259,900 single guide RNA constructs was performed on pancreatic cancer cell lines with very high or very low metastatic capacity, respectively. Functional aspects of some of the identified genes were analysed in vitro. The injection of tumour cells with or without a gene knockout into mice was used to confirm the effect on metastasis. Results: The knockout of 590 genes—and, with higher analysis stringency, 67 genes—affected the viability of metastatic cells substantially, while these genes were not vital to non-metastasizing cells. Further evaluations identified different molecular processes related to this observation. One of the genes was MYBL2, encoding for a well-known transcription factor involved in the regulation of cell survival, proliferation, and differentiation in cancer tissues. In our metastasis-focussed study, no novel functional activity was detected for MYBL2, however. Instead, a metastasis-specific transformation of its genetic interaction with FOXM1 was observed. The interaction was synergistic in cells of low metastatic capacity, while there was a strong switch to a buffering mode in metastatic cells. In vivo analyses confirmed the strong effect of MYBL2 on metastasis. Conclusions: The genes found to be critical for the viability of metastatic cells form a basis for further investigations of the processes responsible for triggering and driving metastasis. As shown for MYBL2, unexpected processes of regulating metastasis might also be involved. Full article

(This article belongs to the Section Cancer Metastasis)

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18 pages, 477 KiB

Open AccessEditor’s ChoiceReview

Risk-Stratified Radiotherapy in Pediatric Cancer

by Rituraj Upadhyay and Arnold C. Paulino

Cancers 2024, 16(20), 3530; https://doi.org/10.3390/cancers16203530 - 18 Oct 2024

Cited by 1 | Viewed by 2108

Abstract

While the cure rate of cancer in children has markedly improved in the last few decades, late effects continue to be a problem in survivors. Radiotherapy, which is a major component of treatment in many cancers, is one of the major agents responsible [...] Read more.

While the cure rate of cancer in children has markedly improved in the last few decades, late effects continue to be a problem in survivors. Radiotherapy, which is a major component of treatment in many cancers, is one of the major agents responsible for late toxicity. In the past decade, radiotherapy has been omitted in patients achieving excellent response to chemotherapy, such as in Hodgkin lymphoma and some Wilms tumors with lung metastases. Likewise, response to chemotherapy has been used to determine whether lower doses of radiation can be delivered in intracranial germinoma and pediatric nasopharyngeal carcinoma. Molecular subtyping in medulloblastoma is currently being employed, and in WNT-pathway M0 tumors, the reduction in radiotherapy dose to the craniospinal axis and tumor bed is currently being investigated. Finally, dose escalation was recently evaluated in patients with rhabdomyosarcoma > 5 cm who do not achieve a complete response to initial 9 weeks of chemotherapy as well as for unresectable Ewing sarcoma patients to improve local control. Full article

(This article belongs to the Special Issue Personalized Radiotherapy in Cancer Care)

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38 pages, 8614 KiB

Open AccessEditor’s ChoiceReview

Enhancing Lymphoma Diagnosis, Treatment, and Follow-Up Using ¹⁸F-FDG PET/CT Imaging: Contribution of Artificial Intelligence and Radiomics Analysis

by Setareh Hasanabadi, Seyed Mahmud Reza Aghamiri, Ahmad Ali Abin, Hamid Abdollahi, Hossein Arabi and Habib Zaidi

Cancers 2024, 16(20), 3511; https://doi.org/10.3390/cancers16203511 - 17 Oct 2024

Cited by 7 | Viewed by 2967

Abstract

Lymphoma, encompassing a wide spectrum of immune system malignancies, presents significant complexities in its early detection, management, and prognosis assessment since it can mimic post-infectious/inflammatory diseases. The heterogeneous nature of lymphoma makes it challenging to definitively pinpoint valuable biomarkers for predicting tumor biology [...] Read more.

Lymphoma, encompassing a wide spectrum of immune system malignancies, presents significant complexities in its early detection, management, and prognosis assessment since it can mimic post-infectious/inflammatory diseases. The heterogeneous nature of lymphoma makes it challenging to definitively pinpoint valuable biomarkers for predicting tumor biology and selecting the most effective treatment strategies. Although molecular imaging modalities, such as positron emission tomography/computed tomography (PET/CT), specifically ¹⁸F-FDG PET/CT, hold significant importance in the diagnosis of lymphoma, prognostication, and assessment of treatment response, they still face significant challenges. Over the past few years, radiomics and artificial intelligence (AI) have surfaced as valuable tools for detecting subtle features within medical images that may not be easily discerned by visual assessment. The rapid expansion of AI and its application in medicine/radiomics is opening up new opportunities in the nuclear medicine field. Radiomics and AI capabilities seem to hold promise across various clinical scenarios related to lymphoma. Nevertheless, the need for more extensive prospective trials is evident to substantiate their reliability and standardize their applications. This review aims to provide a comprehensive perspective on the current literature regarding the application of AI and radiomics applied/extracted on/from ¹⁸F-FDG PET/CT in the management of lymphoma patients. Full article

(This article belongs to the Special Issue PET/CT in Cancers Outcomes Prediction)

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15 pages, 1992 KiB

Open AccessEditor’s ChoiceArticle

Effect of Fluorescence Lymph Node Mapping on Improving Diagnostic Values of CT D3 Lymph Node Staging for Right-Sided Colon Cancer

by Gyung Mo Son, Tae Un Kim, Mi Sook Yun, ChangYeop Kim, In Young Lee, Su Bum Park, Dong-Hoon Shin and Gi Won Ha

Cancers 2024, 16(20), 3496; https://doi.org/10.3390/cancers16203496 - 16 Oct 2024

Cited by 3 | Viewed by 1283

Abstract

Background/Objectives: This study evaluated the impact of fluorescence lymph node mapping (FLNM) using indocyanine green (ICG) on the diagnostic accuracy of preoperative computed tomography (CT) in right-sided colon cancer. Methods: A total of 218 patients who underwent laparoscopic right hemicolectomy with D3 lymph [...] Read more.

Background/Objectives: This study evaluated the impact of fluorescence lymph node mapping (FLNM) using indocyanine green (ICG) on the diagnostic accuracy of preoperative computed tomography (CT) in right-sided colon cancer. Methods: A total of 218 patients who underwent laparoscopic right hemicolectomy with D3 lymph node dissection (LND) were analyzed: 86 patients in the FLNM group and 132 in the conventional surgery group. The FLNM technique allowed for enhanced intraoperative visualization of lymph node (LN) and more precise dissection, improving the identification of metastatic LNs. The diagnostic value of preoperative CT staging was assessed in both the FLNM and control groups by calculating the apparent prevalence, true prevalence, sensitivity, specificity, positive predictive value (PPV), negative predictive value, positive likelihood ratio (PLR), negative likelihood ratio, false positive and false negative proportions, and accuracy. Results: FLNM increased the accuracy of CT staging for detecting D3 LN metastasis in advanced cancer cases, with a higher PPV, PLR, and accuracy. In the FLNM group, the false-positive rate was significantly reduced, and the specificity was higher compared to the control group. Multivariate analysis identified FLNM as an independent factor associated with improved D3 LN metastasis detection. These findings suggest that incorporating FLNM into surgical procedures enhances the diagnostic value of preoperative CT by improving the precision of LND, particularly in patients with advanced colon cancer. Conclusions: The use of FLNM for D3 LND enhances the diagnostic accuracy of cN staging in right-sided colon cancer by improving surgical precision. Full article

(This article belongs to the Special Issue The Surgical Management of Colorectal Cancer)

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24 pages, 5399 KiB

Open AccessEditor’s ChoiceArticle

Whole Exome Sequencing of Intracranial Epidermoid Cysts Reveals Immune-Associated Mechanistic and Potential Targets

by Shruthi Kondaboina, Oscar Parrish, Carolina Angelica Parada and Manuel Ferreira, Jr.

Cancers 2024, 16(20), 3487; https://doi.org/10.3390/cancers16203487 - 15 Oct 2024

Cited by 2 | Viewed by 1601

Abstract

Background/Objectives: Intracranial Epidermoid Cysts (IECs) are rare intracranial tumors primarily treated through surgery. Cyst adherence complicates complete removal, leading to high rates of tumor progression after subtotal resection. The molecular drivers of IEC remain unknown. Consequently, advances in treatment have fallen short. Tumor [...] Read more.

Background/Objectives: Intracranial Epidermoid Cysts (IECs) are rare intracranial tumors primarily treated through surgery. Cyst adherence complicates complete removal, leading to high rates of tumor progression after subtotal resection. The molecular drivers of IEC remain unknown. Consequently, advances in treatment have fallen short. Tumor genetic profiling has revealed potential targets for drug development, including FDA-approved options and reshaping treatment. The genetic landscape of IECs has not been explored. We applied Whole Exome Sequencing (WES) to IECs to gain insights into the mechanisms of oncogenesis and identify potential therapeutic targets. Methods: We performed WES on tumor tissue and matched blood samples, when available. Following GATK best practices, we conducted read processing, quality control, somatic variant calling, and copy-number inference. Data analyses and visualization were conducted in R. Results: Top altered genes are associated with the immune system and tumor microenvironment, suggesting a mechanism of immune evasion. Gene and pathway enrichment revealed a high mutation burden in genes associated with Extracellular Matrix (ECM) and PI3K-AKT-mTOR cascades. Recurrent and deleterious alterations in NOTCH2 and USP8 were identified in 50% and 30% of the cohort, respectively. Frequent amplifications in deubiquitinases and beta-defensins strengthened the involvement of immune mechanisms for oncogenic transformation. Conclusions: Top altered genes and recurrent mutations may play a role in shaping the microenvironment and modulating immune evasion in IECs. USP8 and NOTCH2 may serve as clinically relevant target for IECs. Finally, we present evidence that the crosstalk between the PI3K-Akt-mTOR and ECM signaling pathways may play a role in modulating the immune escape mechanism in IECs. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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10 pages, 1838 KiB

Open AccessEditor’s ChoiceArticle

Examination of Sarcopenia with Obesity as a Prognostic Factor in Patients with Colorectal Cancer Using the Psoas Muscle Mass Index

by Kengo Haruna, Soichiro Minami, Norikatsu Miyoshi, Shiki Fujino, Rie Mizumoto, Yuki Toyoda, Rie Hayashi, Shinya Kato, Mitsunobu Takeda, Yuki Sekido, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Hirofumi Yamamoto, Yuichiro Doki and Hidetoshi Eguchi

Cancers 2024, 16(19), 3429; https://doi.org/10.3390/cancers16193429 - 9 Oct 2024

Cited by 1 | Viewed by 1651

Abstract

Background: Sarcopenia, the age-related loss of muscle mass, is a negative prognostic factor in gastrointestinal cancer. Sarcopenia combined with visceral obesity (sarcopenic obesity) is associated with poor outcomes. We explored the influence of obesity and other factors on the prognosis of patients [...] Read more.

Background: Sarcopenia, the age-related loss of muscle mass, is a negative prognostic factor in gastrointestinal cancer. Sarcopenia combined with visceral obesity (sarcopenic obesity) is associated with poor outcomes. We explored the influence of obesity and other factors on the prognosis of patients with colorectal cancer diagnosed with sarcopenia. Methods: We enrolled 211 patients with colorectal cancer diagnosed with preoperative sarcopenic obesity who underwent radical resection at Osaka University Hospital between January 2009 and January 2012. Muscle mass was assessed using the psoas muscle mass index. Obesity was evaluated by measuring the visceral fat area in the umbilical region. Patients were categorized into two groups: sarcopenia with obesity (SO) and sarcopenia without obesity (non-SO). Overall survival, cancer-specific survival, and cancer-related relapse-free survival (CRRFS) were compared between the two groups. Patient characteristics, including age, sex, body mass index, serum albumin, C-reactive protein, tumor markers, prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and geriatric nutritional risk index (GNRI), were also analyzed. Results: CRRFS was significantly shorter in the SO group than in the non-SO group (p = 0.028). PNI, mGPS, and GNRI were not identified as significant prognostic factors for CRRFS. Multivariate analysis highlighted sarcopenic obesity, elevated carcinoembryonic antigen levels, and unfavorable histological types as significant predictors of poor CRRFS outcomes. Conclusions: Sarcopenic obesity is an independent predictor of poor prognosis in patients with CRC. Thus, interventions aimed at increasing muscle mass and reducing visceral fat could potentially improve the prognosis of these patients. Full article

(This article belongs to the Special Issue Obesity and Cancers)

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17 pages, 2928 KiB

Open AccessEditor’s ChoiceArticle

A Novel Chimeric Oncolytic Virus Mediates a Multifaceted Cellular Immune Response in a Syngeneic B16 Melanoma Model

by Sonja Glauß, Victoria Neumeyer, Lorenz Hanesch, Janina Marek, Nina Hartmann, Gabriela M. Wiedemann and Jennifer Altomonte

Cancers 2024, 16(19), 3405; https://doi.org/10.3390/cancers16193405 - 6 Oct 2024

Cited by 3 | Viewed by 1937

Abstract

Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo [...] Read more.

Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo tumor models. While OVs are known to mediate systemic anti-tumor immune responses, the detailed characterization of local and systemic immune responses to fusogenic oncolytic virotherapy remains unexplored. Methods and Results: We analyzed immune cell compartments in the spleen, blood, tumor-draining lymph nodes (TDLNs), and tumors over the course of VSV-NDV therapy in a bilateral syngeneic melanoma mouse model. Our results revealed significant local infiltration and activation of T lymphocytes in tumors and globally in the blood and spleen. Notably, in vivo CD8⁺ T cell depletion led to complete abrogation of the tumor response, highlighting the crucial role of T cells in promoting the therapeutic effects of oncolytic VSV-NDV. In vitro co-culture experiments enabled the interrogation of human immune cell responses to VSV-NDV-mediated oncolysis. Human peripheral blood mononuclear cells (PBMCs) were efficiently stimulated by exposure to VSV-NDV-infected cancer cells, which recapitulates the in vivo murine findings. Conclusions: Taken together, these data characterize a broad anti-tumor immune cell response to oncolytic VSV-NDV therapy and suggest that CD8⁺ T cells play a decisive role in therapeutic outcome, which supports the further development of this chimeric vector as a multimechanistic immunotherapy for solid cancers. Full article

(This article belongs to the Special Issue Oncolytic Viruses as an Emerging Aspect of Immune Oncology)

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43 pages, 1436 KiB

Open AccessEditor’s ChoiceReview

Orally Ingested Micro- and Nano-Plastics: A Hidden Driver of Inflammatory Bowel Disease and Colorectal Cancer

by Annalisa Bruno, Melania Dovizio, Cristina Milillo, Eleonora Aruffo, Mirko Pesce, Marco Gatta, Piero Chiacchiaretta, Piero Di Carlo and Patrizia Ballerini

Cancers 2024, 16(17), 3079; https://doi.org/10.3390/cancers16173079 - 4 Sep 2024

Cited by 8 | Viewed by 6542

Abstract

Micro- and nano-plastics (MNPLs) can move along the food chain to higher-level organisms including humans. Three significant routes for MNPLs have been reported: ingestion, inhalation, and dermal contact. Accumulating evidence supports the intestinal toxicity of ingested MNPLs and their role as drivers for [...] Read more.

Micro- and nano-plastics (MNPLs) can move along the food chain to higher-level organisms including humans. Three significant routes for MNPLs have been reported: ingestion, inhalation, and dermal contact. Accumulating evidence supports the intestinal toxicity of ingested MNPLs and their role as drivers for increased incidence of colorectal cancer (CRC) in high-risk populations such as inflammatory bowel disease (IBD) patients. However, the mechanisms are largely unknown. In this review, by using the leading scientific publication databases (Web of Science, Google Scholar, Scopus, PubMed, and ScienceDirect), we explored the possible effects and related mechanisms of MNPL exposure on the gut epithelium in healthy conditions and IBD patients. The summarized evidence supports the idea that oral MNPL exposure may contribute to intestinal epithelial damage, thus promoting and sustaining the chronic development of intestinal inflammation, mainly in high-risk populations such as IBD patients. Colonic mucus layer disruption may further facilitate MNPL passage into the bloodstream, thus contributing to the toxic effects of MNPLs on different organ systems and platelet activation, which may, in turn, contribute to the chronic development of inflammation and CRC development. Further exploration of this threat to human health is warranted to reduce potential adverse effects and CRC risk. Full article

(This article belongs to the Special Issue Signaling Mechanisms Underlying Gastrointestinal Tract Tumorigenesis)

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19 pages, 2049 KiB

Open AccessEditor’s ChoiceReview

TP53 Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications

by Chuqi Wang, Jordan Yong Ming Tan, Nishtha Chitkara and Shruti Bhatt

Cancers 2024, 16(17), 3069; https://doi.org/10.3390/cancers16173069 - 3 Sep 2024

Cited by 18 | Viewed by 8857

Abstract

Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range [...] Read more.

Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range of immune-based therapies, such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T, and hematopoietic stem cell transplantation (HSCT). This highlights the role of p53 mutations in driving immune evasion of tumor cells. In this review, we first summarize recent studies revealing mechanisms by which p53-mutant tumors evade immune surveillance from T cells, natural killer (NK) cells, and macrophages. We then review how these mutant tumor cells reshape the tumor microenvironment (TME), modulating bystander cells such as macrophages, neutrophils, and regulatory T (Treg) cells to foster immunosuppression. Additionally, we review clinical observations indicative of immune evasion associated with p53 loss or mutations. Finally, we discuss therapeutic strategies to enhance immune response in p53 wild-type (WT) or mutant tumors. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment in Cancer: Promises and Challenges)

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25 pages, 1386 KiB

Open AccessEditor’s ChoiceReview

Aberrant SWI/SNF Complex Members Are Predominant in Rare Ovarian Malignancies—Therapeutic Vulnerabilities in Treatment-Resistant Subtypes

by Yue Ma, Natisha R. Field, Tao Xie, Sarina Briscas, Emily G. Kokinogoulis, Tali S. Skipper, Amani Alghalayini, Farhana A. Sarker, Nham Tran, Nikola A. Bowden, Kristie-Ann Dickson and Deborah J. Marsh

Cancers 2024, 16(17), 3068; https://doi.org/10.3390/cancers16173068 - 3 Sep 2024

Cited by 2 | Viewed by 3338

Abstract

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations [...] Read more.

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42–67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69–100% of SCCOHT cases and SMARCA2 silencing seen 86–100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade. Full article

(This article belongs to the Special Issue Rare Gynecological Cancers)

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24 pages, 1710 KiB

Open AccessEditor’s ChoiceReview

Recent Treatment Strategies and Molecular Pathways in Resistance Mechanisms of Antiangiogenic Therapies in Glioblastoma

by Md Ataur Rahman and Meser M. Ali

Cancers 2024, 16(17), 2975; https://doi.org/10.3390/cancers16172975 - 27 Aug 2024

Cited by 12 | Viewed by 3413

Abstract

Malignant gliomas present great difficulties in treatment, with little change over the past 30 years in the median survival time of 15 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic [...] Read more.

Malignant gliomas present great difficulties in treatment, with little change over the past 30 years in the median survival time of 15 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic treatments) or destroying formed tumor vasculature (vascular disrupting agents) show promise. This study summarizes the existing knowledge regarding the processes by which glioblastoma (GBM) tumors acquire resistance to antiangiogenic treatments. The discussion encompasses the activation of redundant proangiogenic pathways, heightened tumor cell invasion and metastasis, resistance induced by hypoxia, creation of vascular mimicry channels, and regulation of the tumor immune microenvironment. Subsequently, we explore potential strategies to overcome this resistance, such as combining antiangiogenic therapies with other treatment methods, personalizing treatments for each patient, focusing on new therapeutic targets, incorporating immunotherapy, and utilizing drug delivery systems based on nanoparticles. Additionally, we would like to discuss the limitations of existing methods and potential future directions to enhance the beneficial effects of antiangiogenic treatments for patients with GBM. Therefore, this review aims to enhance the research outcome for GBM and provide a more promising opportunity by thoroughly exploring the mechanisms of resistance and investigating novel therapeutic strategies. Full article

(This article belongs to the Special Issue Current Challenges and Opportunities in Treating Glioma)

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29 pages, 5058 KiB

Open AccessEditor’s ChoiceReview

Non-Small-Cell Lung Cancers (NSCLCs) Harboring RET Gene Fusion, from Their Discovery to the Advent of New Selective Potent RET Inhibitors: “Shadows and Fogs”

by Gianluca Spitaleri, Pamela Trillo Aliaga, Ilaria Attili, Ester Del Signore, Carla Corvaja, Gloria Pellizzari, Jalissa Katrini, Antonio Passaro and Filippo de Marinis

Cancers 2024, 16(16), 2877; https://doi.org/10.3390/cancers16162877 - 19 Aug 2024

Cited by 2 | Viewed by 2820

Abstract

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading [...] Read more.

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the ‘old’ multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events. Full article

(This article belongs to the Special Issue Lung Cancer—Molecular Insights and Targeted Therapies (Volume II))

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36 pages, 955 KiB

Open AccessEditor’s ChoiceReview

The Genetic Analysis and Clinical Therapy in Lung Cancer: Current Advances and Future Directions

by Angela Rina, Debora Maffeo, Francesca Minnai, Martina Esposito, Maria Palmieri, Viola Bianca Serio, Diletta Rosati, Francesca Mari, Elisa Frullanti and Francesca Colombo

Cancers 2024, 16(16), 2882; https://doi.org/10.3390/cancers16162882 - 19 Aug 2024

Cited by 5 | Viewed by 7605

Abstract

Lung cancer, including both non-small cell lung cancer and small cell lung cancer, remains the leading cause of cancer-related mortality worldwide, representing 18% of the total cancer deaths in 2020. Many patients are identified already at an advanced stage with metastatic disease and [...] Read more.

Lung cancer, including both non-small cell lung cancer and small cell lung cancer, remains the leading cause of cancer-related mortality worldwide, representing 18% of the total cancer deaths in 2020. Many patients are identified already at an advanced stage with metastatic disease and have a worsening prognosis. Recent advances in the genetic understanding of lung cancer have opened new avenues for personalized treatments and targeted therapies. This review examines the latest discoveries in the genetics of lung cancer, discusses key biomarkers, and analyzes current clinical therapies based on this genetic information. It will conclude with a discussion of future prospects and potential research directions. Full article

(This article belongs to the Section Clinical Research of Cancer)

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26 pages, 1512 KiB

Open AccessEditor’s ChoiceReview

Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment

by Nikolaos Vitorakis, Antonios N. Gargalionis, Kostas A. Papavassiliou, Christos Adamopoulos and Athanasios G. Papavassiliou

Cancers 2024, 16(16), 2876; https://doi.org/10.3390/cancers16162876 - 19 Aug 2024

Cited by 7 | Viewed by 3207

Abstract

Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells’ metabolism, inhibit drug [...] Read more.

Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells’ metabolism, inhibit drug delivery, enhance immune suppression mechanisms and finally develop resistance to chemotherapy and immunotherapy. New strategies target TME genetic alterations and specific pathways in cell populations of the TME. Complex molecular interactions develop between PDAC cells and TME cell populations including cancer-associated fibroblasts, myeloid-derived suppressor cells, pancreatic stellate cells, tumor-associated macrophages, tumor-associated neutrophils, and regulatory T cells. In the present review, we aim to fully explore the molecular landscape of the pancreatic cancer TME cell populations and discuss current TME targeting strategies to provide thoughts for further research and preclinical testing. Full article

(This article belongs to the Special Issue Clinical Applications of Molecular Subtyping of Pancreatic Cancer)

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20 pages, 642 KiB

Open AccessEditor’s ChoiceReview

Artificial Intelligence in Detection, Management, and Prognosis of Bone Metastasis: A Systematic Review

by Giuseppe Francesco Papalia, Paolo Brigato, Luisana Sisca, Girolamo Maltese, Eliodoro Faiella, Domiziana Santucci, Francesco Pantano, Bruno Vincenzi, Giuseppe Tonini, Rocco Papalia and Vincenzo Denaro

Cancers 2024, 16(15), 2700; https://doi.org/10.3390/cancers16152700 - 29 Jul 2024

Cited by 10 | Viewed by 3884

Abstract

Background: Metastasis commonly occur in the bone tissue. Artificial intelligence (AI) has become increasingly prevalent in the medical sector as support in decision-making, diagnosis, and treatment processes. The objective of this systematic review was to assess the reliability of AI systems in clinical, [...] Read more.

Background: Metastasis commonly occur in the bone tissue. Artificial intelligence (AI) has become increasingly prevalent in the medical sector as support in decision-making, diagnosis, and treatment processes. The objective of this systematic review was to assess the reliability of AI systems in clinical, radiological, and pathological aspects of bone metastases. Methods: We included studies that evaluated the use of AI applications in patients affected by bone metastases. Two reviewers performed a digital search on 31 December 2023 on PubMed, Scopus, and Cochrane library and extracted authors, AI method, interest area, main modalities used, and main objectives from the included studies. Results: We included 59 studies that analyzed the contribution of computational intelligence in diagnosing or forecasting outcomes in patients with bone metastasis. Six studies were specific for spine metastasis. The study involved nuclear medicine (44.1%), clinical research (28.8%), radiology (20.4%), or molecular biology (6.8%). When a primary tumor was reported, prostate cancer was the most common, followed by lung, breast, and kidney. Conclusions: Appropriately trained AI models may be very useful in merging information to achieve an overall improved diagnostic accuracy and treatment for metastasis in the bone. Nevertheless, there are still concerns with the use of AI systems in medical settings. Ethical considerations and legal issues must be addressed to facilitate the safe and regulated adoption of AI technologies. The limitations of the study comprise a stronger emphasis on early detection rather than tumor management and prognosis as well as a high heterogeneity for type of tumor, AI technology and radiological techniques, pathology, or laboratory samples involved. Full article

(This article belongs to the Special Issue Artificial Intelligence and MRI Characterization of Tumors: 2nd Edition)

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17 pages, 1234 KiB

Open AccessEditor’s ChoiceArticle

The Prognostic Impact of HER2-Low and Menopausal Status in Triple-Negative Breast Cancer

by Woong Ki Park, Seok Jin Nam, Seok Won Kim, Jeong Eon Lee, Jonghan Yu, Se Kyung Lee, Jai Min Ryu and Byung Joo Chae

Cancers 2024, 16(14), 2566; https://doi.org/10.3390/cancers16142566 - 17 Jul 2024

Cited by 2 | Viewed by 2099

Abstract

TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data [...] Read more.

TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data on demographics, tumor characteristics, pathologic complete response (pCR) rates and disease-free survival (DFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed. The HER2-low group, compared to the HER2-0 group, showed significantly better DFS, DMFS, OS, BCSS (p = 0.0072, p = 0.0096, p = 0.0180, and p = 0.0001, respectively) with older age and higher rates of postmenopausal status (p < 0.0001). No significant differences in pCR rates were observed. Multivariate analyses identified HER2 status as a significant prognostic factor for DFS (p = 0.048), DMFS (p = 0.018), OS (p = 0.049), and BCSS (p = 0.008). Subgroup analysis revealed that these effects varied with menopausal status, showing more pronounced benefits in postmenopausal women. Our findings suggest that HER2-low TNBC patients exhibit a distinct clinical profile and improved survival compared to HER2-0 TNBC patients, especially in postmenopausal patients. Further research on estrogen and HER2 interaction is needed. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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22 pages, 3817 KiB

Open AccessEditor’s ChoiceArticle

Enhancing Immunotherapy Response Prediction in Metastatic Lung Adenocarcinoma: Leveraging Shallow and Deep Learning with CT-Based Radiomics across Single and Multiple Tumor Sites

by Cécile Masson-Grehaigne, Mathilde Lafon, Jean Palussière, Laura Leroy, Benjamin Bonhomme, Eva Jambon, Antoine Italiano, Sophie Cousin and Amandine Crombé

Cancers 2024, 16(13), 2491; https://doi.org/10.3390/cancers16132491 - 8 Jul 2024

Cited by 3 | Viewed by 1858

Abstract

This study aimed to evaluate the potential of pre-treatment CT-based radiomics features (RFs) derived from single and multiple tumor sites, and state-of-the-art machine-learning survival algorithms, in predicting progression-free survival (PFS) for patients with metastatic lung adenocarcinoma (MLUAD) receiving first-line treatment including immune checkpoint [...] Read more.

This study aimed to evaluate the potential of pre-treatment CT-based radiomics features (RFs) derived from single and multiple tumor sites, and state-of-the-art machine-learning survival algorithms, in predicting progression-free survival (PFS) for patients with metastatic lung adenocarcinoma (MLUAD) receiving first-line treatment including immune checkpoint inhibitors (CPIs). To do so, all adults with newly diagnosed MLUAD, pre-treatment contrast-enhanced CT scan, and performance status ≤ 2 who were treated at our cancer center with first-line CPI between November 2016 and November 2022 were included. RFs were extracted from all measurable lesions with a volume ≥ 1 cm³ on the CT scan. To capture intra- and inter-tumor heterogeneity, RFs from the largest tumor of each patient, as well as lowest, highest, and average RF values over all lesions per patient were collected. Intra-patient inter-tumor heterogeneity metrics were calculated to measure the similarity between each patient lesions. After filtering predictors with univariable Cox p < 0.100 and analyzing their correlations, five survival machine-learning algorithms (stepwise Cox regression [SCR], LASSO Cox regression, random survival forests, gradient boosted machine [GBM], and deep learning [Deepsurv]) were trained in 100-times repeated 5-fold cross-validation (rCV) to predict PFS on three inputs: (i) clinicopathological variables, (ii) all radiomics-based and clinicopathological (full input), and (iii) uncorrelated radiomics-based and clinicopathological variables (uncorrelated input). The Models’ performances were evaluated using the concordance index (c-index). Overall, 140 patients were included (median age: 62.5 years, 36.4% women). In rCV, the highest c-index was reached with Deepsurv (c-index = 0.631, 95%CI = 0.625–0.647), followed by GBM (c-index = 0.603, 95%CI = 0.557–0.646), significantly outperforming standard SCR whatever its input (c-index range: 0.560–0.570, all p < 0.0001). Thus, single- and multi-site pre-treatment radiomics data provide valuable prognostic information for predicting PFS in MLUAD patients undergoing first-line CPI treatment when analyzed with advanced machine-learning survival algorithms. Full article

(This article belongs to the Special Issue Imaging and Molecular Biology as Biomarkers for Lung Cancer)

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17 pages, 4025 KiB

Open AccessEditor’s ChoiceArticle

CRISPR-Cas9 Knockout Screens Identify DNA Damage Response Pathways and BTK as Essential for Cisplatin Response in Diffuse Large B-Cell Lymphoma

by Issa Ismail Issa, Hanne Due, Rasmus Froberg Brøndum, Vidthdyan Veeravakaran, Hulda Haraldsdóttir, Cathrine Sylvester, Asta Brogaard, Soniya Dhanjal, Bernhard Schmierer and Karen Dybkær

Cancers 2024, 16(13), 2437; https://doi.org/10.3390/cancers16132437 - 2 Jul 2024

Cited by 4 | Viewed by 2534

Abstract

The recurrence of diffuse large B-cell lymphoma (DLBCL) has been observed in 40% of cases. The standard of care for refractory/relapsed DLBCL (RR-DLBCL) is platinum-based treatment prior to autologous stem cell transplantation; however, the prognosis for RR-DLBCL patients remains poor. Thus, to identify [...] Read more.

The recurrence of diffuse large B-cell lymphoma (DLBCL) has been observed in 40% of cases. The standard of care for refractory/relapsed DLBCL (RR-DLBCL) is platinum-based treatment prior to autologous stem cell transplantation; however, the prognosis for RR-DLBCL patients remains poor. Thus, to identify genes affecting the cisplatin response in DLBCL, cisplatin-based whole-genome CRISPR-Cas9 knockout screens were performed in this study. We discovered DNA damage response (DDR) pathways as enriched among identified sensitizing CRISPR-mediated gene knockouts. In line, the knockout of the nucleotide excision repair genes XPA and ERCC6 sensitized DLBCL cells to platinum drugs irrespective of proliferation rate, thus documenting DDR as essential for cisplatin sensitivity in DLBCL. Functional analysis revealed that the loss of XPA and ERCC6 increased DNA damage levels and altered cell cycle distribution. Interestingly, we also identified BTK, which is involved in B-cell receptor signaling, to affect cisplatin response. The knockout of BTK increased cisplatin sensitivity in DLBCL cells, and combinatory drug screens revealed a synergistic effect of the BTK inhibitor, ibrutinib, with platinum drugs at low concentrations. Applying local and external DLBCL cohorts, we addressed the clinical relevance of the genes identified in the CRISPR screens. BTK was among the most frequently mutated genes with a frequency of 3–5%, and XPA and ERCC6 were also mutated, albeit at lower frequencies. Furthermore, 27–54% of diagnostic DLBCL samples had mutations in pathways that can sensitize cells to cisplatin. In conclusion, this study shows that XPA and ERCC6, in addition to BTK, are essential for the response to platinum-based drugs in DLBCL. Full article

(This article belongs to the Section Molecular Cancer Biology)

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25 pages, 3138 KiB

Open AccessEditor’s ChoiceReview

Antibody-Drug Conjugates in Urothelial Cancer: From Scientific Rationale to Clinical Development

by Whi-An Kwon, Seo-Yeon Lee, Tae Yoong Jeong, Hyeon Hoe Kim and Min-Kyung Lee

Cancers 2024, 16(13), 2420; https://doi.org/10.3390/cancers16132420 - 30 Jun 2024

Cited by 6 | Viewed by 3365

Abstract

Antibody-drug conjugates (ADCs) have been a significant advancement in cancer therapy, particularly for urothelial cancer (UC). These innovative treatments, originally developed for hematological malignancies, use target-specific monoclonal antibodies linked to potent cytotoxic agents. This rational drug design efficiently delivers cancer cell-killing agents to [...] Read more.

Antibody-drug conjugates (ADCs) have been a significant advancement in cancer therapy, particularly for urothelial cancer (UC). These innovative treatments, originally developed for hematological malignancies, use target-specific monoclonal antibodies linked to potent cytotoxic agents. This rational drug design efficiently delivers cancer cell-killing agents to cells expressing specific surface proteins, which are abundant in UC owing to their high antigen expression. UC is an ideal candidate for ADC therapy, as it enhances on-target efficacy while mitigating systemic toxicity. In recent years, considerable progress has been made in understanding the biology and mechanisms of tumor progression in UC. However, despite the introduction of immune checkpoint inhibitors, advanced UC is characterized by rapid progression and poor survival rates. Targeted therapies that have been developed include the anti-nectin 4 ADC enfortumab vedotin and the fibroblast growth factor receptor inhibitor erdafitinib. Enfortumab vedotin has shown efficacy in prospective studies in patients with advanced UC, alone and in combination with pembrolizumab. The anti-Trop-2 ADC sacituzumab govitecan has also demonstrated effectiveness in single-armed studies. This review highlights the mechanism of action of ADCs, their application in mono- and combination therapies, primary mechanisms of resistance, and future perspectives for their clinical use in UC treatment. ADCs have proven to be an increasingly vital component of the therapeutic landscape for urothelial carcinoma, filling a gap in the treatment of this progressive disease. Full article

(This article belongs to the Special Issue Advances in Drug Delivery for Cancer Therapy)

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24 pages, 348 KiB

Open AccessEditor’s ChoiceReview

Bispecific Antibodies for the Management of Relapsed/Refractory Multiple Myeloma

by Paola Tacchetti, Simona Barbato, Katia Mancuso, Elena Zamagni and Michele Cavo

Cancers 2024, 16(13), 2337; https://doi.org/10.3390/cancers16132337 - 26 Jun 2024

Cited by 7 | Viewed by 3558

Abstract

Bispecific antibodies (BsAbs) are artificially engineered antibodies that can bind simultaneously to the CD3 subunit within the T-cell receptor complex and an antigen on tumor cells, leading to T-cell activation and tumor cell killing. BsAbs against BCMA or GPRC5D have shown impressive clinical [...] Read more.

Bispecific antibodies (BsAbs) are artificially engineered antibodies that can bind simultaneously to the CD3 subunit within the T-cell receptor complex and an antigen on tumor cells, leading to T-cell activation and tumor cell killing. BsAbs against BCMA or GPRC5D have shown impressive clinical activity in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), with some agents having already received regulatory approval after the third (by the European Medicines Agency, EMA) or fourth (by the Food and Drug Administration, FDA) line of therapy; the results of early-phase clinical trials targeting FcRH5 are also promising. Overall, BsAbs as monotherapy correlated with an ORR that exceeded 60%, with a high CR rate ranging between 25% and 50% and a median PFS of around 1 year among patients with a median of 4–6 prior lines of therapy. The main toxicities include cytokine release syndrome, cytopenias, hypogammaglobulinemia, and infections; on-target off-tumor adverse events involving the skin, mucosa, hair, and nails may also occur with anti-GPRC5D BsAbs. Active research to increase their efficacy and improve their tolerance is still in progress, including combination therapies and application in earlier treatment lines and the development of novel agents. A better understanding of the mechanisms of resistance is a challenge and could lead to more personalized approaches. Full article

(This article belongs to the Special Issue Immunotherapy in the Management of Hematologic Malignancy)

18 pages, 5955 KiB

Open AccessEditor’s ChoiceArticle

Inhibition of Histone Deacetylase Activity Increases Cisplatin Efficacy to Eliminate Metastatic Cells in Pediatric Liver Cancers

by Ruhi Gulati, Yasmeen Fleifil, Katherine Jennings, Alex Bondoc, Greg Tiao, James Geller, Lubov Timchenko and Nikolai Timchenko

Cancers 2024, 16(13), 2300; https://doi.org/10.3390/cancers16132300 - 22 Jun 2024

Cited by 4 | Viewed by 1551

Abstract

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer [...] Read more.

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers. Full article

(This article belongs to the Topic Individualized Molecular Mechanisms and Treatment in Tumor Metastasis)

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18 pages, 1834 KiB

Open AccessEditor’s ChoiceReview

Resistance to Targeted Inhibitors of the PI3K/AKT/mTOR Pathway in Advanced Oestrogen-Receptor-Positive Breast Cancer

by Iseult M. Browne and Alicia F. C. Okines

Cancers 2024, 16(12), 2259; https://doi.org/10.3390/cancers16122259 - 18 Jun 2024

Cited by 11 | Viewed by 6828

Abstract

The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the [...] Read more.

The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the three kinases (PI3K, AKT, and mTOR). Although multiple compounds have been developed, at present, there are just three inhibitors approved to target this pathway in patients with advanced ER-positive, HER2-negative breast cancer: everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor). Like most targeted cancer drugs, resistance poses a major problem in the clinical setting and is a factor that has frequently limited the overall efficacy of these agents. Drug resistance can be categorised into intrinsic or acquired resistance depending on the timeframe it has developed within. Whereas intrinsic resistance exists prior to a specific treatment, acquired resistance is induced by a therapy. The majority of patients with ER-positive, HER2-negative advanced breast cancer will likely be offered an inhibitor of the PI3K/AKT/mTOR pathway at some point in their cancer journey, with the options available depending on the approval criteria in place and the cancer’s mutation status. Within this large cohort of patients, it is likely that most will develop resistance at some point, which makes this an area of interest and an unmet need at present. Herein, we review the common mechanisms of resistance to agents that target the PI3K/AKT/mTOR signalling pathway, elaborate on current management approaches, and discuss ongoing clinical trials attempting to mitigate this significant issue. We highlight the need for additional studies into AKT1 inhibitor resistance in particular. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

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