Search Results (1,375)

Despite significant advancements in understanding the pathogenesis and treatment of hematological malignancies, including leukemia and multiple myeloma, the majority of patients continue to experience poor long-term outcomes. This is partly due to the difficulty of accurately recapitulating the malignant microenvironment in vitro, particularly the bone marrow niche. The complexity of the bone marrow microenvironment poses a challenge for the in vitro examination of hematological malignancies. Traditionally, 2D culture and animal models have been utilized, but these representations are limited and have been criticized for their lack of human physiological relevance. In an attempt to overcome this, 3D models have been developed that more accurately recapitulate the in vivo microenvironment. Herein, we present an overview of recent developments in 2D and 3D models used for studying the bone marrow niche in hematological malignancies, highlighting their advantages and limitations. Full article

Cancer is no longer considered as an isolated event. Rather, it occurs because of a complex biological drive orchestrating different cell types, growth factors, cytokines, and signaling pathways within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most populous stromal cells within the complex ecosystem of TME, with significant heterogeneity and plasticity in origin and functional phenotypes. Very enigmatic cells, CAFs determine the progress and outcomes of tumors through extensive reciprocal signaling with different tumors infiltrating immune cells in the TME. In their biological drive, CAFs release numerous chemical mediators and utilize various signaling pathways to recruit and modulate tumor-infiltrating immune cells. The CAF-induced secretome and exosomes render immune cells ineffective for their antitumor activities. Moreover, by upregulating immune inhibitory checkpoints, CAFs create an immunosuppressive TME that impedes the susceptibility of tumor cells to tumor-infiltrating lymphocytes (TILs). Further, by depositing and remodeling extracellular matrix (ECM), CAFs reshape the TME, which enhances tumor growth, invasion, metastasis, and chemoresistance. Understanding of CAF biology and its crosstalk with tumor-infiltrating immune cells is crucial not only to gain insight in tumorigenesis but to optimize the potential of novel targeted immunotherapies for cancers. The complex relationships between CAFs and tumor-infiltrating immune cells remain unclear and need further study. Herein, in this narrative review we have focused on updates of CAF biology and its interactions with tumor-infiltrating immune cells in generating immunosuppressive TME and resistance to cell death. Full article

Background/Objectives: Subcutaneous tumor models are widely used in colorectal cancer (CRC) research due to their experimental accessibility; however, the spatial organization and regulatory mechanisms of their tumor microenvironment remain poorly understood. Methods: Here, we applied spatial transcriptomics to systematically characterize spatial heterogeneity within MC38 subcutaneous tumors in a syngeneic mouse model. Results: We identified two spatially distinct tumor zones, partitioned by cancer-associated fibroblasts (CAFs), that differ markedly in cellular composition, oncogenic signaling, immune infiltration, and metabolic states. One zone exhibited features of TGF-β-driven extracellular matrix remodeling, immune exclusion, and hyperproliferative metabolism, while the other was enriched for immunosuppressive macrophages, metabolic reprogramming via PPAR and AMPK pathways, and high-risk cell populations. Spatially resolved cell–cell communication networks further revealed zone-specific ligand–receptor interactions—such as ANGPTL4–SDC2 and PROS1–AXL—that underpin stromal remodeling and immune evasion and are associated with patient prognosis. Conclusions: Collectively, our study uncovers how region-specific cellular ecosystems and intercellular crosstalk establish prognostically divergent niches within subcutaneous CRC tumors, offering insights into spatially guided therapeutic strategies. Full article

Background/Objectives: Prostate cancer (PCa) is diagnosed at an earlier median age, more advanced stage, and has worse clinical outcomes in African American (AA) men compared to European Americans (EA). Methods: To investigate the role of aberrant DNA methylation in tumor-adjacent stroma (TAS), methyl binding domain sequencing (MBD-seq) was performed on AA (n = 17) and EA (n = 15) PCa patients. This was independently confirmed using the long interspersed nuclear element-1 (LINE-1) assay. Pathway analysis was performed on statistically significantly differentially methylated genes for AA and EA TAS. DNA methylation profiles of primary cultured AA and EA carcinoma-associated fibroblasts (CAFs) were compared with AA and EA TAS. AA and EA CAFs were treated with demethylating agent 5-Azacytidine (5-AzaC). Results: AA TAS exhibited higher global DNA methylation than EA TAS (p-value < 0.001). Of the 3268 differentially methylated regions identified (DMRs, p-value < 0.05), 85% (2787 DMRs) showed increased DNA methylation in AA TAS, comprising 1648 genes, of which 1379 were protein-coding genes. Based on DNA methylation levels, two AA subgroups were identified. Notably, AA patients with higher DNA methylation were predominantly those with higher Gleason scores. Pathway analysis linked methylated genes in AA TAS to several key signaling pathways (p-value < 0.05), including immune response (e.g., IL-1, IL-15, IL-7, IL-8, IL-3, and chemokine), Wnt/β-catenin, androgen, PTEN, p53, TGF-β, and circadian clock regulation. A total of 168 concordantly methylated genes were identified, with 109 genes (65%) showing increased methylation in AA CAFs and TAS (p-value < 0.05). Treatment with 5-AzaC significantly reduced DNA methylation of concordant genes in AA CAFs (p-value < 0.001). Conclusions: These findings suggest a distinct stromal methylome in AA, providing a foundation for integrating demethylating agents into standard therapies. This approach targets the tumor microenvironment, potentially addressing PCa disparities in AA men. Full article

Background: Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and the metabolic activities of both tumor cells and TAMs have an impact on the TME. Moreover, the expression of MICA in tumor cells is closely associated with immune cells in hepatocellular carcinoma (HCC). However, it remains unclear whether MICA expression correlates with TAMs and influences the switch in macrophage phenotype by mediating metabolic alterations. Methods: Various biostatistical tools, qPCR, and IHC staining experiments were utilized to analyze data from The Cancer Genome Atlas (TCGA) and collected HCC tumor tissues. Single-cell RNA sequencing (scRNA-seq) analyses and a co-culture model of HCC cells with macrophages were performed to validate the findings from the biostatistical analyses. Results: Through the intersection of differentially expressed genes (DEGs), metabolism-related genes (MRGs), and co-expression genes (CEGs) with MICA in HCC, the EHHADH gene was identified. Gene set enrichment analyses were conducted to further confirm the role of EHHADH. EHHADH expression is decreased in HCC tumors and can serve as a prognostic biomarker for HCC. Expressions of MICA and EHHADH exhibited significant correlations with various phenotypic macrophages and exerted opposing effects on M1-like and M2-like macrophages infiltrating HCC. The underlying metabolic and molecular mechanisms revealed that MICA in tumor cells induced M2-like polarization through the PPAR/EHHADH pathway, which regulates the fatty acid oxidation (FAO) in macrophages. Conclusions: The metabolic gene EHHADH, which is associated with MICA, led to alterations in M2-like macrophages by promoting heightened fatty acid uptake and augmenting levels of FAO within macrophages. Full article

Background/Objectives: Plexiform neurofibromas (pNFs) are one of the cardinal presentations of NF1 patients, often arising during early childhood. Since selumetinib was approved by the FDA in 2020, the long-term side effects and various responses of mitogen-activated protein kinase inhibitors (MEKi) in pediatric patients necessitate a new strategy. We propose that combining selumetinib with heat shock protein 90 inhibitors (HSP90i) can enhance the inhibitory effects as well as reduce the dosage of selumetinib in combination. We validated the synergistic effects and the significantly improved treatment effects of the combination of selumetinib and HSP90i in pNFs. Methods: We used drug screen data mining to predict the combination of selumetinib and HSP90i. Using cell lines and in vivo mouse models for pNFs, we tested a series of combinations with different concentrations. We validated the in vivo inhibitory effects using the transplanted tumors from DhhCreNf1^f/f mouse models. Results: We demonstrated that combining selumetinib and SNX-2112 or retaspimycin can achieve better tumor inhibition with synergistic effects. The combination significantly delays the progression of mouse pNFs. Conclusions: The combination of selumetinib and HSP90i has significant synergistic effects, provides therapeutic inhibitor effects, and reduces the selumetinib dosage in combination. Full article

Horizontal trafficking of subcellular components, such as nucleic acids, proteins, and membrane fragments, is utilized by tumor cells to facilitate tumor cell proliferation and survival. Conventionally, tumor cells have been known to undergo long-range transfer through the import and export of extracellular vesicles and exosomes. However, other means of intercellular transfer are also employed by tumor cells. These trafficking methods can facilitate changes in anti-tumor immunity and distribute oncogenic protein variants to nearby cells to provide a hospitable tumor microenvironment. The molecular mechanisms that drive many of these cell trafficking mechanisms are conserved, relying on de novo synthesis of filamentous actin. However, the delineation between these processes is not yet known. This review will highlight four recently characterized and underappreciated contact-dependent intercellular trafficking mechanisms: (i) trogocytosis, (ii) entosis, (iii) cell fusion, and (iv) tunneling nanotubes/microtubes utilized by tumor cells to promote a hospitable microenvironment. Full article

Background/objectives: Despite advancements in early diagnosis and clinical practices guided by standardized care protocols, Merkel cell carcinoma (MCC) is marked by an unfavorable prognosis with a 5-year relative survival rate of 65%, based primarily on data collected prior to the introduction of immunotherapy. Regional nodal metastases affect 40–50% of MCC patients, while approximately 33% experience distant dissemination. Among these, bone and bone marrow metastases are particularly notable, although the characteristics and clinical implications of this metastatic disease in MCC remain poorly understood. Methods: A comprehensive review was conducted using the Medline database (via PubMed) up to January 2025. The search strategy included the string “(Merkel cell carcinoma AND (bone OR marrow))”. Results: A total of 1133 (69.3% male and 30.7% female) patients diagnosed with advanced MCC were collected. The median (IQR) age at diagnosis was 67.5 (12.65) years old. Overall, 201 (20.8%) cases of bone and/or bone marrow metastases were identified and linked to a primary known MCC in 75.7% of cases. Bone metastases (BMs) appear as the third most common metastatic site, following the liver (second) and lymph nodes (first). They show mixed biological and radiological behavior, with a marked preference for the axial skeleton over the appendicular one. Addressing the characteristics of metastatic bone disease, neurological symptoms were the most documented, whereas bone marrow involvement and leukemic spread seemed to be primarily related to immunosuppression. Multimodal treatment strategies, including platinum-based chemotherapy and radiotherapy, were the primary approaches adopted, reflecting therapeutic practices from the pre-immunotherapy era. Conclusions: The pattern of metastatic spread in MCC differs among studies, with the bones resulting as the third most common site of distant spread. Excluding head and neck MCC, which seems to be more regularly associated with liver metastases, the relationship between the primary tumor site and the development of bone or bone marrow metastases appears inconsistent. Overall, BMs mostly correlated with advanced MCC stages and poorer survival outcomes, with a median overall survival (OS) of 8 months (range 12.75–4). The integration of international guidelines, evolving evidence from clinical trials, and the expanding role of immune checkpoint inhibitors (ICIs) will contribute to improving systemic disease control and enhance patient care. Full article

Background: Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor with malignant potential. Its diagnosis has grown alongside increased use of abdominal imaging. SPN is suspected after classical findings in abdominal imaging studies; however, endoscopic ultrasound-guided (EUS) fine needle aspiration can support preoperative diagnosis. The treatment of choice is still surgical intervention, with an intent to reach curative resection. The prognosis is excellent. Recently, emerging data on EUS-guided radiofrequency ablation (RFA) suggest changing the choice of treatment for small SPN. Methods: We provide a comprehensive overview on pancreatic SPN with a focus on treatment, adverse events, recurrence rate, and outcomes. In addition, we provide a literature summary and pool data analysis. Results: Overall, 70 papers including 6651 patients were identified. The mean SPN size was 5.8 cm, metastasis rate was 1.9%, and recurrence rate was 3%. Moreover, the mortality rate was low at 0.2%, although high postoperative adverse events were reported (32.4%). Small SPN (<2 cm) was present in 4.1% of the studies. Two studies reported EUS-RFA for small SPN <2 cm, without recurrence at a median follow-up of 18.5 months. Conclusions: SPN still necessitates surgical intervention given its malignant potential. However, EUS-RFA can represent a promising and safe therapeutic option for SPN < 2 cm. Full article

Background: Administration of PARP inhibitors against breast and ovarian cancers with BRCA1 and BRCA2 mutations has shown clinical benefits in patients. However, these agents are also toxic and have a narrow therapeutic index. Objectives: In this work, we aimed to identify membrane proteins that are specifically upregulated in these cancers. Methods: We interrogated public datasets to analyze genes upregulated or downregulated when these mutations were present, compared with wild-type cancers. Surface protein expression and functional annotation analyses were also performed. Results: In breast cancer, we identified 11 upregulated and 44 downregulated transcripts in BRCA1-mut, while 10 upregulated and 57 downregulated transcripts were identified in BRCA2-mut cancers. In ovarian cancer, 79 transcripts were upregulated and 123 were downregulated in BRCA1-mut cancers, while five were upregulated and seven were downregulated in BRCA2-mut tumors. Regarding the biological function related to these genes, in BRCA1-mutated ovarian cancers, the main functions of upregulated genes included MHC assembly or regulation of the interferon gamma pathway; in BRCA2-mut ovarian cancers, regulation of phosphorylation and signaling; in BRCA1-mut breast cancers, cell damage repair and angiogenesis; and finally, in BRCA2-mut breast cancers, cytokine production and T-cell migration. Genes expressed in the surface membrane or extracellular matrix and related to patient outcomes included B3GNT7 and CTSV in BRCA2-mut breast cancers, exhibiting detrimental prognoses. CD6, CXCL9, and CXCL13 were associated with favorable outcomes in BRCA1-mutant ovarian cancers. The last three genes were also correlated with the infiltration of effector T cells and dendritic cells in ovarian tumors. Conclusions: In summary, we identified deregulated candidate genes that could be used as therapeutic targets. Full article

The global increase in early-onset cancers among adolescents and young adults has happened at the same time as the rise in the consumption of ultra-processed foods (UPFs). Far beyond their poor nutritional quality, UPFs are increasingly seen as Trojan horses, complex biological agents that interfere with many functions of the human organism. In this review, we utilise the Trojan horse model to explain the quiet and building health risks from UPFs as foods that seem harmless, convenient, and affordable while secretly delivering endocrine-disrupting chemicals (EDCs), causing chronic low-grade inflammation, altering the microbiome, and producing epigenetic alterations. We bring together new proof showing that UPFs mess up hormonal signals, harm the body’s ability to fight off harmful germs, lead to an imbalance of microbes, and cause detrimental changes linked to cancer. Important components, such as bisphenols and phthalates, can migrate from containers into food, while additional ingredients and effects from cooking disrupt the normal balance of cells. These exposures are especially harmful during vulnerable developmental periods and may lay the groundwork for disease many years later. The Trojan horse model illustrates the hidden nature of UPF-related damage, not through a sudden toxin but via chronic dysregulation of metabolic, hormonal, and genetic control. This model changes focus from usual diet worries to a bigger-picture view of UPFs as causes of life-disrupting damage. Ultimately, this review aims to identify gaps in current knowledge and epidemiological approaches and highlight the need for multi-omics, long-term studies and personalised nutrition plans to assess and reduce the cancer risk associated with UPFs. Recognising UPFs as a silent disruptor is crucial in shaping public health policies and cancer prevention programs targeting younger people. Full article

Background/Objectives: The 3-dimensional (3D) architecture of the genome in the nucleus of a living cell plays an unexpected yet fundamental regulatory role in cell biology. As an imprint of the cellular genetic, epigenetic and metabolic status, it discriminates pathological conditions through conditional changes to long-range 3D interactions (up to 300 kb) and thus could act as a powerful molecular biomarker linked closely to clinical outcomes. Methods: Here an assessment is made of the latest paradigm shift in molecular biology from a supply chain where information flows from DNA to RNA to protein, to the concept of heritable 3D folding of the genome reflecting the epigenetic and metabolic state of the cell, and which serves as a molecular biomarker for complex clinical outcome. Results: While biomarkers based on individual components of the supply chain fail to accurately reflect clinical outcomes, 3D genomics offers highly informative insights, exemplified for immuno-oncology and prostate cancer diagnosis by clinical tests of superior performance, already in practice in the US and UK. Conclusions: A more complete understanding of human biology will require models that account for the flow of information to and from the 3D genomic architecture in living cells, together with its regulation and logic. Integrating these principles into biomarker discovery and therapeutic design, along with other frontline approaches in precision medicine, including multi-omics and other system-level tools, will be essential for advancing precision medicine beyond its current limitations. Full article

Extracellular vesicles (EVs) are released by nearly all types of cells, and they communicate between cells by transporting bioactive molecules, including proteins, DNA, RNA, and lipids. In recent years, RNA carried by EVs, particularly the long-chain non-coding RNA (lncRNA) and circular RNA (circRNA) subtypes, has garnered interest with respect to their role in controlling tumor progression. Among them, there are increasing reports that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) maintain a recently discovered function as transporters of lncRNAs and circRNAs. However, detailed molecular functions of lncRNAs and circRNAs contained in MSC-EVs are not presently summarized, and the efficacy of MSC-EVs as molecular carriers requires further elucidation. This review summarizes the biological characteristics of EVs and the common mechanisms of lncRNAs and circRNAs contained within them. The “double-edged sword” effect and related molecular mechanism of EV-derived lncRNAs (EV-lncRNAs) and circRNAs (EV-circRNAs) between differing tumor types and MSCs are highlighted. The potential of MSC-EVs in the field of tumor diagnosis and treatment is discussed to suggest new directions for the strategy of engineering MSC-EVs as anti-tumor drug carriers. Full article

MicroRNAs (miRNAs) are pivotal modulators of tumor progression and immune function. Given the central role of the immune system in recognizing and eliminating malignant cells, understanding how miRNAs influence immune responses has become essential for advancing cancer therapy. This review explores the emerging roles of miRNAs in orchestrating cancer immunology, emphasizing their regulation of tumor immune surveillance, immune equilibrium, immune evasion, and immunometabolism. We further illustrate how specific miRNAs modulate the tumor microenvironment by shaping immune cell phenotypes, cytokine networks, and antigen presentation. Some miRNAs enhance cytotoxic T lymphocyte activity, while others promote immune escape by expanding regulatory T cells and myeloid-derived suppressor cells. miRNAs also regulate immune checkpoints (e.g., PD-L1 and CTLA-4), metabolic reprogramming, and stress responses that collectively influence tumor immunogenicity. Additionally, miRNAs are gaining traction as biomarkers for immune activity and predictors of immunotherapy response. Therapeutically, miRNA mimics and inhibitors can enhance anti-tumor immunity, particularly when combined with advanced delivery platforms or immune checkpoint inhibitors. However, challenges such as delivery specificity, off-target effects, and the context-dependent nature of miRNA activity remain significant barriers to clinical translation. Despite shortcomings, miRNAs represent a class of immune regulators with substantial therapeutic potential. Accelerated progress in miRNA-guided therapies is anticipated through deepening insights into miRNA regulatory networks, coupled with integrative multi-omics and AI-driven analytical frameworks. Altogether, miRNAs are a promising frontier in next-generation cancer immunotherapy and precision oncology. Full article

Background/Objectives: Osteosarcoma is the most common malignant bone tumor in children, characterized by a high degree of genomic instability, resulting in copy number alterations and genomic rearrangements without disease-defining recurrent mutations. Clinical trials based on molecular characterization have failed to find new effective therapies or improve outcomes over the last 40 years. Methods: To better understand the immune microenvironment of osteosarcoma, we performed single-cell RNA sequencing on six tumor biopsy samples, combined with a previously published cohort of six samples. Additional osteosarcoma samples were profiled using spatial transcriptomics for the validation of discovered subtypes and to add spatial context. Results: Analysis revealed immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), regulatory and exhausted T cells, and LAMP3+ dendritic cells. Conclusions: Using cell–cell communication modeling, we identified robust interactions between MDSCs and other cells, leading to NF-κB upregulation and an immunosuppressive microenvironment, as well as interactions involving regulatory T cells and osteosarcoma cells that promoted tumor progression and a proangiogenic niche. Full article