Colon Fibroblasts and Inflammation: Sparring Partners in Colorectal Cancer Initiation?

Abstract

Colorectal cancer (CRC) is the third most common cause of cancer-related death. Significant improvements in CRC treatment have been made for the last 20 years, on one hand thanks to a better detection, allowing surgical resection of the incriminated area, and on the other hand, thanks to a better knowledge of CRC’s development allowing the improvement of drug strategies. Despite this crucial progress, CRC remains a public health issue. The current model for CRC initiation and progression is based on accumulation of sequential known genetic mutations in the colon epithelial cells’ genome leading to a loss of control over proliferation and survival. However, increasing evidence reveals that CRC initiation is more complex. Indeed, chronic inflammatory contexts, such as inflammatory bowel diseases, have been shown to increase the risk for CRC development in mice and humans. In this manuscript, we review whether colon fibroblasts can go from the main regulators of the ISC homeostasis, regulating not only the renewal process but also the epithelial cells’ differentiation occurring along the colon crypt, to the main player in the initiation of the colorectal cancer process due to chronic inflammation.

Loss of primary cilia promotes inflammation and carcinogenesis

“…Crucial in the regulation of intestinal homeostasis and pathology is the crosstalk between epithelium lining the crypts and neighboring fibroblasts, which are characterized by a remarkable heterogeneity and the capacity to differentiate into functionally distinct subsets (Koliaraki et al , 2020 ; Onfroy‐Roy et al , 2021 ). Different morphogenetic pathways participate in the epithelium‐fibroblast crosstalk, such as Wnt signaling through the secretion of factors from adjacent fibroblasts, which is essential in the maintenance of the epithelial stem cell compartment at the bottom of crypts (Medema & Vermeulen, 2011 ).…”

Wound Healing versus Metastasis: Role of Oxidative Stress

“…Cancer-Associated Fibroblasts (CAFs) are the most predominant stromal cell type in the tumor microenvironment [ 143 ]. They are major producers of ROS [ 144 ], which facilitates metastasis through the activation of angiogenesis [ 145 ]. Moreover, cancer cells induce ROS overproduction in CAFs contributing to a pro-oxidative tumor microenvironment [ 146 ].…”

Wound Healing Versus Metastasis: Role of Oxidative Stress

“…Cancer-Associated Fibroblasts (CAFs) are the most predominant stromal cell type in the tumor microenvironment [111]. They are major producers of ROS [112], which facilitates metastasis through the activation of angiogenesis [113]. Moreover, cancer cells induce ROS overproduction in CAFs contributing to a pro-oxidative tumor microenvironment [114].…”