Cancers

18 pages, 6998 KB

Open AccessEditor’s ChoiceArticle

Early-Stage Lung Adenocarcinoma MDM2 Genomic Amplification Predicts Clinical Outcome and Response to Targeted Therapy

by Abhilasha Sinha, Yong Zou, Ayushi S. Patel, Seungyeul Yoo, Feng Jiang, Takashi Sato, Ranran Kong, Hideo Watanabe, Jun Zhu, Pierre P. Massion, Alain C. Borczuk and Charles A. Powell

Cancers 2022, 14(3), 708; https://doi.org/10.3390/cancers14030708 - 29 Jan 2022

Cited by 16 | Viewed by 5400

Abstract

Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer [...] Read more.

Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer cases. Lung adenocarcinoma is a highly heterogeneous disease and patients often display variable histopathological morphology, genetic alterations, and genomic aberrations. Recent advances in transcriptomic and genetic profiling of lung adenocarcinoma by investigators, including our group, has provided better stratification of this heterogeneous disease, which can facilitate devising better treatment strategies suitable for targeted patient cohorts. In a recent study we have shown gene expression profiling identified novel clustering of early stage LUAD patients and correlated with tumor invasiveness and patient survival. In this study, we focused on copy number alterations in LUAD patients. SNP array data identified amplification at chromosome 12q15 on MDM2 locus and protein overexpression in a subclass of LUAD patients with an invasive subtype of the disease. High copy number amplification and protein expression in this subclass correlated with poor overall survival. We hypothesized that MDM2 copy number and overexpression predict response to MDM2-targeted therapy. In vitro functional data on a panel of LUAD cells showed that MDM2-targeted therapy effectively suppresses cell proliferation, migration, and invasion in cells with MDM2 amplification/overexpression but not in cells without MDM2 amplification, independent of p53 status. To determine the key signaling mechanisms, we used RNA sequencing (RNA seq) to examine the response to therapy in MDM2-amplified/overexpressing p53 mutant and wild-type LUAD cells. RNA seq data shows that in MDM2-amplified/overexpression with p53 wild-type condition, the E2F → PEG10 → MMPs pathway is operative, while in p53 mutant genetic background, MDM2-targeted therapy abrogates tumor progression in LUAD cells by suppressing epithelial to mesenchymal transition (EMT) signaling. Our study provides a potentially clinically relevant strategy of selecting LUAD patients for MDM2-targeted therapy that may provide for increased response rates and, thus, better survival. Full article

(This article belongs to the Special Issue Tumor Heterogeneity)

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19 pages, 1643 KB

Open AccessEditor’s ChoiceReview

Update on Management Recommendations for Advanced Cutaneous Squamous Cell Carcinoma

by Jesús García-Foncillas, Antonio Tejera-Vaquerizo, Onofre Sanmartín, Federico Rojo, Javier Mestre, Salvador Martín, Ignacio Azinovic and Ricard Mesía

Cancers 2022, 14(3), 629; https://doi.org/10.3390/cancers14030629 - 27 Jan 2022

Cited by 29 | Viewed by 13341

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, the incidence of which has risen over the last years. Although cSCC rarely metastasizes, early detection and treatment of primary tumours are critical to limit progression and local invasion. [...] Read more.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, the incidence of which has risen over the last years. Although cSCC rarely metastasizes, early detection and treatment of primary tumours are critical to limit progression and local invasion. Several prognostic factors related to patients’ clinicopathologic profile and tumour features have been identified as high-risk markers and included in the stratification scales, but their association with regional control or survival is uncertain. Therefore, decision-making on the diagnosis and management of cSCC should be made based on each individual patient’s characteristics. Recent advances in non-invasive imaging techniques and molecular testing have enhanced clinical diagnostic accuracy. Surgical excision is the mainstay of local treatment, whereas radiotherapy (RT) is recommended for patients with inoperable disease or in specific circumstances. Novel systemic treatments including immunotherapies and targeted therapies have changed the therapeutic landscape for cSCC. The anti-PD-1 agent cemiplimab is currently the only FDA/EMA-approved first-line therapy for patients with locally advanced or metastatic cSCC who are not candidates for curative surgery or RT. Given the likelihood of recurrence and the increased risk of developing multiple cSCC, close follow-up should be performed during the first years of treatment and continued long-term surveillance is warranted. Full article

(This article belongs to the Special Issue Prevention, Diagnosis and Treatment of Skin Cancer)

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23 pages, 14888 KB

Open AccessEditor’s ChoiceReview

Cancer-on-a-Chip: Models for Studying Metastasis

by Xiaojun Zhang, Mazharul Karim, Md Mahedi Hasan, Jacob Hooper, Riajul Wahab, Sourav Roy and Taslim A. Al-Hilal

Cancers 2022, 14(3), 648; https://doi.org/10.3390/cancers14030648 - 27 Jan 2022

Cited by 53 | Viewed by 11435

Abstract

The microfluidic-based cancer-on-a-chip models work as a powerful tool to study the tumor microenvironment and its role in metastasis. The models recapitulate and systematically simplify the in vitro tumor microenvironment. This enables the study of a metastatic process in unprecedented detail. This review [...] Read more.

The microfluidic-based cancer-on-a-chip models work as a powerful tool to study the tumor microenvironment and its role in metastasis. The models recapitulate and systematically simplify the in vitro tumor microenvironment. This enables the study of a metastatic process in unprecedented detail. This review examines the development of cancer-on-a-chip microfluidic platforms at the invasion/intravasation, extravasation, and angiogenesis steps over the last three years. The on-chip modeling of mechanical cues involved in the metastasis cascade are also discussed. Finally, the popular design of microfluidic chip models for each step are discussed along with the challenges and perspectives of cancer-on-a-chip models. Full article

(This article belongs to the Special Issue Modeling Cancer in Microfluidic Chips)

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42 pages, 5014 KB

Open AccessEditor’s ChoiceReview

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

by Nora Berois, Alvaro Pittini and Eduardo Osinaga

Cancers 2022, 14(3), 645; https://doi.org/10.3390/cancers14030645 - 27 Jan 2022

Cited by 96 | Viewed by 14112

Abstract

Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to [...] Read more.

Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control. Full article

(This article belongs to the Special Issue Advances in Tumor Glycans)

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57 pages, 2143 KB

Open AccessEditor’s ChoiceReview

Clinical Evidence for Thermometric Parameters to Guide Hyperthermia Treatment

by Adela Ademaj, Danai P. Veltsista, Pirus Ghadjar, Dietmar Marder, Eva Oberacker, Oliver J. Ott, Peter Wust, Emsad Puric, Roger A. Hälg, Susanne Rogers, Stephan Bodis, Rainer Fietkau, Hans Crezee and Oliver Riesterer

Cancers 2022, 14(3), 625; https://doi.org/10.3390/cancers14030625 - 26 Jan 2022

Cited by 31 | Viewed by 6578

Abstract

Hyperthermia (HT) is a cancer treatment modality which targets malignant tissues by heating to 40–43 °C. In addition to its direct antitumor effects, HT potently sensitizes the tumor to radiotherapy (RT) and chemotherapy (CT), thereby enabling complete eradication of some tumor entities as [...] Read more.

Hyperthermia (HT) is a cancer treatment modality which targets malignant tissues by heating to 40–43 °C. In addition to its direct antitumor effects, HT potently sensitizes the tumor to radiotherapy (RT) and chemotherapy (CT), thereby enabling complete eradication of some tumor entities as shown in randomized clinical trials. Despite the proven efficacy of HT in combination with classic cancer treatments, there are limited international standards for the delivery of HT in the clinical setting. Consequently, there is a large variability in reported data on thermometric parameters, including the temperature obtained from multiple reference points, heating duration, thermal dose, time interval, and sequence between HT and other treatment modalities. Evidence from some clinical trials indicates that thermal dose, which correlates with heating time and temperature achieved, could be used as a predictive marker for treatment efficacy in future studies. Similarly, other thermometric parameters when chosen optimally are associated with increased antitumor efficacy. This review summarizes the existing clinical evidence for the prognostic and predictive role of the most important thermometric parameters to guide the combined treatment of RT and CT with HT. In conclusion, we call for the standardization of thermometric parameters and stress the importance for their validation in future prospective clinical studies. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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27 pages, 12636 KB

Open AccessEditor’s ChoiceReview

Chemotherapy Side-Effects: Not All DNA Damage Is Equal

by Winnie M. C. van den Boogaard, Daphne S. J. Komninos and Wilbert P. Vermeij

Cancers 2022, 14(3), 627; https://doi.org/10.3390/cancers14030627 - 26 Jan 2022

Cited by 307 | Viewed by 31028

Abstract

Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence [...] Read more.

Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence of numerous features of accelerated aging, seriously affecting quality of life, has now become one of the most pressing problems associated with (pediatric) cancer treatment. Chemotherapies frequently target and damage the DNA, causing mutations or genome instability, a major hallmark of both cancer and aging. However, there are numerous types of chemotherapeutic drugs that are genotoxic and interfere with DNA metabolism in different ways, each with their own biodistribution, kinetics, and biological fate. Depending on the type of DNA lesion produced (e.g., interference with DNA replication or RNA transcription), the organ or cell type inflicted (e.g., cell cycle or differentiation status, metabolic state, activity of clearance and detoxification mechanisms, the cellular condition or micro-environment), and the degree of exposure, outcomes of cancer treatment can largely differ. These considerations provide a conceptual framework in which different classes of chemotherapeutics contribute to the development of toxicities and accelerated aging of different organ systems. Here, we summarize frequently observed side-effects in (pediatric) ex-cancer patients and discuss which types of DNA damage might be responsible. Full article

(This article belongs to the Special Issue Genomic Instability in Tumor Evolution and Therapy Response)

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16 pages, 862 KB

Open AccessEditor’s ChoiceReview

Machine Learning and Deep Learning Applications in Multiple Myeloma Diagnosis, Prognosis, and Treatment Selection

by Alessandro Allegra, Alessandro Tonacci, Raffaele Sciaccotta, Sara Genovese, Caterina Musolino, Giovanni Pioggia and Sebastiano Gangemi

Cancers 2022, 14(3), 606; https://doi.org/10.3390/cancers14030606 - 25 Jan 2022

Cited by 61 | Viewed by 8842

Abstract

Artificial intelligence has recently modified the panorama of oncology investigation thanks to the use of machine learning algorithms and deep learning strategies. Machine learning is a branch of artificial intelligence that involves algorithms that analyse information, learn from that information, and then employ [...] Read more.

Artificial intelligence has recently modified the panorama of oncology investigation thanks to the use of machine learning algorithms and deep learning strategies. Machine learning is a branch of artificial intelligence that involves algorithms that analyse information, learn from that information, and then employ their discoveries to make abreast choice, while deep learning is a field of machine learning basically represented by algorithms inspired by the organization and function of the brain, named artificial neural networks. In this review, we examine the possibility of the artificial intelligence applications in multiple myeloma evaluation, and we report the most significant experimentations with respect to the machine and deep learning procedures in the relevant field. Multiple myeloma is one of the most common haematological malignancies in the world, and among them, it is one of the most difficult ones to cure due to the high occurrence of relapse and chemoresistance. Machine learning- and deep learning-based studies are expected to be among the future strategies to challenge this negative-prognosis tumour via the detection of new markers for their prompt discovery and therapy selection and by a better evaluation of its relapse and survival. Full article

(This article belongs to the Special Issue Applications of Machine Learning and Statistical Modeling in Precision Oncology)

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20 pages, 1950 KB

Open AccessEditor’s ChoiceReview

Peptide Receptor Radionuclide Therapy with [¹⁷⁷Lu]Lu-DOTA-TATE in Patients with Advanced GEP NENS: Present and Future Directions

by Maria I. del Olmo-García, Stefan Prado-Wohlwend, Pilar Bello, Angel Segura and Juan F. Merino-Torres

Cancers 2022, 14(3), 584; https://doi.org/10.3390/cancers14030584 - 24 Jan 2022

Cited by 20 | Viewed by 7498

Abstract

This review article summarizes findings published in the last years on peptide receptor radionuclide therapy in GEP NENs, as well as potential future developments and directions. Unanswered questions remain, such as the following: Which is the correct dose and individual dosimetry? Which is [...] Read more.

This review article summarizes findings published in the last years on peptide receptor radionuclide therapy in GEP NENs, as well as potential future developments and directions. Unanswered questions remain, such as the following: Which is the correct dose and individual dosimetry? Which is the place for salvage PRRT-Lu? Whicht is the role of PRRT-Lu in the pediatric population? Which is the optimal sequencing of PRRT-Lu in advanced GEP NETs? Which is the place of PRRT-Lu in G3 NENs? These, and future developments such as inclusion new radiopharmaceuticals and combination therapy with different agents, such as radiosensitizers, will be discussed. Full article

(This article belongs to the Special Issue Molecular Targeting in Cancer: Imaging and Therapy)

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14 pages, 635 KB

Open AccessEditor’s ChoiceReview

Strategies for Improving the Efficacy of CAR T Cells in Solid Cancers

by Jon Amund Kyte

Cancers 2022, 14(3), 571; https://doi.org/10.3390/cancers14030571 - 23 Jan 2022

Cited by 16 | Viewed by 6387

Abstract

Therapy with T cells equipped with chimeric antigen receptors (CARs) shows strong efficacy against leukaemia and lymphoma, but not yet against solid cancers. This has been attributed to insufficient T cell persistence, tumour heterogeneity and an immunosuppressive tumour microenvironment. The present article provides [...] Read more.

Therapy with T cells equipped with chimeric antigen receptors (CARs) shows strong efficacy against leukaemia and lymphoma, but not yet against solid cancers. This has been attributed to insufficient T cell persistence, tumour heterogeneity and an immunosuppressive tumour microenvironment. The present article provides an overview of key strategies that are currently investigated to overcome these hurdles. Basic aspects of CAR design are revisited, relevant for tuning the stimulatory signal to the requirements of solid tumours. Novel approaches for enhancing T cell persistence are highlighted, based on epigenetic or post-translational modifications. Further, the article describes CAR T strategies that are being developed for overcoming tumour heterogeneity and the escape of cancer stem cells, as well as for countering prevalent mechanisms of immune suppression in solid cancers. In general, personalised medicine is faced with a lack of drugs matching the patient’s profile. The advances and flexibility of modern gene engineering may allow for the filling of some of these gaps with tailored CAR T approaches addressing mechanisms identified as important in the individual patient. At this point, however, CAR T cell therapy remains unproved in solid cancers. The further progress of the field will depend on bringing novel strategies into clinical evaluation, while maintaining safety. Full article

(This article belongs to the Special Issue Current Advances in Chimeric Antigen Receptor Technology)

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19 pages, 4641 KB

Open AccessEditor’s ChoiceArticle

Slip versus Slop: A Head-to-Head Comparison of UV-Protective Clothing to Sunscreen

by Elizabeth G. Berry, Joshua Bezecny, Michael Acton, Taylor P. Sulmonetti, David M. Anderson, Haskell W. Beckham, Rebecca A. Durr, Takahiro Chiba, Jennifer Beem, Douglas E. Brash, Rajan Kulkarni, Pamela B. Cassidy and Sancy A. Leachman

Cancers 2022, 14(3), 542; https://doi.org/10.3390/cancers14030542 - 21 Jan 2022

Cited by 32 | Viewed by 12211

Abstract

Ultraviolet radiation (UVR) exposure is the most important modifiable risk factor for skin cancer development. Although sunscreen and sun-protective clothing are essential tools to minimize UVR exposure, few studies have compared the two modalities head-to-head. This study evaluates the UV-protective capacity of four [...] Read more.

Ultraviolet radiation (UVR) exposure is the most important modifiable risk factor for skin cancer development. Although sunscreen and sun-protective clothing are essential tools to minimize UVR exposure, few studies have compared the two modalities head-to-head. This study evaluates the UV-protective capacity of four modern, sun-protective textiles and two broad-spectrum, organic sunscreens (SPF 30 and 50). Sun Protection Factor (SPF), Ultraviolet Protection Factor (UPF), Critical Wavelength (CW), and % UVA- and % UVB-blocking were measured for each fabric. UPF, CW, % UVA- and % UVB-blocking were measured for each sunscreen at 2 mg/cm² (recommended areal density) and 1 mg/cm² (simulating real-world consumer application). The four textiles provided superior UVR protection when compared to the two sunscreens tested. All fabrics blocked erythemogenic UVR better than the sunscreens, as measured by SPF, UPF, and % UVB-blocking. Each fabric was superior to the sunscreens in blocking full-spectrum UVR, as measured by CW and % UVA-blocking. Our data demonstrate the limitations of sunscreen and UV-protective clothing labeling and suggest the combination of SPF or UPF with % UVA-blocking may provide more suitable measures for broad-spectrum protection. While sunscreen remains an important photoprotective modality (especially for sites where clothing is impractical), these data suggest that clothing should be considered the cornerstone of UV protection. Full article

(This article belongs to the Special Issue Melanoma: Prevention and Molecular Epidemiology)

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16 pages, 1064 KB

Open AccessEditor’s ChoiceReview

Emerging Role of Epigenetic Alterations as Biomarkers and Novel Targets for Treatments in Pancreatic Ductal Adenocarcinoma

by Marcus T. T. Roalsø, Øyvind H. Hald, Marina Alexeeva and Kjetil Søreide

Cancers 2022, 14(3), 546; https://doi.org/10.3390/cancers14030546 - 21 Jan 2022

Cited by 10 | Viewed by 4223

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Emerging evidence shows that epigenetic alterations are present in PDAC. The changes are potentially reversible and therefore promising therapeutic targets. Epigenetic aberrations also influence the tumor microenvironment with the potential to [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Emerging evidence shows that epigenetic alterations are present in PDAC. The changes are potentially reversible and therefore promising therapeutic targets. Epigenetic aberrations also influence the tumor microenvironment with the potential to modulate and possibly enhance immune-based treatments. Epigenetic marks can also serve as diagnostic screening tools, as epigenetic changes occur at early stages of the disease. Further, epigenetics can be used in prognostication. The field is evolving, and this review seeks to provide an updated overview of the emerging role of epigenetics in the diagnosis, treatment, and prognostication of PDAC. Full article

(This article belongs to the Special Issue Epigenetic Detection and Regulation of Cancer Biomarkers)

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18 pages, 2848 KB

Open AccessEditor’s ChoiceArticle

Platelet Count and Survival after Cancer

by Vasily Giannakeas, Joanne Kotsopoulos, Jennifer D. Brooks, Matthew C. Cheung, Laura Rosella, Lorraine Lipscombe, Mohammad R. Akbari, Peter C. Austin and Steven A. Narod

Cancers 2022, 14(3), 549; https://doi.org/10.3390/cancers14030549 - 21 Jan 2022

Cited by 38 | Viewed by 8228

Abstract

Thrombocytosis is associated with cancer progression and death for many cancer types. It is unclear if platelet count is also associated with cancer survival. We conducted a cohort study of 112,231 adults in Ontario with a diagnosis of cancer between January 2007 and [...] Read more.

Thrombocytosis is associated with cancer progression and death for many cancer types. It is unclear if platelet count is also associated with cancer survival. We conducted a cohort study of 112,231 adults in Ontario with a diagnosis of cancer between January 2007 and December 2016. We included patients who had a complete blood count (CBC) completed in the 30 days prior to their cancer diagnosis. Subjects were assigned to one of three categories according to platelet count: low (≤25th percentile), medium (>25 to <75th percentile), and high (≥75th percentile). Study subjects were followed from the date of their cancer diagnosis for cancer-specific death. Of the 112,231 eligible cancer patients in the cohort study, 40,329 (35.9%) died from their cancer in the follow-up period. Relative to those with a medium platelet count, the rate of cancer-specific death was higher among individuals with a high platelet count (HR 1.52; 95%CI 1.48–1.55) and was lower among individuals with a low platelet count (HR 0.91; 95%CI 0.88–0.93). A high platelet count was associated with poor survival for many cancer types. Platelet count could potentially be used as a risk stratification measure for cancer patients. Full article

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24 pages, 2004 KB

Open AccessEditor’s ChoiceReview

Novel Cellular Therapies for Hepatocellular Carcinoma

by Harriet Roddy, Tim Meyer and Claire Roddie

Cancers 2022, 14(3), 504; https://doi.org/10.3390/cancers14030504 - 20 Jan 2022

Cited by 25 | Viewed by 6971

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Most patients present with advanced disease, and current gold-standard management using tyrosine kinase inhibitors or immune checkpoint inhibitors (ICIs) offers modest clinical benefit. Cellular immune therapies targeting HCC are [...] Read more.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Most patients present with advanced disease, and current gold-standard management using tyrosine kinase inhibitors or immune checkpoint inhibitors (ICIs) offers modest clinical benefit. Cellular immune therapies targeting HCC are currently being tested in the laboratory and in clinical trials. Here, we review the landscape of cellular immunotherapy for HCC, defining antigenic targets, outlining the range of cell therapy products being applied in HCC (such as CAR-T and TCR-T), and exploring how advanced engineering solutions may further enhance this therapeutic approach. Full article

(This article belongs to the Collection Novel Therapies for Hepatocellular Carcinoma)

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21 pages, 3019 KB

Open AccessEditor’s ChoiceArticle

CXCR2 Mediates Distinct Neutrophil Behavior in Brain Metastatic Breast Tumor

by Simrit Safarulla, Ankit Madan, Fei Xing and Arvind Chandrasekaran

Cancers 2022, 14(3), 515; https://doi.org/10.3390/cancers14030515 - 20 Jan 2022

Cited by 27 | Viewed by 6276

Abstract

Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of [...] Read more.

Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of the breast cancer cells (BrM) dynamically activate the corresponding CXCR2 receptors on the neutrophils, thereby resulting in the modulation of certain key functional neutrophil responses towards the BrM. Using established neutrophil-tumor biomimetic co-culture models, we show that the upregulation of CXCR2 increases the recruitment of Tumor-Associated Neutrophils (TANs) towards the BrM, to enable location-favored formation of Neutrophil Extracellular Traps (NETs). Inhibition of CXCR2 using small molecule antagonist AZD5069 reversed this behavior, limiting the neutrophil responses to the BrM and retarding the reciprocal tumor development. We further demonstrate that abrogation of NETs formation using Neutrophil Elastase Inhibitor (NEI) significantly decreases the influx of neutrophils towards BrM but not to their parental tumor, suggesting that CXCR2 activation could be used by the brain metastatic tumors as a mechanism to program the tumor-infiltrating TANs into a pro-NETotic state, so as to assume a unique spatial distribution that assists in the subsequent migration and invasion of the metastatic tumor cells. This new perspective indicates that CXCR2 is a critical target for suppressing neutrophilic inflammation in brain metastasis. Full article

(This article belongs to the Special Issue Neutrophils in Cancer: Role and Therapeutic Strategies)

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15 pages, 1412 KB

Open AccessEditor’s ChoiceReview

AXL Receptor Tyrosine Kinase as a Promising Therapeutic Target Directing Multiple Aspects of Cancer Progression and Metastasis

by Marie-Anne Goyette and Jean-François Côté

Cancers 2022, 14(3), 466; https://doi.org/10.3390/cancers14030466 - 18 Jan 2022

Cited by 56 | Viewed by 7743

Abstract

The receptor tyrosine kinase AXL is emerging as a key player in tumor progression and metastasis and its expression correlates with poor survival in a plethora of cancers. While studies have shown the benefits of AXL inhibition for the treatment of metastatic cancers, [...] Read more.

The receptor tyrosine kinase AXL is emerging as a key player in tumor progression and metastasis and its expression correlates with poor survival in a plethora of cancers. While studies have shown the benefits of AXL inhibition for the treatment of metastatic cancers, additional roles for AXL in cancer progression are still being explored. This review discusses recent advances in understanding AXL’s functions in different tumor compartments including cancer, vascular, and immune cells. AXL is required at multiple steps of the metastatic cascade where its activation in cancer cells leads to EMT, invasion, survival, proliferation and therapy resistance. AXL activation in cancer cells and various stromal cells also results in tumor microenvironment deregulation, leading to modulation of angiogenesis, fibrosis, immune response and hypoxia. A better understanding of AXL’s role in these processes could lead to new therapeutic approaches that would benefit patients suffering from metastatic diseases. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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15 pages, 701 KB

Open AccessEditor’s ChoiceReview

Molecular Targets of Triple-Negative Breast Cancer: Where Do We Stand?

by Emma E. Newton, Lauren E. Mueller, Scout M. Treadwell, Cindy A. Morris and Heather L. Machado

Cancers 2022, 14(3), 482; https://doi.org/10.3390/cancers14030482 - 18 Jan 2022

Cited by 44 | Viewed by 7310

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Due to its heterogeneity and lack of hormone receptor expression, this subtype is more likely to metastasize and resist treatment attempts than are other forms of breast cancer. Due to the [...] Read more.

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Due to its heterogeneity and lack of hormone receptor expression, this subtype is more likely to metastasize and resist treatment attempts than are other forms of breast cancer. Due to the absence of targetable receptors, chemotherapy and breast conserving surgery have been the predominant treatment options for patients. However, resistance to chemotherapy and local recurrence of the tumors is frequent. Emerging immunotherapies have begun to change treatment plans for patients diagnosed with TNBC. In this review, we discuss the various immune pathways identified in TNBC and the role they play as targets for new potential treatment choices. Various therapeutic options that inhibit key pathways in cellular growth cycles, DNA repair mechanisms, epithelial mesenchymal transition, and immunosuppression have been shown to improve survival in patients with this disease. With promising results thus far, continued studies of immunotherapy and neoadjuvant therapy options for TNBC are likely to alter the treatment course for these diagnoses in the future. Full article

(This article belongs to the Special Issue Unraveling the Etiology, Therapeutics, and Molecular Signatures of Triple-Negative Breast Cancer)

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24 pages, 1884 KB

Open AccessEditor’s ChoiceReview

Tumor Cell Infiltration into the Brain in Glioblastoma: From Mechanisms to Clinical Perspectives

by Fidan Seker-Polat, Nareg Pinarbasi Degirmenci, Ihsan Solaroglu and Tugba Bagci-Onder

Cancers 2022, 14(2), 443; https://doi.org/10.3390/cancers14020443 - 17 Jan 2022

Cited by 146 | Viewed by 14456

Abstract

Glioblastoma is the most common and malignant primary brain tumor, defined by its highly aggressive nature. Despite the advances in diagnostic and surgical techniques, and the development of novel therapies in the last decade, the prognosis for glioblastoma is still extremely poor. One [...] Read more.

Glioblastoma is the most common and malignant primary brain tumor, defined by its highly aggressive nature. Despite the advances in diagnostic and surgical techniques, and the development of novel therapies in the last decade, the prognosis for glioblastoma is still extremely poor. One major factor for the failure of existing therapeutic approaches is the highly invasive nature of glioblastomas. The extreme infiltrating capacity of tumor cells into the brain parenchyma makes complete surgical removal difficult; glioblastomas almost inevitably recur in a more therapy-resistant state, sometimes at distant sites in the brain. Therefore, there are major efforts to understand the molecular mechanisms underpinning glioblastoma invasion; however, there is no approved therapy directed against the invasive phenotype as of now. Here, we review the major molecular mechanisms of glioblastoma cell invasion, including the routes followed by glioblastoma cells, the interaction of tumor cells within the brain environment and the extracellular matrix components, and the roles of tumor cell adhesion and extracellular matrix remodeling. We also include a perspective of high-throughput approaches utilized to discover novel players for invasion and clinical targeting of invasive glioblastoma cells. Full article

(This article belongs to the Special Issue Research in Aggressive Brain Tumors: Biology and Precision Therapy)

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16 pages, 14033 KB

Open AccessEditor’s ChoiceArticle

Biglycan Promotes Cancer Stem Cell Properties, NFκB Signaling and Metastatic Potential in Breast Cancer Cells

by Kanakaraju Manupati, Ritama Paul, Mingang Hao, Michael Haas, Zhaoqun Christine Bian, Tammy M. Holm, Jun-Lin Guan and Syn Kok Yeo

Cancers 2022, 14(2), 455; https://doi.org/10.3390/cancers14020455 - 17 Jan 2022

Cited by 18 | Viewed by 4306

Abstract

It is a major challenge to treat metastasis due to the presence of heterogenous BCSCs. Therefore, it is important to identify new molecular targets and their underlying molecular mechanisms in various BCSCs to improve treatment of breast cancer metastasis. Here, we performed RNA [...] Read more.

It is a major challenge to treat metastasis due to the presence of heterogenous BCSCs. Therefore, it is important to identify new molecular targets and their underlying molecular mechanisms in various BCSCs to improve treatment of breast cancer metastasis. Here, we performed RNA sequencing on two distinct co-existing BCSC populations, ALDH⁺ and CD29^hi CD61⁺ from PyMT mammary tumor cells and detected upregulation of biglycan (BGN) in these BCSCs. Genetic depletion of BGN reduced BCSC proportions and tumorsphere formation. Furthermore, BCSC associated aggressive traits such as migration and invasion were significantly reduced by depletion of BGN. Glycolytic and mitochondrial metabolic assays also revealed that BCSCs exhibited decreased metabolism upon loss of BGN. BCSCs showed decreased activation of the NFκB transcription factor, p65, and phospho-IκB levels upon BGN ablation, indicating regulation of NFκB pathway by BGN. To further support our data, we also characterized CD24⁻/CD44⁺ BCSCs from human luminal MCF-7 breast cancer cells. These CD24⁻/CD44⁺ BCSCs similarly exhibited reduced tumorigenic phenotypes, metabolism and attenuation of NFκB pathway after knockdown of BGN. Finally, loss of BGN in ALDH⁺ and CD29^hi CD61⁺ BCSCs showed decreased metastatic potential, suggesting BGN serves as an important therapeutic target in BCSCs for treating metastasis of breast cancer. Full article

(This article belongs to the Special Issue Signalling Pathways of Cancer Stem Cells)

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14 pages, 1672 KB

Open AccessEditor’s ChoiceArticle

Comprehensive Approach to Distinguish Patients with Solid Tumors from Healthy Controls by Combining Androgen Receptor Mutation p.H875Y with Cell-Free DNA Methylation and Circulating miRNAs

by Elena Tomeva, Olivier J. Switzeny, Clemens Heitzinger, Berit Hippe and Alexander G. Haslberger

Cancers 2022, 14(2), 462; https://doi.org/10.3390/cancers14020462 - 17 Jan 2022

Cited by 24 | Viewed by 8012

Abstract

Liquid biopsy-based tests emerge progressively as an important tool for cancer diagnostics and management. Currently, researchers focus on a single biomarker type and one tumor entity. This study aimed to create a multi-analyte liquid biopsy test for the simultaneous detection of several solid [...] Read more.

Liquid biopsy-based tests emerge progressively as an important tool for cancer diagnostics and management. Currently, researchers focus on a single biomarker type and one tumor entity. This study aimed to create a multi-analyte liquid biopsy test for the simultaneous detection of several solid cancers. For this purpose, we analyzed cell-free DNA (cfDNA) mutations and methylation, as well as circulating miRNAs (miRNAs) in plasma samples from 97 patients with cancer (20 bladder, 9 brain, 30 breast, 28 colorectal, 29 lung, 19 ovarian, 12 pancreas, 27 prostate, 23 stomach) and 15 healthy controls via real-time qPCR. Androgen receptor p.H875Y mutation (AR) was detected for the first time in bladder, lung, stomach, ovarian, brain, and pancreas cancer, all together in 51.3% of all cancer samples and in none of the healthy controls. A discriminant function model, comprising cfDNA mutations (COSM10758, COSM18561), cfDNA methylation markers (MLH1, MDR1, GATA5, SFN) and miRNAs (miR-17-5p, miR-20a-5p, miR-21-5p, miR-26a-5p, miR-27a-3p, miR-29c-3p, miR-92a-3p, miR-101-3p, miR-133a-3p, miR-148b-3p, miR-155-5p, miR-195-5p) could further classify healthy and tumor samples with 95.4% accuracy, 97.9% sensitivity, 80% specificity. This multi-analyte liquid biopsy-based test may help improve the simultaneous detection of several cancer types and underlines the importance of combining genetic and epigenetic biomarkers. Full article

(This article belongs to the Special Issue Liquid Nucleic Acid-Based Biomarkers in Solid Tumors)

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16 pages, 1973 KB

Open AccessEditor’s ChoiceArticle

Machine Learning Using Real-World and Translational Data to Improve Treatment Selection for NSCLC Patients Treated with Immunotherapy

by Arsela Prelaj, Mattia Boeri, Alessandro Robuschi, Roberto Ferrara, Claudia Proto, Giuseppe Lo Russo, Giulia Galli, Alessandro De Toma, Marta Brambilla, Mario Occhipinti, Sara Manglaviti, Teresa Beninato, Achille Bottiglieri, Giacomo Massa, Emma Zattarin, Rosaria Gallucci, Edoardo Gregorio Galli, Monica Ganzinelli, Gabriella Sozzi, Filippo G. M. de Braud, Marina Chiara Garassino, Marcello Restelli, Alessandra Laura Giulia Pedrocchi and Francesco Trovo' Show full author list Hide full author list

Cancers 2022, 14(2), 435; https://doi.org/10.3390/cancers14020435 - 16 Jan 2022

Cited by 24 | Viewed by 4831

Abstract

(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions [...] Read more.

(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions in aNSCLC patients treated with IO. (2) Methods: Real world data and the blood microRNA signature classifier (MSC) were used. Patients were divided into responders (R) and non-responders (NR) to determine if the overall survival of the patients was likely to be shorter or longer than 24 months from baseline IO. (3) Results: One-hundred sixty-four out of 200 patients (i.e., only those ones with PD-L1 data available) were considered in the model, 73 (44.5%) were R and 91 (55.5%) NR. Overall, the best model was the linear regression (RL) and included 5 features. The model predicting R/NR of patients achieved accuracy ACC = 0.756, F1 score F1 = 0.722, and area under the ROC curve AUC = 0.82. LR was also the best-performing model in predicting patients with long survival (24 months OS), achieving ACC = 0.839, F1 = 0.908, and AUC = 0.87. (4) Conclusions: The results suggest that the integration of multifactorial data provided by ML techniques is a useful tool to select NSCLC patients as candidates for IO. Full article

(This article belongs to the Special Issue Cancer: Advances in T Cell-Based Clinical Immunotherapies)

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20 pages, 993 KB

Open AccessEditor’s ChoiceReview

STAT3 Signaling in Breast Cancer: Multicellular Actions and Therapeutic Potential

by Sarah Q. To, Rhynelle S. Dmello, Anna K. Richards, Matthias Ernst and Ashwini L. Chand

Cancers 2022, 14(2), 429; https://doi.org/10.3390/cancers14020429 - 15 Jan 2022

Cited by 62 | Viewed by 18910

Abstract

Interleukin (IL)-6 family cytokines, such as IL-6 and IL-11, are defined by the shared use of the gp130 receptor for the downstream activation of STAT3 signaling and the activation of genes which contribute to the “hallmarks of cancer”, including proliferation, survival, invasion and [...] Read more.

Interleukin (IL)-6 family cytokines, such as IL-6 and IL-11, are defined by the shared use of the gp130 receptor for the downstream activation of STAT3 signaling and the activation of genes which contribute to the “hallmarks of cancer”, including proliferation, survival, invasion and metastasis. Increased expression of these cytokines, or the ligand-specific receptors IL-6R and IL-11RA, in breast tumors positively correlate to disease progression and poorer patient outcome. In this review, we examine evidence from pre-clinical studies that correlate enhanced IL-6 and IL-11 mediated gp130/STAT3 signaling to the progression of breast cancer. Key processes by which the IL-6 family cytokines contribute to the heterogeneous nature of breast cancer, immune evasion and metastatic potential, are discussed. We examine the latest research into the therapeutic targeting of IL-6 family cytokines that inhibit STAT3 transcriptional activity as a potential breast cancer treatment, including current clinical trials. The importance of the IL-6 family of cytokines in cellular processes that promote the development and progression of breast cancer warrants further understanding of the molecular basis for its actions to help guide the development of future therapeutic targets. Full article

(This article belongs to the Special Issue Multicellular Effects of STAT3 in the Tumour Microenvironment)

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16 pages, 1073 KB

Open AccessEditor’s ChoiceReview

The Evolution of Ovarian Carcinoma Subclassification

by Martin Köbel and Eun Young Kang

Cancers 2022, 14(2), 416; https://doi.org/10.3390/cancers14020416 - 14 Jan 2022

Cited by 73 | Viewed by 21949

Abstract

The phenotypically informed histotype classification remains the mainstay of ovarian carcinoma subclassification. Histotypes of ovarian epithelial neoplasms have evolved with each edition of the WHO Classification of Female Genital Tumours. The current fifth edition (2020) lists five principal histotypes: high-grade serous carcinoma (HGSC), [...] Read more.

The phenotypically informed histotype classification remains the mainstay of ovarian carcinoma subclassification. Histotypes of ovarian epithelial neoplasms have evolved with each edition of the WHO Classification of Female Genital Tumours. The current fifth edition (2020) lists five principal histotypes: high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), mucinous carcinoma (MC), endometrioid carcinoma (EC) and clear cell carcinoma (CCC). Since histotypes arise from different cells of origin, cell lineage-specific diagnostic immunohistochemical markers and histotype-specific oncogenic alterations can confirm the morphological diagnosis. A four-marker immunohistochemical panel (WT1/p53/napsin A/PR) can distinguish the five principal histotypes with high accuracy, and additional immunohistochemical markers can be used depending on the diagnostic considerations. Histotypes are further stratified into molecular subtypes and assessed with predictive biomarker tests. HGSCs have recently been subclassified based on mechanisms of chromosomal instability, mRNA expression profiles or individual candidate biomarkers. ECs are composed of the same molecular subtypes (POLE-mutated/mismatch repair-deficient/no specific molecular profile/p53-abnormal) with the same prognostic stratification as their endometrial counterparts. Although methylation analyses and gene expression and sequencing showed at least two clusters, the molecular subtypes of CCCs remain largely elusive to date. Mutational and immunohistochemical data on LGSC have suggested five molecular subtypes with prognostic differences. While our understanding of the molecular composition of ovarian carcinomas has significantly advanced and continues to evolve, the need for treatment options suitable for these alterations is becoming more obvious. Further preclinical studies using histotype-defined and molecular subtype-characterized model systems are needed to expand the therapeutic spectrum for women diagnosed with ovarian carcinomas. Full article

(This article belongs to the Special Issue Molecular Testing for Pathologic Diagnosis, Prediction and Prognostication in Gynecologic Cancers: Utility and Limitations)

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12 pages, 3312 KB

Open AccessEditor’s ChoiceReview

A Breakthrough Brought about by Targeting KRAS^G12C: Nonconformity Is Punished

by Wenjuan Ning, Zhang Yang, Gregor J. Kocher, Patrick Dorn and Ren-Wang Peng

Cancers 2022, 14(2), 390; https://doi.org/10.3390/cancers14020390 - 13 Jan 2022

Cited by 17 | Viewed by 5697

Abstract

KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRAS^G12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable—that is, until the advent of G12C inhibitors, which [...] Read more.

KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRAS^G12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable—that is, until the advent of G12C inhibitors, which put an end to this legend by covalently targeting the G12C (glycine to cysteine) substitution in the switch-II pocket of the protein, inhibiting the affinity of the mutant KRAS with GTP and subsequently the downstream signaling pathways, such as Raf/MEK/ERK. KRAS^G12C-selective inhibitors, e.g., the FDA-approved AMG510 and MRTX849, have demonstrated potent clinical efficacy and selectivity in patients with KRAS^G12C-driven cancers only, which spares other driver KRAS mutations (e.g., G12D/V/S, G13D, and Q61H) and has ushered in an unprecedented breakthrough in the field in recent decades. However, accumulating evidence from preclinical and clinical studies has shown that G12C-targeted therapeutics as single agents are inevitably thwarted by drug resistance, a persistent problem associated with targeted therapies. A promising strategy to optimize G12C inhibitor therapy is combination treatments with other therapeutic agents, the identification of which is empowered by the insightful appreciation of compensatory signaling pathways or evasive mechanisms, such as those that attenuate immune responses. Here, we review recent advances in targeting KRAS^G12C and discuss the challenges of KRAS^G12C inhibitor therapy, as well as future directions. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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27 pages, 3431 KB

Open AccessEditor’s ChoiceArticle

The Anti-Proliferative Effect of PI3K/mTOR and ERK Inhibition in Monolayer and Three-Dimensional Ovarian Cancer Cell Models

by Elizabeth Dunn, Kenny Chitcholtan, Peter Sykes and Ashley Garrill

Cancers 2022, 14(2), 395; https://doi.org/10.3390/cancers14020395 - 13 Jan 2022

Cited by 12 | Viewed by 3839

Abstract

Most ovarian cancer patients are diagnosed with advanced stage disease, which becomes unresponsive to chemotherapeutic treatments. The PI3K/AKT/mTOR and the RAS/RAF/MEK/ERK kinase signaling pathways are attractive targets for potential therapeutic inhibitors, due to the high frequency of mutations to PTEN, PIK3CA, KRAS and [...] Read more.

Most ovarian cancer patients are diagnosed with advanced stage disease, which becomes unresponsive to chemotherapeutic treatments. The PI3K/AKT/mTOR and the RAS/RAF/MEK/ERK kinase signaling pathways are attractive targets for potential therapeutic inhibitors, due to the high frequency of mutations to PTEN, PIK3CA, KRAS and BRAF in several ovarian cancer subtypes. However, monotherapies targeting one of these pathways have shown modest effects in clinical trials. This limited efficacy of the agents could be due to upregulation and increased signaling via the adjacent alternative pathway. In this study, the efficacy of combined PI3K/mTOR (BEZ235) and ERK inhibition (SCH772984) was investigated in four human ovarian cancer cell lines, grown as monolayer and three-dimensional cell aggregates. The inhibitor combination reduced cellular proliferation in a synergistic manner in OV-90 and OVCAR8 monolayers and in OV-90, OVCAR5 and SKOV3 aggregates. Sensitivity to the inhibitors was reduced in three-dimensional cell aggregates in comparison to monolayers. OV-90 cells cultured in large spheroids were sensitive to the inhibitors and displayed a robust synergistic antiproliferative response to the inhibitor combination. In contrast, OVCAR8 spheroids were resistant to the inhibitors. These findings suggest that combined PI3K/mTOR and ERK inhibition could be a useful strategy for overcoming treatment resistance in ovarian cancer and warrants further preclinical investigation. Additionally, in some cell lines the use of different three-dimensional models can influence cell line sensitivity to PI3K/mTOR and RAS/RAF/MEK/ERK pathway inhibitors. Full article

(This article belongs to the Special Issue Three-Dimensional Culture Systems in Cancer Research)

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26 pages, 3675 KB

Open AccessEditor’s ChoiceReview

Clinical Significance and Regulation of ERK5 Expression and Function in Cancer

by Matilde Monti, Jacopo Celli, Francesco Missale, Francesca Cersosimo, Mariapia Russo, Elisa Belloni, Anna Di Matteo, Silvia Lonardi, William Vermi, Claudia Ghigna and Emanuele Giurisato

Cancers 2022, 14(2), 348; https://doi.org/10.3390/cancers14020348 - 11 Jan 2022

Cited by 23 | Viewed by 6368

Abstract

Extracellular signal-regulated kinase 5 (ERK5) is a unique kinase among MAPKs family members, given its large structure characterized by the presence of a unique C-terminal domain. Despite increasing data demonstrating the relevance of the ERK5 pathway in the growth, survival, and differentiation of [...] Read more.

Extracellular signal-regulated kinase 5 (ERK5) is a unique kinase among MAPKs family members, given its large structure characterized by the presence of a unique C-terminal domain. Despite increasing data demonstrating the relevance of the ERK5 pathway in the growth, survival, and differentiation of normal cells, ERK5 has recently attracted the attention of several research groups given its relevance in inflammatory disorders and cancer. Accumulating evidence reported its role in tumor initiation and progression. In this review, we explore the gene expression profile of ERK5 among cancers correlated with its clinical impact, as well as the prognostic value of ERK5 and pERK5 expression levels in tumors. We also summarize the importance of ERK5 in the maintenance of a cancer stem-like phenotype and explore the major known contributions of ERK5 in the tumor-associated microenvironment. Moreover, although several questions are still open concerning ERK5 molecular regulation, different ERK5 isoforms derived from the alternative splicing process are also described, highlighting the potential clinical relevance of targeting ERK5 pathways. Full article

(This article belongs to the Special Issue Cancer Genomics: Interpreting the Changing Landscape in Cancer Diagnosis and Treatment)

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34 pages, 1631 KB

Open AccessEditor’s ChoiceReview

Pathophysiological Integration of Metabolic Reprogramming in Breast Cancer

by Roberto Corchado-Cobos, Natalia García-Sancha, Marina Mendiburu-Eliçabe, Aurora Gómez-Vecino, Alejandro Jiménez-Navas, Manuel Jesús Pérez-Baena, Marina Holgado-Madruga, Jian-Hua Mao, Javier Cañueto, Sonia Castillo-Lluva and Jesús Pérez-Losada

Cancers 2022, 14(2), 322; https://doi.org/10.3390/cancers14020322 - 10 Jan 2022

Cited by 20 | Viewed by 6305

Abstract

Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. The triggers of these metabolic changes are located in the tumor parenchymal cells, where oncogenic mutations induce an imperative need to proliferate and cause tumor initiation and progression. Cancer cells [...] Read more.

Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. The triggers of these metabolic changes are located in the tumor parenchymal cells, where oncogenic mutations induce an imperative need to proliferate and cause tumor initiation and progression. Cancer cells undergo significant metabolic reorganization during disease progression that is tailored to their energy demands and fluctuating environmental conditions. Oxidative stress plays an essential role as a trigger under such conditions. These metabolic changes are the consequence of the interaction between tumor cells and stromal myofibroblasts. The metabolic changes in tumor cells include protein anabolism and the synthesis of cell membranes and nucleic acids, which all facilitate cell proliferation. They are linked to catabolism and autophagy in stromal myofibroblasts, causing the release of nutrients for the cells of the tumor parenchyma. Metabolic changes lead to an interstitium deficient in nutrients, such as glucose and amino acids, and acidification by lactic acid. Together with hypoxia, they produce functional changes in other cells of the tumor stroma, such as many immune subpopulations and endothelial cells, which lead to tumor growth. Thus, immune cells favor tissue growth through changes in immunosuppression. This review considers some of the metabolic changes described in breast cancer. Full article

(This article belongs to the Special Issue Understanding and Modelling Metabolic Reprogramming in Breast Cancer)

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20 pages, 4654 KB

Open AccessEditor’s ChoiceArticle

Metabolomic Phenotyping of Gliomas: What Can We Get with Simplified Protocol for Intact Tissue Analysis?

by Paulina Zofia Goryńska, Kamila Chmara, Bogumiła Kupcewicz, Krzysztof Goryński, Karol Jaroch, Dariusz Paczkowski, Jacek Furtak, Marek Harat and Barbara Bojko

Cancers 2022, 14(2), 312; https://doi.org/10.3390/cancers14020312 - 9 Jan 2022

Cited by 11 | Viewed by 3362

Abstract

Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions [...] Read more.

Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions related to therapeutic strategies are based on genetic testing and histological analysis of the tumor, with molecular biomarkers still being sought to complement the diagnostic panel. This work aims to enable the metabolomic characterization of cancer tissue and the discovery of potential biomarkers via high-resolution mass spectrometry coupled to liquid chromatography and a solvent-free sampling protocol that uses a microprobe to extract metabolites directly from intact tumors. The metabolomic analyses were performed independently from genetic and histological testing and at a later time. Despite the small cohort analyzed in this study, the results indicated that the proposed method is able to identify metabolites associated with different malignancy grades of glioma, as well as IDH and 1p19q codeletion mutations. A comparison of the constellation of identified metabolites and the results of standard tests indicated the validity of using the characterization of one comprehensive tumor phenotype as a reflection of all diagnostically meaningful information. Due to its simplicity, the proposed analytical approach was verified as being compatible with a surgical environment and applicable for large-scale studies. Full article

(This article belongs to the Collection Diagnostic and Therapeutic Challenges in Patients with Primary or Secondary Brain Tumor)

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12 pages, 2379 KB

Open AccessEditor’s ChoiceReview

Hyperthermia: A Potential Game-Changer in the Management of Cancers in Low-Middle-Income Group Countries

by Niloy R. Datta, Bharati M. Jain, Zatin Mathi, Sneha Datta, Satyendra Johari, Ashok R. Singh, Pallavi Kalbande, Pournima Kale, Vitaladevuni Shivkumar and Stephan Bodis

Cancers 2022, 14(2), 315; https://doi.org/10.3390/cancers14020315 - 9 Jan 2022

Cited by 24 | Viewed by 4219

Abstract

Loco-regional hyperthermia at 40–44 °C is a multifaceted therapeutic modality with the distinct triple advantage of being a potent radiosensitizer, a chemosensitizer and an immunomodulator. Risk difference estimates from pairwise meta-analysis have shown that the local tumour control could be improved by 22.3% [...] Read more.

Loco-regional hyperthermia at 40–44 °C is a multifaceted therapeutic modality with the distinct triple advantage of being a potent radiosensitizer, a chemosensitizer and an immunomodulator. Risk difference estimates from pairwise meta-analysis have shown that the local tumour control could be improved by 22.3% (p < 0.001), 22.1% (p < 0.001) and 25.5% (p < 0.001) in recurrent breast cancers, locally advanced cervix cancer (LACC) and locally advanced head and neck cancers, respectively by adding hyperthermia to radiotherapy over radiotherapy alone. Furthermore, thermochemoradiotherapy in LACC have shown to reduce the local failure rates by 10.1% (p = 0.03) and decrease deaths by 5.6% (95% CI: 0.6–11.8%) over chemoradiotherapy alone. As around one-third of the cancer cases in low-middle-income group countries belong to breast, cervix and head and neck regions, hyperthermia could be a potential game-changer and expected to augment the clinical outcomes of these patients in conjunction with radiotherapy and/or chemotherapy. Further, hyperthermia could also be a cost-effective therapeutic modality as the capital costs for setting up a hyperthermia facility is relatively low. Thus, the positive outcomes evident from various phase III randomized trials and meta-analysis with thermoradiotherapy or thermochemoradiotherapy justifies the integration of hyperthermia in the therapeutic armamentarium of clinical management of cancer, especially in low-middle-income group countries. Full article

(This article belongs to the Special Issue Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation)

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19 pages, 1309 KB

Open AccessEditor’s ChoiceReview

The Implementation of TNFRSF Co-Stimulatory Domains in CAR-T Cells for Optimal Functional Activity

by Yuan He, Martijn Vlaming, Tom van Meerten and Edwin Bremer

Cancers 2022, 14(2), 299; https://doi.org/10.3390/cancers14020299 - 8 Jan 2022

Cited by 30 | Viewed by 7591

Abstract

The Tumor Necrosis Factor Receptor Superfamily (TNFRSF) is a large and important immunoregulatory family that provides crucial co-stimulatory signals to many if not all immune effector cells. Each co-stimulatory TNFRSF member has a distinct expression profile and a unique functional impact on various [...] Read more.

The Tumor Necrosis Factor Receptor Superfamily (TNFRSF) is a large and important immunoregulatory family that provides crucial co-stimulatory signals to many if not all immune effector cells. Each co-stimulatory TNFRSF member has a distinct expression profile and a unique functional impact on various types of cells and at different stages of the immune response. Correspondingly, exploiting TNFRSF-mediated signaling for cancer immunotherapy has been a major field of interest, with various therapeutic TNFRSF-exploiting anti-cancer approaches such as 4-1BB and CD27 agonistic antibodies being evaluated (pre)clinically. A further application of TNFRSF signaling is the incorporation of the intracellular co-stimulatory domain of a TNFRSF into so-called Chimeric Antigen Receptor (CAR) constructs for CAR-T cell therapy, the most prominent example of which is the 4-1BB co-stimulatory domain included in the clinically approved product Kymriah. In fact, CAR-T cell function can be clearly influenced by the unique co-stimulatory features of members of the TNFRSF. Here, we review a select group of TNFRSF members (4-1BB, OX40, CD27, CD40, HVEM, and GITR) that have gained prominence as co-stimulatory domains in CAR-T cell therapy and illustrate the unique features that each confers to CAR-T cells. Full article

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20 pages, 4267 KB

Open AccessEditor’s ChoiceArticle

PRMT1 Regulates EGFR and Wnt Signaling Pathways and Is a Promising Target for Combinatorial Treatment of Breast Cancer

by Samyuktha Suresh, Solène Huard, Amélie Brisson, Fariba Némati, Rayan Dakroub, Coralie Poulard, Mengliang Ye, Elise Martel, Cécile Reyes, David C. Silvestre, Didier Meseure, André Nicolas, David Gentien, Hussein Fayyad-Kazan, Muriel Le Romancer, Didier Decaudin, Sergio Roman-Roman and Thierry Dubois

Cancers 2022, 14(2), 306; https://doi.org/10.3390/cancers14020306 - 8 Jan 2022

Cited by 26 | Viewed by 5128

Abstract

Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. PRMT1 depletion decreases [...] Read more.

Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. PRMT1 depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. PRMT1 enzymatic activity is also required to stimulate the canonical Wnt pathway. Type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients as well as erlotinib, an EGFR inhibitor. Therefore, targeting PRMT1 in combination with these chemotherapies may improve existing treatments for TNBC patients. Full article

(This article belongs to the Section Cancer Therapy)

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17 pages, 596 KB

Open AccessEditor’s ChoiceReview

Programmed Death-Ligand 1 (PD-L1) as Immunotherapy Biomarker in Breast Cancer

by Martín Núñez Abad, Silvia Calabuig-Fariñas, Miriam Lobo de Mena, Susana Torres-Martínez, Clara García González, José Ángel García García, Vega Iranzo González-Cruz and Carlos Camps Herrero

Cancers 2022, 14(2), 307; https://doi.org/10.3390/cancers14020307 - 8 Jan 2022

Cited by 48 | Viewed by 8632

Abstract

Breast cancer constitutes the most common malignant neoplasm in women around the world. Approximately 12% of patients are diagnosed with metastatic stage, and between 5 and 30% of early or locally advanced BC patients will relapse, making it an incurable disease. PD-L1 ligation [...] Read more.

Breast cancer constitutes the most common malignant neoplasm in women around the world. Approximately 12% of patients are diagnosed with metastatic stage, and between 5 and 30% of early or locally advanced BC patients will relapse, making it an incurable disease. PD-L1 ligation is an immune inhibitory molecule of the activation of T cells, playing a relevant role in numerous types of malignant tumors, including BC. The objective of the present review is to analyze the role of PD-L1 as a biomarker in the different BC subtypes, adding clinical trials with immune checkpoint inhibitors and their applicable results. Diverse trials using immunotherapy with anti-PD-1/PD-L1 in BC, as well as prospective or retrospective cohort studies about PD-L1 in BC, were included. Despite divergent results in the reviewed studies, PD-L1 seems to be correlated with worse prognosis in the hormone receptor positive subtype. Immune checkpoints inhibitors targeting the PD-1/PD-L1 axis have achieved great response rates in TNBC patients, especially in combination with chemotherapy, making immunotherapy a new treatment option in this scenario. However, the utility of PD-L1 as a predictive biomarker in the rest of BC subtypes remains unclear. In addition, predictive differences have been found in response to immunotherapy depending on the stage of the tumor disease. Therefore, a better understanding of tumor microenvironment, as well as identifying new potential biomarkers or combined index scores, is necessary in order to make a better selection of the subgroups of BC patients who will derive benefit from immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Advances in Breast Cancer Research: From Biology to Pathology)

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24 pages, 2675 KB

Open AccessEditor’s ChoiceReview

Dynamic Cancer Cell Heterogeneity: Diagnostic and Therapeutic Implications

by Valerie Jacquemin, Mathieu Antoine, Geneviève Dom, Vincent Detours, Carine Maenhaut and Jacques E. Dumont

Cancers 2022, 14(2), 280; https://doi.org/10.3390/cancers14020280 - 7 Jan 2022

Cited by 51 | Viewed by 10080

Abstract

Though heterogeneity of cancers is recognized and has been much discussed in recent years, the concept often remains overlooked in different routine examinations. Indeed, in clinical or biological articles, reviews, and textbooks, cancers and cancer cells are generally presented as evolving distinct entities [...] Read more.

Though heterogeneity of cancers is recognized and has been much discussed in recent years, the concept often remains overlooked in different routine examinations. Indeed, in clinical or biological articles, reviews, and textbooks, cancers and cancer cells are generally presented as evolving distinct entities rather than as an independent heterogeneous cooperative cell population with its self-oriented biology. There are, therefore, conceptual gaps which can mislead the interpretations/diagnostic and therapeutic approaches. In this short review, we wish to summarize and discuss various aspects of this dynamic evolving heterogeneity and its biological, pathological, clinical, diagnostic, and therapeutic implications, using thyroid carcinoma as an illustrative example. Full article

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21 pages, 2241 KB

Open AccessEditor’s ChoiceArticle

ATX-101, a Peptide Targeting PCNA, Has Antitumor Efficacy Alone or in Combination with Radiotherapy in Murine Models of Human Glioblastoma

by Giovanni Luca Gravina, Alessandro Colapietro, Andrea Mancini, Alessandra Rossetti, Stefano Martellucci, Luca Ventura, Martina Di Franco, Francesco Marampon, Vincenzo Mattei, Leda Assunta Biordi, Marit Otterlei and Claudio Festuccia

Cancers 2022, 14(2), 289; https://doi.org/10.3390/cancers14020289 - 7 Jan 2022

Cited by 27 | Viewed by 4197

Abstract

Cell proliferation requires the orchestrated actions of a myriad of proteins regulating DNA replication, DNA repair and damage tolerance, and cell cycle. Proliferating cell nuclear antigen (PCNA) is a master regulator which interacts with multiple proteins functioning in these processes, and this makes [...] Read more.

Cell proliferation requires the orchestrated actions of a myriad of proteins regulating DNA replication, DNA repair and damage tolerance, and cell cycle. Proliferating cell nuclear antigen (PCNA) is a master regulator which interacts with multiple proteins functioning in these processes, and this makes PCNA an attractive target in anticancer therapies. Here, we show that a cell-penetrating peptide containing the AlkB homolog 2 PCNA-interacting motif (APIM), ATX-101, has antitumor activity in a panel of human glioblastoma multiforme (GBM) cell lines and patient-derived glioma-initiating cells (GICs). Their sensitivity to ATX-101 was not related to cellular levels of PCNA, or p53, PTEN, or MGMT status. However, ATX-101 reduced Akt/mTOR and DNA-PKcs signaling, and a correlation between high Akt activation and sensitivity for ATX-101 was found. ATX-101 increased the levels of γH2AX, DNA fragmentation, and apoptosis when combined with radiotherapy (RT). In line with the in vitro results, ATX-101 strongly reduced tumor growth in two subcutaneous xenografts and two orthotopic GBM models, both as a single agent and in combination with RT. The ability of ATX-101 to sensitize cells to RT is promising for further development of this compound for use in GBM. Full article

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20 pages, 3735 KB

Open AccessEditor’s ChoiceReview

Potential Role of CXCL13/CXCR5 Signaling in Immune Checkpoint Inhibitor Treatment in Cancer

by Ching-Hung Hsieh, Cheng-Zhe Jian, Liang-In Lin, Guan-Sian Low, Ping-Yun Ou, Chiun Hsu and Da-Liang Ou

Cancers 2022, 14(2), 294; https://doi.org/10.3390/cancers14020294 - 7 Jan 2022

Cited by 47 | Viewed by 9822

Abstract

Immune checkpoint inhibitors (ICIs), including antibodies that target programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA4), represent some of the most important breakthroughs in new drug development for oncology therapy from the past decade. [...] Read more.

Immune checkpoint inhibitors (ICIs), including antibodies that target programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA4), represent some of the most important breakthroughs in new drug development for oncology therapy from the past decade. CXC chemokine ligand 13 (CXCL13) exclusively binds CXC chemokine receptor type 5 (CXCR5), which plays a critical role in immune cell recruitment and activation and the regulation of the adaptive immune response. CXCL13 is a key molecular determinant of the formation of tertiary lymphoid structures (TLSs), which are organized aggregates of T, B, and dendritic cells that participate in the adaptive antitumor immune response. CXCL13 may also serve as a prognostic and predictive factor, and the role played by CXCL13 in some ICI-responsive tumor types has gained intense interest. This review discusses how CXCL13/CXCR5 signaling modulates cancer and immune cells to promote lymphocyte infiltration, activation by tumor antigens, and differentiation to increase the antitumor immune response. We also summarize recent preclinical and clinical evidence regarding the ICI-therapeutic implications of targeting the CXCL13/CXCR5 axis and discuss the potential role of this signaling pathway in cancer immunotherapy. Full article

(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)

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39 pages, 7132 KB

Open AccessEditor’s ChoiceReview

The Renaissance of Cyclin Dependent Kinase Inhibitors

by Tobias Ettl, Daniela Schulz and Richard Josef Bauer

Cancers 2022, 14(2), 293; https://doi.org/10.3390/cancers14020293 - 7 Jan 2022

Cited by 54 | Viewed by 12899

Abstract

Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor [...] Read more.

Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor entities. Their success is reflected in clinical approvals of specific CDK4/6 inhibitors for breast cancer. This review provides a detailed insight into the molecular mechanisms of CDKs as well as a general overview of CDK inhibition. It also summarizes the latest research approaches and current advances in the treatment of head and neck cancer with CDK inhibitors. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results in tumor therapy. Indeed, recent studies have shown a synergistic effect of CDK inhibition together with chemo- and radio- and immunotherapy in cancer treatment to overcome tumor evasion, which may lead to a renaissance of CDK inhibitors. Full article

(This article belongs to the Special Issue The Renaissance of CDK Inhibition in Cancer Therapy)

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22 pages, 7485 KB

Open AccessEditor’s ChoiceArticle

Onco-miR-21 Promotes Stat3-Dependent Gastric Cancer Progression

by Janson Tse, Thomas Pierce, Annalisa L. E. Carli, Mariah G. Alorro, Stefan Thiem, Eric G. Marcusson, Matthias Ernst and Michael Buchert

Cancers 2022, 14(2), 264; https://doi.org/10.3390/cancers14020264 - 6 Jan 2022

Cited by 28 | Viewed by 3621

Abstract

MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the [...] Read more.

MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the spontaneous Stat3-dependent formation of inflammation-associated gastric tumors in Gp130^F^/F mice, we functionally established miR-21 as a Stat3-controlled driver of tumor growth and progression. We reconciled our discoveries by identifying several conserved Stat3 binding motifs upstream of the miR-21 gene promoter, and showed that the systemic administration of a miR-21-specific antisense oligonucleotide antagomir reduced the established gastric tumor burden in Gp130^F^/F mice. We molecularly delineated the therapeutic benefits of miR-21 inhibition with the functional restoration of PTEN in vitro and in vivo, alongside an attenuated epithelial-to-mesenchymal transition and the extracellular matrix remodeling phenotype of tumors. We corroborated our preclinical findings by correlating high STAT3 and miR-21 expression with the reduced survival probability of gastric cancer patients. Collectively, our results provide a molecular framework by which miR-21 mediates inflammation-associated gastric cancer progression, and establish miR-21 as a robust therapeutic target for solid malignancies characterized by excessive Stat3 activity. Full article

(This article belongs to the Special Issue Multicellular Effects of STAT3 in the Tumour Microenvironment)

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17 pages, 4020 KB

Open AccessEditor’s ChoiceArticle

Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression

by James Drury, Piotr G. Rychahou, Courtney O. Kelson, Mariah E. Geisen, Yuanyuan Wu, Daheng He, Chi Wang, Eun Y. Lee, B. Mark Evers and Yekaterina Y. Zaytseva

Cancers 2022, 14(1), 252; https://doi.org/10.3390/cancers14010252 - 5 Jan 2022

Cited by 44 | Viewed by 7125

Abstract

Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in [...] Read more.

Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis has not been studied. Here, we demonstrate that high expression of CD36 promotes invasion of CRC cells. Consistently, CD36 promoted lung metastasis in the tail vein model and GI metastasis in the cecum injection model. RNA-Seq analysis of CRC cells with altered expression of CD36 revealed an association between high expression of CD36 and upregulation of MMP28, a novel member of the metallopeptidase family of proteins. Using shRNA-mediated knockdown and overexpression of CD36, we confirmed that CD36 regulates MMP28 expression in CRC cells. siRNA-mediated knockdown of MMP28 decreases invasion of CRC cells, suggesting that MMP28 regulates the metastatic properties of cells downstream of CD36. Importantly, high expression of MMP28 leads to a significant decrease in active E-cadherin and an increase in the products of E-cadherin cleavage, CTF1 and CTF2. In summary, upregulation of CD36 expression promotes the metastatic properties of CRC via upregulation of MMP28 and an increase in E-cadherin cleavage, suggesting that targeting the CD36–MMP28 axis may be an effective therapeutic strategy for CRC metastasis. Full article

(This article belongs to the Special Issue Insight into Fatty Acid Metabolism in Colorectal Cancer)

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26 pages, 1734 KB

Open AccessEditor’s ChoiceReview

Harnessing Antitumor CD4⁺ T Cells for Cancer Immunotherapy

by Myriam Ben Khelil, Yann Godet, Syrine Abdeljaoued, Christophe Borg, Olivier Adotévi and Romain Loyon

Cancers 2022, 14(1), 260; https://doi.org/10.3390/cancers14010260 - 5 Jan 2022

Cited by 48 | Viewed by 9788

Abstract

Over the past decades, CD4⁺ T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4⁺ T cells during antitumor immunity. CD4⁺ T cells can [...] Read more.

Over the past decades, CD4⁺ T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4⁺ T cells during antitumor immunity. CD4⁺ T cells can either suppress or promote the antitumor cytotoxic CD8⁺ T cell responses, either in secondary lymphoid organs or in the tumor. In this review, we provide an overview of the multifaceted role of different CD4⁺ T cell subsets in cancer immune response and their contribution during cancer therapies. Specifically, we focus on the latest progress regarding the impact of CD4⁺ T cell modulation on immunotherapies and other cancer therapies and discuss the prospect for harnessing CD4⁺ T cells to control tumor progression and prevent recurrence in patients. Full article

(This article belongs to the Special Issue CD4 T Cells and Cancer Immune Response)

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13 pages, 2379 KB

Open AccessEditor’s ChoiceArticle

Delta-Radiomics Predicts Response to First-Line Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients with Liver Metastases

by Valentina Giannini, Laura Pusceddu, Arianna Defeudis, Giulia Nicoletti, Giovanni Cappello, Simone Mazzetti, Andrea Sartore-Bianchi, Salvatore Siena, Angelo Vanzulli, Francesco Rizzetto, Elisabetta Fenocchio, Luca Lazzari, Alberto Bardelli, Silvia Marsoni and Daniele Regge

Cancers 2022, 14(1), 241; https://doi.org/10.3390/cancers14010241 - 4 Jan 2022

Cited by 32 | Viewed by 7514

Abstract

The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after [...] Read more.

The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after the first cycle of first-line FOLFOX, and 107 radiomics features were computed by subtracting textural features of CT at baseline from those at timepoint 1 (TP1). LmCRC were classified as nonresponders (R−) if they showed progression of disease (PD), according to RECIST1.1, before 8 months, and as responders (R+), otherwise. After feature selection, we developed a decision tree statistical model trained using all lmCRC coming from one hospital. The final output was a delta-radiomics signature subsequently validated on an external dataset. Sensitivity, specificity, positive (PPV), and negative (NPV) predictive values in correctly classifying individual lesions were assessed on both datasets. Per-lesion sensitivity, specificity, PPV, and NPV were 99%, 94%, 95%, 99%, 85%, 92%, 90%, and 87%, respectively, in the training and validation datasets. The delta-radiomics signature was able to reliably predict R− lmCRC, which were wrongly classified by lesion RECIST as R+ at TP1, (93%, averaging training and validation set, versus 67% of RECIST). The delta-radiomics signature developed in this study can reliably predict the response of individual lmCRC to oxaliplatin-based chemotherapy. Lesions forecasted as poor or nonresponders by the signature could be further investigated, potentially paving the way to lesion-specific therapies. Full article

(This article belongs to the Collection Artificial Intelligence in Oncology)

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14 pages, 1475 KB

Open AccessEditor’s ChoiceReview

Fatty Acid Metabolism in Myeloid-Derived Suppressor Cells and Tumor-Associated Macrophages: Key Factor in Cancer Immune Evasion

by Sophiya Siddiqui and Rainer Glauben

Cancers 2022, 14(1), 250; https://doi.org/10.3390/cancers14010250 - 4 Jan 2022

Cited by 28 | Viewed by 5774

Abstract

The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, [...] Read more.

The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, differentiation, and polarization from tumor suppressive into immune suppressive phenotypes. Macrophages represent one of the major immune infiltrates into TME. Blood monocyte-derived macrophages and myeloid derived suppressor cells (MDSCs) infiltrating into the TME potentiate hostile tumor progression by polarizing into immunosuppressive tumor-associated macrophages (TAMs). Recent studies in the field of immunometabolism focus on metabolic reprogramming at the TME in polarizing tumor-associated macrophages (TAMs). Lipid droplets (LD), detected in almost every eukaryotic cell type, represent the major source for intra-cellular fatty acids. Previously, LDs were mainly described as storage sites for fatty acids. However, LDs are now recognized to play an integral role in cellular signaling and consequently in inflammation and metabolism-mediated phenotypical changes in immune cells. In recent years, the role of LD dependent metabolism in macrophage functionality and phenotype has been being investigated. In this review article, we discuss fatty acids stored in LDs, their role in modulating metabolism of tumor-infiltrating immune cells and, therefore, in shaping the cancer progression. Full article

(This article belongs to the Special Issue Epigenetic and Metabolic Alterations in the Tumor Microenvironment)

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16 pages, 524 KB

Open AccessEditor’s ChoiceReview

The Impact of Biomarkers in Pancreatic Ductal Adenocarcinoma on Diagnosis, Surveillance and Therapy

by Niklas Sturm, Thomas J. Ettrich and Lukas Perkhofer

Cancers 2022, 14(1), 217; https://doi.org/10.3390/cancers14010217 - 3 Jan 2022

Cited by 39 | Viewed by 5350

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors of recurrence or early detection of PDAC. Enhanced understanding of molecular tumorigenesis and treatment response triggered the identification of novel biomarkers as predictors for response to conventional chemotherapy or targeted therapy. In conclusion, progress has been made especially in the prediction of therapy response with biomarkers. The use of molecules for early detection and recurrence of PDAC is still at an early stage, but there are promising approaches in noninvasive biomarkers, composite panels and scores that can already ameliorate the current clinical practice. The present review summarizes the current state of research on biomarkers for diagnosis and therapy of pancreatic cancer. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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15 pages, 3727 KB

Open AccessEditor’s ChoiceArticle

Phototheranostics of Cervical Neoplasms with Chlorin e6 Photosensitizer

by Aida Gilyadova, Anton Ishchenko, Artem Shiryaev, Polina Alekseeva, Kanamat Efendiev, Radmila Karpova, Maxim Loshchenov, Victor Loschenov and Igor Reshetov

Cancers 2022, 14(1), 211; https://doi.org/10.3390/cancers14010211 - 2 Jan 2022

Cited by 22 | Viewed by 4755

Abstract

(1) Purpose: Improving the treatment effectiveness of intraepithelial neoplasia of the cervix associated with human papillomavirus infection, based on the application of the method of photodynamic therapy with simultaneous laser excitation of fluorescence to clarify the boundaries of cervical neoplasms. (2) Methods: Examination [...] Read more.

(1) Purpose: Improving the treatment effectiveness of intraepithelial neoplasia of the cervix associated with human papillomavirus infection, based on the application of the method of photodynamic therapy with simultaneous laser excitation of fluorescence to clarify the boundaries of cervical neoplasms. (2) Methods: Examination and treatment of 52 patients aged 22 to 53 years with morphologically and cytologically confirmed mild to severe intraepithelial cervix neoplasia, preinvasive, micro-invasive, and squamous cell cervix carcinoma. All patients were carriers of human papillomavirus infection. The patients underwent photodynamic therapy with simultaneous laser excitation of fluorescence. The combined use of video and spectral fluorescence diagnostics for cervical neoplasms made it possible to control the photodynamic therapy process at all stages of the procedure. Evaluation of the photodynamic therapy of intraepithelial cervical neoplasms was carried out with colposcopic examination, cytological conclusion, and morphological verification of the biopsy material after the photodynamic therapy course. The success of human papillomavirus therapy was assessed based on the results of the polymerase chain reaction. (3) Results. The possibility of simultaneous spectral fluorescence diagnostics and photodynamic therapy using a laser source with a wavelength of 660 nm has been established, making it possible to assess the fluorescence index in real-time and control the photobleaching of photosensitizers in the irradiated area. The treatment of all 52 patients was successful after the first photodynamic therapy procedure. According to the PCR test of the discharge from the cervical canal, the previously identified HPV types were not observed in 48 patients. Previously identified HPV types were absent after repeated PDT in four patients (CIN III (n = 2), CIS (n = 2)). In 80.8% of patients, regression of the lesion was noted. (4) Conclusions. The high efficiency of photodynamic therapy with intravenous photosensitizer administration of chlorin e6 has been demonstrated both in relation to eradication therapy of human papillomavirus and in relation to the treatment of intraepithelial lesions of the cervix. Full article

(This article belongs to the Special Issue Innovative Cancer Treatments and Photodynamic Therapy)

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18 pages, 3590 KB

Open AccessEditor’s ChoiceArticle

Combining an Autophagy Inhibitor, MPT0L145, with Abemaciclib Is a New Therapeutic Strategy in GBM Treatment

by Tsung-Han Hsieh, Muh-Lii Liang, Jia-Huei Zheng, Yu-Chen Lin, Yu-Chen Yang, Thanh-Hoa Vo, Jing-Ping Liou, Yun Yen and Chun-Han Chen

Cancers 2021, 13(23), 6117; https://doi.org/10.3390/cancers13236117 - 4 Dec 2021

Cited by 7 | Viewed by 4165

Abstract

Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is [...] Read more.

Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is still dismal. Therefore, a new therapeutic strategy is urgently needed. CDK4/6 inhibitors are newly FDA-approved agents to treat HR-positive, HER2-negative advanced, and metastatic breast cancers, and preclinical results showed that CDK4/6 inhibitors significantly reduced cell proliferation and tumor growth. However, several studies have suggested that CDK4/6 inhibitor-induced non-genetic changes caused treatment failure, including autophagy activation. Therefore, this study aimed to combine an autophagy inhibitor, MPT0L145, with abemaciclib to improve therapeutic efficiency. The use of abemaciclib effectively inhibited cell proliferation via suppression of RB phosphorylation and induced autophagy activation in GBM cancer cells. MPT0L145 treatment alone not only blocked autophagy activation, but also induced generation of ROS and DNA damage in a concentration-dependent manner. Importantly, MPT0L145 had a comparable penetration ability to TMZ in our blood brain barrier permeability assay. Combined MPT0L145 with abemaciclib significantly reduced cell proliferation, suppressed RB phosphorylation, and increased ROS production. In conclusion, the data suggested that blocking autophagy by MPT0L145 synergistically sensitized GBM cancer cells to abemaciclib and represents a potential therapeutic strategy for treating GBM in the future. Full article

(This article belongs to the Special Issue Brain Tumors: Molecular and Cell Biology for Target Therapy)

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16 pages, 3828 KB

Open AccessEditor’s ChoiceArticle

Brain-Derived Neurotrophic Factor, Neutrophils and Cysteinyl Leukotriene Receptor 1 as Potential Prognostic Biomarkers for Patients with Colon Cancer

by Syrina F. Mehrabi, Souvik Ghatak, Lubna M. Mehdawi, Geriolda Topi, Shakti Ranjan Satapathy and Anita Sjölander

Cancers 2021, 13(21), 5520; https://doi.org/10.3390/cancers13215520 - 3 Nov 2021

Cited by 6 | Viewed by 3515

Abstract

The tumor microenvironment has been recognized as a complex network in which immune cells play an important role in cancer progression. We found significantly higher CD66b neutrophil expression in tumor tissue than in matched normal mucosa in the Malmö colon cancer (CC) cohort [...] Read more.

The tumor microenvironment has been recognized as a complex network in which immune cells play an important role in cancer progression. We found significantly higher CD66b neutrophil expression in tumor tissue than in matched normal mucosa in the Malmö colon cancer (CC) cohort and poorer survival of stage I-III patients with high CD66b expression. Additionally, mice lacking CysLT₁R expression (cysltr1^−/−) produce less brain-derived neurotrophic factor (BDNF) compared to WT mice and Montelukast (a CysLT₁R antagonist)-treated mice also reduced BDNF expression in a mouse xenograft model with human SW480 CC cells. CD66b and BDNF expression was significantly higher in patient tumor tissues than in the matched normal mucosa. The univariate Cox PH analysis yielded CD66b and BDNF as an independent predictor of overall survival, which was also found in the public TCGA-COAD dataset. We also discovered a strong positive correlation between CD66b, BDNF and CysLT₁R expression in the Malmö CC cohort and in the TCGA-COAD dataset. Our data suggest that CD66b/BDNF/CysLT₁R expression as a prognostic combined biomarker signature for CC patients. Full article

(This article belongs to the Section Cancer Biomarkers)

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25 pages, 1192 KB

Open AccessEditor’s ChoiceReview

Genetic Landscape and Emerging Therapies in Uveal Melanoma

by Rino S. Seedor, Marlana Orloff and Takami Sato

Cancers 2021, 13(21), 5503; https://doi.org/10.3390/cancers13215503 - 2 Nov 2021

Cited by 25 | Viewed by 8230

Abstract

Despite successful treatment of primary uveal melanoma, up to 50% of patients will develop systemic metastasis. Metastatic disease portends a poor outcome, and no adjuvant or metastatic therapy has been FDA approved. The genetic landscape of uveal melanoma is unique, providing prognostic and [...] Read more.

Despite successful treatment of primary uveal melanoma, up to 50% of patients will develop systemic metastasis. Metastatic disease portends a poor outcome, and no adjuvant or metastatic therapy has been FDA approved. The genetic landscape of uveal melanoma is unique, providing prognostic and potentially therapeutic insight. In this review, we discuss our current understanding of the molecular and cytogenetic mutations in uveal melanoma, and the importance of obtaining such information. Most of our knowledge is based on primary uveal melanoma and a better understanding of the mutational landscape in metastatic uveal melanoma is needed. Clinical trials targeting certain mutations such as GNAQ/GNA11, BAP1, and SF3B1 are ongoing and promising. We also discuss the role of liquid biopsies in uveal melanoma in this review. Full article

(This article belongs to the Special Issue Metastatic Uveal Melanoma)

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14 pages, 8959 KB

Open AccessEditor’s ChoiceReview

Tumor Heterogeneity and Consequences for Bladder Cancer Treatment

by Etienne Lavallee, John P. Sfakianos and David J. Mulholland

Cancers 2021, 13(21), 5297; https://doi.org/10.3390/cancers13215297 - 22 Oct 2021

Cited by 34 | Viewed by 5093

Abstract

Acquired therapeutic resistance remains a major challenge in cancer management and associates with poor oncological outcomes in most solid tumor types. A major contributor is tumor heterogeneity (TH) which can be influenced by the stromal; immune and epithelial tumor compartments. We hypothesize that [...] Read more.

Acquired therapeutic resistance remains a major challenge in cancer management and associates with poor oncological outcomes in most solid tumor types. A major contributor is tumor heterogeneity (TH) which can be influenced by the stromal; immune and epithelial tumor compartments. We hypothesize that heterogeneity in tumor epithelial subpopulations—whether de novo or newly acquired—closely regulate the clinical course of bladder cancer. Changes in these subpopulations impact the tumor microenvironment including the extent of immune cell infiltration and response to immunotherapeutics. Mechanisms driving epithelial tumor heterogeneity (EpTH) can be broadly categorized as mutational and non-mutational. Mechanisms regulating lineage plasticity; acquired cellular mutations and changes in lineage-defined subpopulations regulate stress responses to clinical therapies. If tumor heterogeneity is a dynamic process; an increased understanding of how EpTH is regulated is critical in order for clinical therapies to be more sustained and durable. In this review and analysis, we assess the importance and regulatory mechanisms governing EpTH in bladder cancer and the impact on treatment response. Full article

(This article belongs to the Special Issue Systemic Treatment of Advanced Bladder Cancer – Status Update)

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25 pages, 6772 KB

Open AccessEditor’s ChoiceReview

Cancer-Associated Fibroblast Functions as a Road-Block in Cancer Therapy

by Pradip De, Jennifer Aske and Nandini Dey

Cancers 2021, 13(20), 5246; https://doi.org/10.3390/cancers13205246 - 19 Oct 2021

Cited by 38 | Viewed by 6153

Abstract

The journey of a normal resident fibroblast belonging to the tumor microenvironment (TME) from being a tumor pacifier to a tumor patron is fascinating. We introduce cancer-associated fibroblast (CAF) as a crucial component of the TME. Activated-CAF partners with tumor cells and all [...] Read more.

The journey of a normal resident fibroblast belonging to the tumor microenvironment (TME) from being a tumor pacifier to a tumor patron is fascinating. We introduce cancer-associated fibroblast (CAF) as a crucial component of the TME. Activated-CAF partners with tumor cells and all components of TME in an established solid tumor. We briefly overview the origin, activation, markers, and overall functions of CAF with a particular reference to how different functions of CAF in an established tumor are functionally connected to the development of resistance to cancer therapy in solid tumors. We interrogate the role of CAF in mediating resistance to different modes of therapies. Functional diversity of CAF in orchestrating treatment resistance in solid tumors portrays CAF as a common orchestrator of treatment resistance; a roadblock in cancer therapy Full article

(This article belongs to the Special Issue Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies)

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15 pages, 1359 KB

Open AccessEditor’s ChoiceReview

MSC-Derived Extracellular Vesicles in Tumors and Therapy

by Tianjiao Luo, Juliane von der Ohe and Ralf Hass

Cancers 2021, 13(20), 5212; https://doi.org/10.3390/cancers13205212 - 18 Oct 2021

Cited by 55 | Viewed by 4425

Abstract

Exosomes derived from mesenchymal stroma-/stem-like cells (MSCs) as part of extracellular vesicles are considered cell-free biocompatible nanovesicles that promote repair activities of damaged tissues or organs by exhibiting low immunogenic and cytotoxic effects. Contributions to regenerative activities include wound healing, maintenance of stem [...] Read more.

Exosomes derived from mesenchymal stroma-/stem-like cells (MSCs) as part of extracellular vesicles are considered cell-free biocompatible nanovesicles that promote repair activities of damaged tissues or organs by exhibiting low immunogenic and cytotoxic effects. Contributions to regenerative activities include wound healing, maintenance of stem cell niches, beneficial regenerative effects in various diseases, and reduction of senescence. However, the mode of action in MSC-derived exosomes strongly depends on the biological content like different regulatory microRNAs that are determined by the tissue origin of MSCs. In tumors, MSCs use indirect and direct pathways in a communication network to interact with cancer cells. This leads to mutual functional changes with the acquisition of an aberrant tumor-associated MSC phenotype accompanied by altered cargo in the exosomes. Consequently, MSC-derived exosomes either from normal tissue-originating MSCs or from aberrant tumor-associated MSCs can confer different actions on tumor development. These processes exhibiting tumor-inhibitory and tumor-supportive effects with a focus on exosome microRNA content will be discriminated and discussed within this review. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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22 pages, 553 KB

Open AccessEditor’s ChoiceReview

Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View

by Justus Körfer, Florian Lordick and Ulrich T. Hacker

Cancers 2021, 13(20), 5216; https://doi.org/10.3390/cancers13205216 - 18 Oct 2021

Cited by 34 | Viewed by 6063

Abstract

Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition [...] Read more.

Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition of distinct molecular subtypes. These efforts have in parallel built a basis for the development of novel molecularly stratified treatment approaches. Based on this molecular characterization, an increasing number of specific genomic alterations can potentially serve as treatment targets. Consequently, the development of promising compounds is ongoing. In this review, key molecular alterations in gastric and gastroesophageal junction cancers will be addressed. Finally, the current status of the translation of targeted therapy towards clinical applications will be reviewed. Full article

(This article belongs to the Special Issue New Molecular Insights for GC Characterization and Treatment)

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16 pages, 3674 KB

Open AccessEditor’s ChoiceReview

Could Photodynamic Therapy Be a Promising Therapeutic Modality in Hepatocellular Carcinoma Patients? A Critical Review of Experimental and Clinical Studies

by Abhishek Kumar, Olivier Moralès, Serge Mordon, Nadira Delhem and Emmanuel Boleslawski

Cancers 2021, 13(20), 5176; https://doi.org/10.3390/cancers13205176 - 15 Oct 2021

Cited by 30 | Viewed by 4591

Abstract

Photodynamic Therapy (PDT) relies on local or systemic administration of a light-sensitive dye, called photosensitizer, to accumulate into the target site followed by excitation with light of appropriate wavelength and fluence. This photo-activated molecule reacts with the intracellular oxygen to induce selective cytotoxicity [...] Read more.

Photodynamic Therapy (PDT) relies on local or systemic administration of a light-sensitive dye, called photosensitizer, to accumulate into the target site followed by excitation with light of appropriate wavelength and fluence. This photo-activated molecule reacts with the intracellular oxygen to induce selective cytotoxicity of targeted cells by the generation of reactive oxygen species. Hepatocellular carcinoma (HCC), one of the leading causes of cancer-associated mortality worldwide, has insufficient treatment options available. In this review, we discuss the mechanism and merits of PDT along with its recent developments as an anti-cancerous therapy. We also highlight the application of this novel therapy for diagnosis, visualization, and treatment of HCC. We examine the underlying challenges, some pre-clinical and clinical studies, and possibilities of future studies associated with PDT. Finally, we discuss the mechanism of an active immune response by PDT and thereafter explored the role of PDT in the generation of anti-tumor immune response in the context of HCC, with an emphasis on checkpoint inhibitor-based immunotherapy. The objective of this review is to propose PDT as a plausible adjuvant to existing therapies for HCC, highlighting a feasible combinatorial approach for HCC treatment. Full article

(This article belongs to the Special Issue Innovative Cancer Treatments and Photodynamic Therapy)

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