CAFs, a heterogeneous population of stromal cells, are known for their multifaceted functions within the tumor microenvironment. In gastrointestinal cancers, CAFs play pivotal roles in modulating the Extracellular Matrix (ECM), promoting angiogenesis, and facilitating immune evasion. While traditionally considered promoters of tumor growth, recent research has uncovered a nuanced view of CAFs, revealing their dynamic nature and context-dependent functions. In the initial stages of gastrointestinal cancer, CAFs often support tumor growth through the secretion of growth factors, cytokines, and remodeling of the ECM. Their paracrine interactions with cancer cells create a permissive environment for tumorigenesis, fostering cell proliferation and survival. As gastrointestinal tumors progress, CAFs contribute to angiogenesis, promoting the formation of new blood vessels that sustain the growing tumor. Moreover, CAFs actively participate in the metastatic process by facilitating cancer cell invasion and migration through the secretion of pro-migratory factors [3].
Gastrointestinal CAFs exert a profound influence on the immune landscape within the tumor microenvironment. They can modulate immune cell functions, creating an immunosuppressive milieu that shields cancer cells from immune surveillance. This immunomodulatory role poses challenges for immunotherapeutic interventions. In advanced stages of gastrointestinal cancer, CAFs contribute to therapeutic resistance. Their interactions with cancer cells can confer resistance to chemotherapy and targeted therapies, limiting the efficacy of conventional treatment approaches. Understanding the mechanisms behind this resistance is critical for devising strategies to overcome treatment hurdles. The dynamic functions of gastrointestinal CAFs are orchestrated by complex molecular signaling pathways. Tumor-derived factors, including Transforming Growth Factor-Beta (TGF-β), Platelet-Derived Growth Factor (PDGF), and Fibroblast Growth Factor (FGF), play pivotal roles in activating CAFs. Epigenetic modifications and post-translational alterations further contribute to the heterogeneity and plasticity of CAFs, allowing them to adapt to changing tumor conditions [4].
Recent studies have unraveled the heterogeneity within the CAF population, indicating that different subsets of CAFs may have distinct functions. Subpopulations such as myofibroblastic CAFs, inflammatory CAFs, and senescent CAFs exhibit diverse phenotypes and functions in gastrointestinal tumors. Understanding this heterogeneity is crucial for developing targeted therapies that selectively interfere with pro-tumorigenic CAF subsets. Given the evolving understanding of gastrointestinal CAFs, there is growing interest in exploring them as potential therapeutic targets. Strategies aimed at disrupting CAF functions include targeting specific signaling pathways, modulating the tumor immune microenvironment, and developing agents that selectively deplete pro-tumorigenic CAF subsets. Precision medicine approaches tailored to individual patients' CAF profiles hold promise for enhancing treatment outcomes [5].