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Figure 2: Recruitment of tumour-promoting immune cells contributes to progression and metastasis. (a) Representative images of tissue sections (normal colonic mucosa, carcinoma, and liver metastases) immunostained with CD68, a marker of macrophages with a M2-phenotype. (b) A schematic and simplified model as to how TAMs might contribute to tumour development and metastasis. CRC arises by genetic damages, mutations, and deregulated signaling pathways; metastatic spread, instead, is promoted by communications between tumour and immune cells. Normal colonic tissues show specialized macrophages residing in well-defined niches. The functions of TAMs during tumour progression may depend on their intrinsic plasticity and adaptability mediated by factors controlling the balance between the M1 and M2 phenotype. We suggest that at least two mechanisms may play a role in the prometastatic function of TAMs: (1) M2-macrophages produce a dense layer surrounding invasive cancer cells resulting in heterotypic interactions between the tumour and the host stroma; (2) invasive cancer cells can acquire immunophenotypic traits (i.e., CD68) due to cell fusion between macrophages and cancer cells facilitating homotypic interactions with the host stroma and TAMs. (c) Polarized, CD68 positive, M2-macrophages may have distinct functions depending on their density or distribution between the invasive edges and intraepithelial areas (ratio IM/IE ×100). CD68 expression is not confined to the infiltrating TAMs but is extended to a significant fraction of the malignant cells. These parameters correlate with the mismatch repair (MMR) status and patients’ disease specific survival in our cohort of 82 CRC patients. IE: intraepithelial; IM: invasive margin; MMR pro and MMR neg indicate MMR proficient and deficient tumours, respectively. The value is reported in each graph.