Cancer-Associated Fibroblast-Induced Resistance to Chemotherapy and Radiotherapy in Gastrointestinal Cancers

Abstract

Simple Summary Gastrointestinal (GI) cancers are primary malignant tumors associated with cancer-related deaths worldwide. Although chemotherapy and radiotherapy are essential modalities to improve patient survival, many patients show resistance to these therapies. Various clinical studies have suggested that cancer-associated fibroblasts (CAFs) play a significant role in this resistance. In this review, we discuss CAF-produced cytokines, chemokines, growth factors, and exosomes, as well as desmoplastic reactions, all of which could be involved in cancer therapy resistance. In the future, the heterogeneity of CAFs should be considered such that CAF subtypes involved in cancer therapy resistance may be identified, thus improving the efficacy of chemotherapy and radiotherapy in GI cancers. Abstract In the past few decades, the role of cancer-associated fibroblasts (CAFs) in resistance to therapies for gastrointestinal (GI) cancers has emerged. Clinical studies focusing on GI cancers have revealed that the high expression of CAF-related molecules within tumors is significantly correlated with unfavorable therapeutic outcomes; however, the exact mechanisms whereby CAFs enhance resistance to chemotherapy and radiotherapy in GI cancers remain unclear. The cells of origin of CAFs in GI cancers include normal resident fibroblasts, mesenchymal stem cells, endothelial cells, pericytes, and even epithelial cells. CAFs accumulated within GI cancers produce cytokines, chemokines, and growth factors involved in resistance to therapies. CAF-derived exosomes can be engaged in stroma-related resistance to treatments, and several non-coding RNAs, such as miR-92a, miR-106b, CCAL, and H19, are present in CAF-derived exosomes and transferred to GI cancer cells. The CAF-induced desmoplastic reaction interferes with drug delivery to GI cancer cells, evoking resistance to chemotherapy. However, due to the heterogeneity of CAFs in GI cancers, identifying the exact mechanism underlying CAF-induced resistance may be difficult. Recent advancements in single-cell “omics” technologies could offer clues for revealing the specific subtypes and biomarkers related to resistance.