3890

Pleomorphic Adenoma Gene 1 (PLAG1) is a proto-oncogene on human chromosome 8q12 whose oncogenic activation is a crucial event in the development of several human tumours, so far including pleomorphic adenoma of the salivary glands, lipoblastoma, hepatoblastoma, and AML. The oncogenic potential of PLAG1 has been confirmed in in vitro experiments. Furthermore, generation of conditional PLAG1 transgenic mouse strains revealed tumour development in a variety of targeted tissues, establishing the versatility of the PLAG1 oncogene. IGF-II and IGF-IR have been identified as key pathway elements in these tumors, similarly as in many human tumours. These observations point towards the possibility that the murine PLAG1-induced tumor model systems provide a window of opportunity for therapeutic intervention studies.

Here, we induced aP2-cre-mediated overexpression of the PLAG1 proto-oncogene in conditional PLAG1 transgenic mice. It has been reported that the aP2 promoter controls expression predominantly in adipose tissue. Surprisingly, aP2-cre-mediated activation of PLAG1 expression results in cavernous angiomatosis, preferably in the immediate surrounding of fat cells. Correspondingly, we were able to attenuate the cellular specificity of the aP2 promoter, used to target PLAG1 expression to adipogenic cells, by establishing aP2 expression in endothelial cells. Furthermore, we developed an in vitro model system that could form a basis for further standardized research of the impact of PLAG1 expression in adipogenic cells.

In light of these observations, the observed phenotype could be due, at least in part, by aP2-cre-mediated activation of PLAG1 expression in endothelial cells.However, since lesions always tend to occur in the immediate surrounding of fat cells and since PLAG1 increases the levels of Igf-2, which could impact Vegf levels, PLAG1 overexpression could lead to an increasingly favorable local environment for endothelial cell proliferation. Our biological model systems could eventually lead to more insight into the molecular pathogenesis of hemangiomas and, as such, could impact both the discovery of new diagnostics and therapeutics.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA