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The inflammatory milieu plays an important role in colon cancer development and progression. Previously, we have shown that tumor‐associated macrophages (TAMs), an important component of the tumor microenvironment, are enriched in tumors compared with normal tissue and confer a poorer prognosis. In the present study, we found that matrix metallopeptidase‐9 (MMP‐9), which degrades extracellular matrix proteins, was increased in biopsies from colon cancer patients and in mouse xenografts with SW480 cell‐derived tumors. SW480 colon cancer cells exposed to M2‐like macrophage‐conditioned medium (M2‐medium) exhibited increased MMP‐9 mRNA, protein expression and gelatinase activity. A similar effect was obtained by the addition of tumor necrosis factor‐α (TNFα) and leukotriene D 4 (LTD 4 ). MMP‐9 expression and activity were reduced by a TNFα blocking antibody adalimumab and a cysteinyl leukotriene receptor 1 (CysLTR1, the receptor for LTD 4 ) antagonist montelukast. M2‐medium also induced changes in the epithelial–mesenchymal transition (EMT) markers E‐cadherin, β‐catenin, vimentin, and snail in SW480 cells. We also found that both M2‐medium and TNFα and LTD 4 induced stabilization/nuclear translocation of β‐catenin. Furthermore, we also observed an elongated phenotype that may indicate increased invasiveness, as confirmed in a collagen I invasion assay. M2‐medium increased the invasive ability, and a similar effect was also obtained by the addition of TNFα and LTD 4 . The specific MMP inhibitor I or adalimumab and montelukast reduced the number of invasive cells. In conclusion, our findings show that M2‐medium enriched in TNFα and LTD 4 promote colon cancer cell invasion via MMP‐9 expression and activation and the induction of EMT.
Vinnakota et al. (Wed,) studied this question.