Role of Toll-like receptors in microbiota-associated gastrointestinal cancer metastasis

Abstract

Toll-like receptors (TLRs) serve as specific pattern recognition molecules that bind to microbial components to activate innate immunity and instruct and modulate adaptive immunity in the face of immunological danger. Accumulating evidence supports that TLR signaling pathway responses to luminal microbes participate in the development of gastrointestinal malignancies. This review summarizes current knowledge on the roles of TLR in microbiota-associated gastrointestinal cancer metastasis, focusing on TLR recognition of microbiota ligands, initiating inflammation, and promoting tumorigenesis, as well as the therapeutic strategies to target TLR. Studying the link between TLR signaling and gastrointestinal malignancies offers the possibility to identify novel ways to both prevent and treat gastrointestinal cancer.

The Role of Toll-Like Receptors in Colorectal Cancer Progression: Evidence for Epithelial to Leucocytic Transition

“…Ninety percent of patients who succumb to their disease have metastatic lesions ( 30 ). TLR expression in tumors is linked to increased grade and distant metastasis ( 2 , 18 , 21 , 31 ). The ability of a tumor cell to detach from its epithelial neighbors, break through the basement membrane, and invade nearby tissues is, in part, the result of a long history of aberrant TLR signaling.…”

“…Integrin signaling is used in healthy systems to aid immune cell trafficking ( 61 ). Aberrant expression of these integrins via TLR signaling allows circulating tumor cells to respond to the same trafficking mechanisms that an immune cell uses to migrate to distal sites ( 2 , 32 , 62 , 63 ). Similar examples have been shown with integrins in colon cancer ( 64 ), breast cancer ( 65 ), and melanoma ( 66 ).…”

“…In the healthy gastrointestinal (GI) tract, TLRs are expressed by intestinal epithelial cells (IEC) and play a role in immune modulation and tissue homeostasis by stimulating the immune response to bacterial pathogens, attenuating the immune response against favorable microbes, sensing breakdown of the protective intestinal barriers, and triggering proliferative signaling ( 6 , 10 , 11 ). The lumen of the gut is subjected to continual interactions with the microbiome and would be in a constant state of inflammation were it not for the controlled expression and normal function of these TLRs ( 2 , 6 ).…”

“…Microbial imbalance and/or dysregulation of these responses leads to chronic inflammation of the bowel ( 15 ). Chronic inflammation is correlated with initiation of cancer development and in the progression of cancer into more aggressive forms of malignancies ( 2 ). Aberrant TLR signaling and the resulting cytokine imbalance leads to increased epithelial proliferation and decreased cell death ( 19 ).…”

“…Additionally, an active immune environment creates selection pressures for initiating cancer cells resulting in the evolution of an immune-evasive tumor phenotype ( 14 ). Furthermore, TLR dysregulation is implicated in cancer invasion and metastasis ( 2 , 19 – 21 ). Understanding the role of TLRs in the natural evolution of metastatic disease is crucial for developing new therapies and optimizing current treatments.…”