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

SIMPLE SUMMARY: The versatile crosstalk between cancer cells and cancer-associated fibroblasts (CAFs) of the tumour microenvironment (TME) drives colorectal carcinogenesis and heterogeneity. Colorectal cancer (CRC) can be classified by the anatomical sites from which the cancer arises, either from the right or left colon. Although the cancer cell–CAF interaction is being widely studied, its role in the progression of cancer in the right and left colon and cancer heterogeneity are still yet to be elucidated. Further insight into the complex interaction between different cellular components in the cancer niche, their evolutionary process and their influence on cancer progression would propel the discovery of effective targeted CRC therapy. 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.