Mast cell ablation causes enhanced intestinal tumor formation in APC^Min/+ mice. Free

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The tumor microenvironment has been shown to both positively and negatively influence tumor progression. Matrix proteinases, often derived from stromal inflammatory cells, have been shown to affect all stages of tumorigenesis and tumor progression. Normally, matrix proteinases are important mediators of tissue remodeling and contribute to several normal physiological processes including wound healing and blood clotting as well as pathological processes such as inflammatory bowel disease, ulcerative colitis and cancer progression. An important consideration is that matrix proteinases often act in broad cascades, where one upstream proteolytic event has several downstream proteolytic consequences.

In the Min (Multiple intestinal neoplasia) mouse model, a single missense mutation in codon 850 of the APC tumor suppressor gene results in mice presenting with multiple focal tumors throughout the intestine, similar to human patients with familial adenomatous polyposis (FAP). Previously, our lab has shown that genetic ablation of MMP-7 results in a 58% reduction of tumor multiplicity in Min mice (Wilson et al., 1997). Furthermore, by in situ hybridization we have identified other MMPs that are more abundantly expressed in tumors compared with normal intestinal tissue. In order to examine broad proteolytic changes in tumors involving multiple classes of proteinases, in conjunction with the proteinase consortium and Affymetrix, we developed the Hu/Mu ProtIn array. This array contains probe sets for 1172 genes of human and murine origin including all known human and murine MMPs as well as other proteinases, substrates and inhibitors.

Using this array we assayed RNA derived from intestinal tumors of APC^Min/+ mice and from age matched wild-type controls. In particular, we detected a striking increase in several proteases of mast cell origin present in tumor tissue absent from normal intestinal tissue. This apparent increase of mast cell protease expression was corroborated by histochemical detection of chymase, a mast cell marker, which demonstrated an increased density of mast cells in intestinal tumors. To assess whether mast cells functionally contributed to tumor formation in the Min model, we crossed c-kit^W-sh/W-sh (Sash) mice, a mast cell deficient line, into the Min background. Sash mice lack mucosal mast cells, but otherwise have a normal complement of immune cells. Genetic ablation of mucosal mast cells was found to both increase tumor incidence by 50%, and increase tumor size in 17 week-old Min animals. Proliferation, as measured by BrdU incorporation, and apoptosis, as measured by TUNEL, were similar in both groups.

Although mast cells have been suggested to contribute to tumor formation through the production of histamine and proteases, our data suggest that they are protective at least in this spontaneous model of benign tumor development.