EXPRESSION OF VASCULAR-PERMEABILITY FACTOR (VASCULAR ENDOTHELIAL GROWTH-FACTOR) AND ITS RECEPTORS IN ADENOCARCINOMAS OF THE GASTROINTESTINAL-TRACT

Vascular permeability factor (VPF) is one of the most potent known ind ucers of microvascular hyperpermeability; in addition, it is a selecti ve endothelial cell growth factor, hence its alternate name, vascular endothelial growth factor. VPF exerts its actions on the microvasculat ure by interacting with specific endothelial cell receptors. VPF is ex pressed by many transplantable animal tumors, by tumor cell lines in c ulture, and by certain normal cells in situ. The purpose of the presen t investigation was to determine whether and with what consistency VPF and its endothelial cell receptors are expressed in primary autochtho nous human tumors of gastrointestinal tract origin, as determined by i n situ hybridization and immunohistochemistry. Twenty-one primary aden ocarcinomas (17 colon, 2 stomach, 1 small bowel, and 1 pancreas) were studied. The malignant epithelial cells expressed VPF mRNA strongly, i n contrast to normal epithelium, hyperplastic polyps, and adenomas, wh ich expressed little or no VPF mRNA. VPF expression was further increa sed in tumor cells immediately adjacent to zones of tumor necrosis; in such areas, occasional stromal cells also expressed VPF mRNA. tn the ten colon carcinomas studied, tumor cells stained for VPF protein by i mmunohistochemistry. The endothelial cells of nearby stromal blood ves sels also stained for VPF by immunohistochemistry and in addition expr essed mRNAs encoding the VPF receptors flt-1 and kdr as determined by in situ hybridization. Endothelial cells away from the tumor did not s tain for VPF and no definite mRNA expression for flt-1 or kdr was dete cted by in situ hybridization. The ganglion cells of the myenteric ple xus of normal bowel expressed VPF mRNA and protein. These data indicat e that primary autochthonous human tumors of gastrointestinal origin r egularly express both VPF mRNA and VPF protein and that adjacent strom al vessels express mRNAs for both known VPF receptors. VPF is likely t o contribute to tumor growth by promoting angiogenesis and stroma form ation, both directly through its action as an endothelial cell growth factor, and indirectly, by increasing vascular permeability, thereby l eading to plasma protein extravasation, fibrin deposition, and the eve ntual replacement of the resulting matrix with vascularized stroma.