Research Abstract

Inflammatory processes in the tumor stroma are increasingly implicated in tumorigenesis and associated angiogenesis. While most effort to elucidate the mediators involved focus on cytokines, the role of non-proteinaceous autacoids have received little attention. We recently discovered that the eicosanoids such as epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid (AA), have potent tumor promoting activities. Overexpression of the CYP enzymes (which convert AA to EETs) or genetic abrogation of the enzyme sEH (which metabolizes EETs) were used to increase EET levels in transgenic mice. In both cases increased EETs dramatically stimulated angiogenesis, tumor growth, and metastasis. Consistently, reducing endogenous EETs using specific EET-antagonists or through endothelial-specific overexpression of sEH inhibited tumor growth. Thus, we hypothesize that EET in endothelium is a potent regulator of tumor growth and metastasis. Eicosanoids such as EETs may thus be a key paracrine mediator of the tumor promoting role of inflammation. The overall goal of the Panigrahy laboratory is thus is to elucidate the mechanisms by which eicosanoids such as EETs can stimulate tumor growth. Understanding the role of eicosanoids in tumorigenesis is of direct clinical relevance as the pharmacologically accessible autacoids system, such as EETs, may offer an entirely new system of targets for anti-stromal and anti-angiogenesis strategies in cancer therapy.