Angiogenesis is imperative for growth of solid tumors. Recent studies on breast cancer have demonstrated a correlation between high intratumoral microvessel count and poor prognosis. Our research efforts are presently focusing on neovascularization in human breast cancer. We are examining if the tissue inhibitor of metalloproteinases-1 (TIMP-1) plays a role in tumor progression and neovascularization of breast cancer. The studies have focused on the following questions: a) what is the mechanism involved in the angiogenesis inhibitory activity of TIMP- 1?; b) is TIMP-1 expressed in human breast cancer?; c) does TIMP-1 overexpression in breast cancer cell lines influence the production of angiogenic factors? In addressing these questions, the following results have been obtained: 1) a 66 kDa form of recombinant TIMP-1 (rTIMP-1) which did not exhibit any metalloproteinase inhibitory activity, blocked completely angiogenesis in vitro; 2) altered morphology and induction of the transforming growth factor ` (TGF`) was observed in a breast carcinoma cell line, following transfection with TIMP-1; 3) TIMP-1 RNA expression was significantly higher in human breast carcinomas than the matching adjacent nonneoplastic tissues. The highest levels of TIMP-1 transcripts were found at the tumor-stromal interface and around tumor blood vessels. The above findings further support emerging evidence that TIMP-1 has a broader function in tumor biology than being a regulator of metalloproteinase activity. The synthetic flavonoid, flavone acetic acid (FAA) has been shown to mediate vascular collapse of solid tumors in rodents. We have initiated studies in an attempt to understand the mechanism responsible for the FAA-mediated targeting of tumor vasculature. In culture, FAA inhibited completely proliferation of large vessel EC at 250 microg/ml and microvascular EC at 100 microg/ml in the absence of cytotoxicity. FAA also inhibited in vivo angiogenesis and in vitro angiogenesis. These findings suggest that the antitumor activity of FAA may, at least in part, be through its angiogenic inhibitor properties.
