The Versatile Roles of Cancer-Associated Fibroblasts in Colorectal Cancer and Therapeutic Implications

Abstract

The tumor microenvironment (TME) is populated by abundant cancer-associated fibroblasts (CAFs) that radically influence the disease progression across many cancers, including the colorectal cancer (CRC). In theory, targeting CAFs holds great potential in optimizing CRC treatment. However, attempts to translate the therapeutic benefit of CAFs into clinic practice face many obstacles, largely due to our limited understanding of the heterogeneity in their origins, functions, and mechanisms. In recent years, accumulating evidence has uncovered some cellular precursors and molecular markers of CAFs and also revealed their versatility in impacting various hallmarks of CRC, together helping us to better define the population of CAFs and also paving the way toward their future therapeutic targeting for CRC treatment. In this review, we outline the emerging concept of CAFs in CRC, with an emphasis on their origins, biomarkers, prognostic significance, as well as their functional roles and underlying mechanisms in CRC biology. At last, we discuss the prospect of harnessing CAFs as promising therapeutic targets for the treatment of patients with CRC.

Epigallocatechin‑3‑gallate hinders metabolic coupling to suppress colorectal cancer malignancy through targeting aerobic glycolysis in cancer‑associated fibroblasts

“…High amounts of lactic acid secreted by CAFs with an upregulated expression of MCT4 as an energy substrate are absorbed by cancer cells, and these participate in the metabolic alteration of cancer cells, thereby enhancing tumor malignancy. In the present study, the western blotting results showed that the expression levels of α-SMA and FAP, the two most widely used markers for identifying CAFs ( 41 , 42 ), were upregulated in HIFs after co-culture. Moreover, the results from the immunofluorescence staining experiments confirmed the upregulation of α-SMA and FAP, and a narrower, longer and spindle-shaped morphology of the cells was observed in the induced CAFs that was similar to that commonly exhibited in activated fibroblasts, as one of their characteristic features in CAFs ( 43 ).…”

“…Although the exact method of identifying CAFs is still controversial, it is generally hypothesized that CAFs are derived from activated myofibroblasts in the TME. The typical spindle-shaped morphology changes compared with quiescent fibroblasts, and the upregulation of several specific CAF markers that are widely used, such as α-SMA, FAP and IL-6, can be used to identify CAFs ( 41 - 43 ). Recently, co-culture with cancer cells has become a way to obtain and study CAFs in vitro ( 44 , 45 ).…”

The Role of Inflammatory Cytokines in the Pathogenesis of Colorectal Carcinoma—Recent Findings and Review

“…Elevated IL-8 expression changes the tumor microenvironment in favor of metastasis through increasing neutrophil and tumor-associated macrophages' infiltration [110]. Additionally, recent studies suggest that cancer cells and CAFs can produce IL-8 to further promote growth and metastasis [111]. IL-8 is considered an independent adverse prognosis factor in colorectal carcinoma.…”

Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer

“…Myofibroblasts, cancer-associated fibroblasts (CAFs), and CSCs secrete a range of growth factors and signaling proteins such as the agonist Wnt3a and the antagonist Notum in the TME [ 24 , 165 ], both essential for canonical Wnt signaling transduction. Recently, a new mechanism for tumor resistance was proposed, suggesting that APC-deficient cell clones become “supercompetitive” through TME modulation, secreting Wnt antagonists such as Notum, which inhibit the survival of normal ISC neighboring cells, inducing their differentiation [ 79 , 80 , 81 ].…”