Crosstalk between colorectal cancer cells and tumour-associated macrophages

University dissertation from Cell Pathology

Abstract: Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of death from cancer worldwide. People suffering from inflammatory bowel disease, such as Crohns’ disease and ulcerative colitis, are at an increased risk of developing CRC. The development of CRC is highly influenced by the tumour microenvironment. Tumour cells are able to recruit macrophages and change their behaviour. These tumour-associated macrophages (TAMs) were of the M2 phenotype (CD206+). In CRC patient tissues and xenografts from mouse model, presence of increased amount of M2 macrophages was observed. M2 macrophages derived from human monocyte cell line THP-1 secreted high levels of IL-8 and leukotriene D4 (LTD4), which induced colon cancer cell migration, and Th2 cytokines (IL-4, IL-10) to maintain a tumoral immunosuppressive environment. Remodelling of extracellular matrix (ECM) occurs in CRC. CD47 binding to ?2?1 integrin could regulate cyclooxygenase-2 expression and cell migration on collagen I surface in intestinal epithelial cells. CD47 is involved in crosstalk between colon cancer cells and macrophages by interacting with its ligand signal-regulatory protein ? on macrophages. This interaction enhanced cell migration of CRC cells and TAMs. IL-8 and LTD4 could induce CD47 expression in CRC cells. Matrix metalloproteinases (MMPs) are enzymes degrading ECM. The enhanced levels of MMP-7 and -9 mRNA expressions and increased cell invasion into matrigel were observed in colon cancer cells upon stimulation with TAM-conditioned medium. These findings provide more evidence that TAMs play an important role in CRC progression. CD47, as a key regulator of crosstalk between colon cancer cells and TAMs, could thus be a therapeutic target for CRC.