The role of toll-like receptors in colorectal cancer progression: evidence for epithelial to leucocytic transition

Abstract

Toll-like receptors (TLRs) are expressed by immune cells, intestinal epithelium, and tumor cells. In the homeostatic setting, they help to regulate control over invading pathogens and maintain the epithelial lining of the large and small intestines. Aberrant expression of certain TLRs by tumor cells can induce growth inhibition while others contribute to tumorigenesis and progression. Activation of these TLRs can induce inflammation, tumor cell proliferation, immune evasion, local invasion, and distant metastasis. These TLR-influenced behaviors have similarities with properties observed in leukocytes, suggesting that tumors may be hijacking immune programs to become more aggressive. The concept of epithelial to leucocytic-transition (ELT) is proposed, akin to epithelial to mesenchymal transition, in which tumors develop the ability to activate leucocytic traits otherwise inaccessible to epithelial cells. Understanding the mechanisms of ELT could lead to novel therapeutic strategies for inhibiting tumor metastasis.

Keywords: ELT; cell plasticity; colorectal cancer; epithelial to leucocytic transition; immune evasion; inflammation; metastasis; toll-like receptors.

Figure 1

Epithelial to leucocytic transition (ELT) is the acquisition of immune properties by tumor cells. Epithelial tumor cells (purple box) can make transition to a mesenchymal phenotype (orange box), which enhances local motility and remodeling of the extracellular matrix (ECM). Tumor cells undergoing ELT (green box) can gain the ability to (1) evade the immune system at the primary tumor site, (2) access the lymphatic system, (3) circulate through the vasculature, home to favorable sites of metastasis, and extravasate into a metastatic niche, and (4) avoid destruction by the immune system at the site of metastasis.