Colorectal cancer (CRC) progression and eventually metastasis is directed in many aspects by a circuitous ecosystem consisting of an extracellular matrix scaffold populated by cancer-associated fibroblasts (CAFs), endothelial cells, and diverse immune cells. CAFs are recruited from local tissue-resident fibroblasts or pericryptal fibroblasts and distant fibroblast precursors. CAFs are highly abundant in CRC. In this review, we apply the metastasis-promoting communication of colorectal CAFs to 10 cancer hallmarks described by Hanahan and Weinberg. CAFs influence innate and adaptive tumor immune responses. Using datasets from previously published work, we re-explore the potential messages implicated in this process. Fibroblasts present in metastasis (metastasis-associated fibroblasts) from CRC may have other characteristics and functional roles than CAFs in the primary tumor. Since CAFs connect metastasis-promoting communication, CAF markers are potential prognostic biomarkers. CAFs and their products are possible targets for novel therapeutic strategies.
Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer, a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAFs are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell-cycle arrest, and secretion of paracrine mediators, including insulin-like growth factor-1 (IGF1). Subsequently, RT-activated CAFs promoted survival of colorectal cancer cells, as well as a metabolic switch favoring glutamine consumption through IGF1 receptor (IGF1R) activation. RT followed by IGF1R neutralization in orthotopic colorectal cancer models reduced the number of mice with organ metastases. Activation of the downstream IGF1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from rectal cancer patients after neoadjuvant chemoradiotherapy. Taken together, our data support the notion that paracrine IGF1/IGF1R signaling initiated by RT-activated CAF worsens colorectal cancer progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival. These findings reveal that paracrine IGF1/IGF1R signaling promotes colorectal cancer progression, establishing a preclinical rationale to target this activation loop. .
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