Exogenous introduction of tissue inhibitor of metalloproteinase 2 reduces accelerated growth of TGF-β-disrupted diffuse-type gastric carcinoma

Diffuse-type gastric carcinoma is characterized by rapid progression and poor prognosis. High expression of transforming growth factor (TGF)-beta and thick stromal fibrosis are observed in this type of gastric carcinoma. We have previously shown that disruption of TGF-beta signaling via introduction of a dominant negative form of the TGF-beta type II receptor (dnT beta RII) into diffuse-type gastric cancer cell lines, including OCUM-2MLN, caused accelerated tumor growth through induction of tumor angiogenesis in vivo. In the present study, we show that TGF-beta induces upregulation of expression of tissue inhibitor of metalloproteinase 2 (TIMP2) in the OCUM-2MLN cell line in vitro, and that expression of TIMP2 is repressed by dnT beta RII expression in vivo. Transplantation of the OCUM-2MLN cells to nude mice exhibited accelerated tumor growth in response to dnT beta RII expression, which was completely abolished when TIMP2 was coexpressed with dnT beta RII. Although the blood vessel density of TIMP2-expressing tumors was only slightly decreased, the degree of hypoxia in tumor tissues was significantly increased and pericytes covering tumor vasculature were decreased by TIMP2 expression in OCUM-2MLN cells, suggesting that the function of tumor vasculatures was repressed by TIMP2 and consequently tumor growth was reduced. These findings provide evidence that one of the mechanisms of the increase in angiogenesis in diffuse-type gastric carcinoma is the downregulation of the anti-angiogenic protein TIMP2. (Cancer Sci 2010; 101: 2398-2403).