MedComm – Oncology最新文献

Metastasis remains a leading cause of cancer-related deaths, defined by a complex, multi-step process in which tumor cells spread and form secondary growths in distant tissues. Despite substantial progress in understanding metastasis, the molecular mechanisms driving this process and the development of effective therapies remain incompletely understood. Elucidating the molecular pathways governing metastasis is essential for the discovery of innovative therapeutic targets. The rapid advancements in sequencing technologies and the expansion of biological databases have significantly deepened our understanding of the molecular drivers of metastasis and associated drug resistance. This review focuses on the molecular drivers of metastasis, particularly the roles of genetic mutations, epigenetic changes, and post-translational modifications in metastasis progression. We also examine how the tumor microenvironment influences metastatic behavior and explore emerging therapeutic strategies, including targeted therapies and immunotherapies. Finally, we discuss future research directions, stressing the importance of novel treatment approaches and personalized strategies to overcome metastasis and improve patient outcomes. By integrating contemporary insights into the molecular basis of metastasis and therapeutic innovation, this review provides a comprehensive framework to guide future research and clinical advancements in metastatic cancer.

Osimertinib resistance remains a significant challenge in the treatment of non-small cell lung cancer (NSCLC). N⁶-methyladenosine (m⁶A) modifications are closely linked to various mechanisms of anticancer resistance and autophagy, offering new avenues for targeted therapies. However, the role of m⁶A-mediated autophagy in osimertinib-resistant NSCLC is still unclear. In this study, we utilized multi-omics sequencing analysis and found that overexpression of the m⁶A methyltransferase METTL3 contributes to osimertinib resistance in NSCLC. Importantly, we identified that METTL3 positively regulates the expression of the autophagy-related gene ubiquinone-cytochrome C reductase complex assembly factor 2 (UQCC2) through an m⁶A-dependent mechanism. Further, we confirmed that METTL3 knockdown leads to UQCC2 downregulation and triggers autophagy activation. Interestingly, lomitapide, a cholesterol-lowering drug, was repurposed to enhance the sensitivity of cancer cells to therapy by inhibiting METTL3, which in turn activated autophagy-associated cell death pathways, reversing osimertinib resistance. This study emphasizes the critical role of the METTL3/UQCC2 axis in autophagy-mediated drug resistance and positions lomitapide as a promising METTL3 inhibitor and autophagy inducer with potential therapeutic effects, either alone or in combination with other anticancer agents, in patients with osimertinib-resistant NSCLC.

Chimeric antigen receptor (CAR) T cells have demonstrated promising results in hematological malignancies; however, challenges remain in treating solid tumors. New CARs with more effectiveness and lower side effects are needed. Ephrin type-A receptor 2 (EphA2) belongs to the Ephrin family of receptor tyrosine kinases, which is overexpressed in several solid malignancies. Compared with some single-chain variable fragment (ScFv) CARs that exhibit excessively high affinity for their targets, natural receptor/ligand-based CARs maintain inherent affinity for their binding partners, potentially balancing cytotoxicity and side effects to better meet clinical needs. Here, we designed a CAR targeting EphA2-positive cancer cells by exploiting the extracellular domain of its natural ligand Ephrin A1 (EFNA1). EFNA1 CAR-T cells exhibited specific cytotoxicity against various cancer cells and cancer stem-like cells in vitro, and significantly suppressed tumor growth in a pancreatic cancer xenograft mouse model. Moreover, although these CAR-T cells specifically targeted mouse EphA2 and killed mouse tumor cell lines in vitro, they did not induce obvious side effects in mice. Additionally, it also showed good safety in rhesus macaques. Collectively, these results validate the therapeutic effectiveness and safety of EFNA1 CAR-T cells for treating solid tumors.

The success of cancer therapy has been significantly hampered by various mechanisms of therapeutic resistance. Chief among these mechanisms is the presence of clonal heterogeneity within an individual tumor mass. The introduction of the concept of cancer stem cells (CSCs)—a rare and immature subpopulation with tumorigenic potential that contributes to intratumoral heterogeneity—has deepened our understanding of drug resistance. Given the characteristics of CSCs, such as increased drug-efflux activity, enhanced DNA-repair capacity, high metabolic plasticity, adaptability to oxidative stress, and/or upregulated detoxifying aldehyde dehydrogenase (ALDH) enzymes, CSCs have been recognized as a theoretical reservoir for resistant diseases. Implicit in this recognition is the possibility that CSC-targeted therapeutic strategies might offer a breakthrough in overcoming drug resistance in cancer patients. Herein, we summarize the generation of CSCs and our current understanding of the mechanisms underlying CSC-mediated therapeutic resistance. This extended knowledge has progressively been translated into novel anticancer therapeutic strategies and significantly enriched the available options for combination treatments, all of which are anticipated to improve clinical outcomes for patients experiencing CSC-related relapse.

Oxidative stress results from an imbalance between the production and neutralization of reactive oxygen species. It induces oxidative damage to cellular components including proteins, lipids, nucleic acids, and membranes, therefore intrinsically linking to aging-related diseases such as cancer, cardiovascular disease, and neurological disorders. Emerging evidence suggests that oxidative stress may promote tumor development by influencing various aspects of cellular senescence, such as its onset, pro-inflammatory secretion, and alteration of cellular function and structure. Modulating oxidative stress to target cellular senescence offers a novel strategy for cancer prevention and treatment. However, a thorough grasp of the specific mechanisms at play is lacking. This review will present the association between oxidative stress and cellular senescence and their regulatory role in tumor progression and treatment, with emphasis on senescence-associated secretory phenotype, immunosenescence and therapy-induced senescence. Current agents and strategies that remove side effects of cellular senescence via killing senescent cancer cells or modulating oxidative stress to improve antitumor efficacy will be summarized. This review will help readers better understand the complex relationship between oxidative stress and senescence in cancer, and will also provide a basis for further research in this area.

Cancer stem cells (CSCs) are a small group of tumor cells with the capacity to undergo self-renewal and differentiation. These cells not only initiate and maintain tumor growth, but also confer resistance to current cancer therapies. CSCs display a high degree of plasticity and can be generated under therapeutic stress via dedifferentiation from non-stem-like tumor cells, suggesting the necessity simultaneously targeting CSCs and bulk tumor cells to achieve the best therapeutic effect. Despite the findings that therapeutic stress induces CSC plasticity, the mechanisms underpinning CSC formation and therapeutic resistance are not fully defined. Tumor cells display elevated levels of reactive oxygen species (ROS), contributed by rapid proliferation, enhanced metabolic demands and oncogenic signaling. CSCs achieve redox homeostasis partly by regulating redox-sensitive transcription factors (TFs), including NRF2, HIF-1α, BACH1, NF-kB, FOXOs, AP-1, and others. This review aims to summarize the roles and underlying mechanisms of these TFs in regulation of CSCs and tumor progression from the perspectives of stem cell maintenance, metabolic reprogramming, epithelial–mesenchymal transition (EMT) and angiogenesis. We also discuss the potentials of utilizing specific inhibitors for these TFs in suppressing drug resistance and metastasis by repressing CSC activity, an approach that may provide new targeted therapies for advanced cancer and improve patient outcome.

Colorectal cancer (CRC) ranks as one of the most common malignancies worldwide. Myeloid-derived suppressor cells (MDSCs) represent an immunosuppressive heterogeneous population of immature monocytes and granulocytes constituting a major obstacle for CRC therapy. Previous studies demonstrated that WNT2 is enriched in tumor microenvironment (TME), promoting CRC progression. However, the role of WNT2 in regulating MDSCs to facilitate CRC progression remains largely unexplored. Our analysis of The Cancer Genome Atlas (TCGA) database and blood samples from 50 primary and recurrent CRC patients revealed a positive correlation between WNT2 expression and MDSCs abundance. Treatment with recombinant WNT2 protein significantly enhanced the accumulation and immunosuppressive function of MDSCs in vitro. Conversely, anti-WNT2 monoclonal antibody remarkably reduced the percentage and functional activity of MDSCs in CRC tumor-bearing mice. Mechanistic analyses further demonstrated that WNT2 mediates MDSCs activities through the p38 MAPK/Akt pathway. Collectively, our findings not only highlight the pivotal role of WNT2 in CRC progression by enhancing MDSCs activities within the TME, but also provide evidence that WNT2 levels and MDSCs abundance in peripheral blood could serve as predictive biomarkers for early diagnosis and prognosis of CRC patients.