Dynamic Co-Evolution of Cancer Cells and Cancer-Associated Fibroblasts: Role in Right- and Left-Sided Colon Cancer Progression and Its Clinical Relevance

Abstract

Cancer is a result of a dynamic evolutionary process. It is composed of cancer cells and the tumour microenvironment (TME). One of the major cellular constituents of TME, cancer-associated fibroblasts (CAFs) are known to interact with cancer cells and promote colorectal carcinogenesis. The accumulation of these activated fibroblasts is linked to poor diagnosis in colorectal cancer (CRC) patients and recurrence of the disease. However, the interplay between cancer cells and CAFs is yet to be described, especially in relation to the sidedness of colorectal carcinogenesis. CRC, which is the third most commonly diagnosed cancer globally, can be classified according to the anatomical region from which they originate: left-sided (LCRC) and right-sided CRC (RCR). Both cancers differ in many aspects, including in histology, evolution, and molecular signatures. Despite occurring at lower frequency, RCRC is often associated with worse diagnosis compared to LCRC. The differences in molecular profiles between RCRC and LCRC also influence the mode of treatment that can be used to specifically target these cancer entities. A better understanding of the cancer cell–CAF interplay and its association with RCRC and LRCR progression will provide better insight into potential translational aspects of targeted treatment for CRC.

Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model

“…For several cancer types including hepatocellular carcinoma, pancreatic cancer, breast cancer, lung cancer, melanoma, and colon cancer it has been demonstrated that tumor cells interaction with CAFs promotes EMT and the metastatic phenotype (Kubo et al, 2016;Domen et al, 2021;Shelton et al, 2021;Ahmad Zawawi and Musa, 2022;Ando et al, 2022;Hu et al, 2022). Direct and indirect mechanisms have been shown to influence tumor metastasis by CAFs: i) ECM remodeling by secretion of collagens, fibronectin, and proteoglycans (Scott et al, 2019); ii) paracrine communication through exosomes, growth factors and cytokines that promote stemness and metastasis, such as: transforming growth factor β -TGFβ, Chemokine (CC motif) ligand 2 (CCL2), Interleukin-6 (IL-6), Hepatocyte growth factor (HGF), Osteopontin (OPN) and Stromal cell-derived factor 1 (SDF-1) (Linares et al, 2020); iii) direct contact with cancer cells and facilitated invasion and select gene transcription (Yamaguchi and Sakai, 2015;Liu et al, 2019).…”

Crosstalk of angiogenesis-related subtypes, establishment of a prognostic signature and immune infiltration characteristics in colorectal adenocarcinoma

“…Compared with left-sided CRC (LCRC), right-sided CRC (RCRC) is usually associated with poor prognosis, and also presents more advanced N stage, larger tumor size, poorly differentiated tumors, as well as higher probability of lymphatic vascular invasion ( 48 ). In addition, RCRC also presented higher hypermethylation and higher microsatellite instability (MSI) frequency than LRCR ( 26 , 49 ). Higher risk score was associated with worse survival rate and higher MSI-high proportion, which was consistent with phenotypic characteristics of RCRC.…”

Spheroids and organoids derived from colorectal cancer as tools for in vitro drug screening

“…CRC is a highly complex and heterogeneous disease, contributed by cancer epithelial cells and the TME [ 36 ]. TME constitutes multiple cellular components neighbouring to the colonic crypt of cancer epithelial cells including fibroblasts, immune cells, and endothelial cells and intricate network of extracellular matrix (ECM) which have been reported to promote colorectal carcinogenesis and confer chemoresistance [ 37 ].…”