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.
Highlights
Cancers originating from the gastrointestinal (GI) tract, including the esophagus, stomach, colorectum, liver, and pancreas, are common malignancies and are the primary cause of cancer-related mortalities worldwide [1]
In the current review, we have focused on a substantial amount of evidence related to the correlation between cancer-associated fibroblasts (CAFs) and chemotherapy and radiotherapy resistance in GI cancers (Figure 3, Table 2)
Recent studies have demonstrated that small extracellular vesicles, such as exosomes containing miRNAs and long non-coding RNAs (lncRNAs), can control the epigenetic regulation of genes related to drug response
Summary
Cancers originating from the gastrointestinal (GI) tract, including the esophagus, stomach, colorectum, liver, and pancreas, are common malignancies and are the primary cause of cancer-related mortalities worldwide [1]. Targeting agents that block the interaction between cancer cells and the TME may improve treatment outcomes in GI cancer patients [10]. Recent phase II clinical trials testing angiotensin I receptor blockers as inhibitors of CAF activation and pegvorhyaluronidase alfa as a decomposer of hyaluronan accumulated by CAFs; these trials have described improved outcomes in PDAC patients [23,24]. These agents have not yet been approved as a treatment of choice for GI cancers, accumulating evidence suggests that targeting CAFs in GI cancers is promising (Table 1). Other CRC studies reported a significant correlation between a high proportion of α-SMA-expressing CAFs and resistance to 5-fluorouracil plus oxaliplatin-based chemotherapy [26]
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