Abstract 528: Leukotrienes modulate expression and activity of matrix metalloproteinases (MMPs) in colorectal cancer cells

Abstract

Abstract Background: Pro-inflammatory cysteinyl leukotrienes (CysLTs) have been implicated to play a role in colon cancer. Previously, we have shown that leukotriene D4 (LTD4) signaling via the CysLT1 receptor is linked to tumorigenic processes. Elevated CysLT1R expression in tumoral tissue correlates with a poor prognosis in colon cancer patients; and CysLT1R signaling promotes intestinal epithelial cells’ proliferation, survival and migration. Tumor-associated macrophages (TAMs) have been shown to promote cancers’ progression and invasion. These activated macrophages (CD68+) are not only a major source of CysLTs in tumoral tissues, but also have been shown to promote cancer cells’ invasion, indicating that TAMs are part of the mechanism whereby inflammation promotes cancers’ progression. In addition to releasing pro-inflammatory mediators, TAMs also can produce protease enzymes at primary tumoral sites, both of which are tumor-promoting factors. Matrix metalloproteinase (MMPs), a family of zinc-dependent proteases, are proteolytic enzymes intimately linked to tumors’ invasion and progression. Although additional functions of MMPs have emerged recently, they are well known for their ability to degrade the extracellular matrix and basement membranes, facilitating tumoral cells’ invasion and tumors’ metastasis. However, little is known about a possible relation between pro-inflammatory mediators such as leukotrienes and MMPs’ expression and activities in colon cancer. Aim: The study's overall objective is to explore a possible correlation between TAM-derived pro-inflammatory leukotrienes and MMPs and their inhibitors in colon cancer. Methods: Using different human colon cancer cell lines and normal human embryonic intestinal epithelial cells, we explored MMPs’ expression in the absence or presence of leukotrienes. We employed various techniques such as RT-PCR, Immuno-histochemical, -fluorescent staining, Western blotting, ELISA and cell migration assays. Results: We first examined selected MMPs’ expression level in non-transformed human intestinal epithelial cells; Int 407 cells; and the human colon cancer cell lines Caco-2, HT-29 and CysLT1R-transfected Caco-2 cells at the mRNA level. We detected significant increases in the expression of MMP-2, MMP-3 and MMP-7 after 12 and 24 hours of LTD4 stimulation. In addition to these increases in MMPs’ expression, we observed an enhanced invasion capacity of CysLT1R-transfected Caco-2 cells compared to empty vector-transfected Caco-2 cells in the presence of LTD4. Conclusion: These preliminary in vitro findings indicate that TAM-derived leukotrienes can modulate MMPs’ expression in colon cancer, and thus their invading capacity. Further investigations will address how leukotrienes affect MMPs’ expression and activities in colon cancer cells and tumors. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 528.