Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage

Abstract

The intestinal epithelium acts as a physical barrier that separates the intestinal microbiota from the host and is critical for preserving intestinal homeostasis. The barrier is formed by tightly linked intestinal epithelial cells (IECs) (i.e. enterocytes, goblet cells, neuroendocrine cells, tuft cells, Paneth cells, and M cells), which constantly self-renew and shed. IECs also communicate with microbiota, coordinate innate and adaptive effector cell functions. In this review, we summarize the signaling pathways contributing to intestinal cell fates and homeostasis functions. We focus especially on intestinal stem cell proliferation, cell junction formation, remodelling, hypoxia, the impact of intestinal microbiota, the immune system, inflammation, and metabolism. Recognizing the critical role of KRAS mutants in colorectal cancer, we highlight the connections of KRAS signaling pathways in coordinating these functions. Furthermore, we review the impact of KRAS colorectal cancer mutants on pathway rewiring associated with disruption and dysfunction of the normal intestinal homeostasis. Given that KRAS is still considered undruggable and the development of treatments that directly target KRAS are unlikely, we discuss the suitability of targeting pathways downstream of KRAS as well as alterations of cell extrinsic/microenvironmental factors as possible targets for modulating signaling pathways in colorectal cancer.

Analysis of Common Somatic Mutations in Colorectal Carcinoma and Associated Dysregulated Pathways

“…Therefore, understanding biological pathways downstream of KRAS and their link to the cancer phenotype needs to be further explored. 20 KRAS, as a component of epidermal growth factor receptor (EGFR) pathway, leads to constitutive activation of RAF/MEK/ ERK pathway, PI3K signaling via MTOR, and the transcription factor NF-kB.A member of RAF protein family, BRAF, may undergo gain of function mutation triggering MAPK pathway. 17 KRAS and BRAF mutations are considered to be mutually exclusive.…”

Gut microbiota composition in chemotherapy and targeted therapy of patients with metastatic colorectal cancer

“…The KRAS gene, a member of the RAS gene family, is associated with many signaling pathways, including those related to inflammation, the immune system, and metabolism. The gut microbiota is a key factor because it maintains intestinal homeostasis through these pathways (40). Variations in the KRAS gene can disrupt normal signaling functions and hamper intestinal homeostasis.…”

“…Variations in the KRAS gene can disrupt normal signaling functions and hamper intestinal homeostasis. The accumulative effect can result in CRC tumorigenesis and affect CRC treatment outcomes (40). Microbiota can significantly differ between CRC tissues with and without KRAS gene variations (41).…”

“…During our treatment course, the bevacizumab group comprised both the wild-type and RAS gene variation carriers (Figure 1). The KRAS gene is associated with various signaling pathways and can alter treatment outcomes (26,40,41). The relationship between the KRAS gene and human gut microbiota remains unclear.…”

Progress in the application of hydrogels in immunotherapy of gastrointestinal tumors

“…The success of CAR-T cells in treating hematological malignancies has raised the hope of using them in solid tumor therapy as well (Hoo et al., 2013 ). Despite this, the disappointing consequences of CAR-T therapy against gastrointestinal tumors are closely related to numerous obstacles (Rajendrakumar et al., 2018 ; Ternet & Kiel, 2021 ). After systemic administration of CAR-T cells, these cells display poor antitumor activity because they have difficulty identifying, infiltrating, and expanding within the immunosuppressive TME (Martinez & Moon, 2019 ).…”