Transgenic expression of VEGF in intestinal epithelium drives mesenchymal cell interactions and epithelial neoplasia.
OBJECTIVE
Vascular endothelial growth factor (VEGF) is expressed robustly in human colon neoplasia and is a major new "rational" target of therapy for cancers of the colon and other organs. Nonetheless, the mechanism(s) of action of VEGF-targeted therapies and the biologic roles of VEGF in tumorigenesis have not been well defined. We used a transgenic approach to directly test the hypothesis that augmented VEGF expression can drive progression of intestinal neoplasia.


METHODS
Transgenic mouse lines were generated with moderate (vilVEGF1) and high (vilVEGF2) VEGF expression from the intestinal epithelium. vilVEGF1 mice were bred to Min mice (adenomatous polyposis coli [APC] +/-). Colon epithelial cells from an APC patient were cocultured with endothelial cells and fibroblasts.


RESULTS
vilVEGF mice were generally healthy but displayed red small intestines. Vessels were larger and more numerous in the submucosa but not the mucosa. The mucosa showed striking stromal and epithelial hypercellularity, with increased epithelial proliferation. Many crypts formed cysts composed of relatively undifferentiated epithelial cells surrounded by cells with endothelial and myofibroblast markers. Compared with Min controls, vilVEGF1-Min mice developed 6-fold more intestinal adenomas of all sizes, with more advanced histologic features. Polycystic masses were also observed. Coculture of human colonocytes with endothelial cells and fibroblasts directly stimulated colonocyte proliferation.


CONCLUSIONS
Augmented VEGF expression from intestinal epithelium potently stimulated cross talk with mesenchymal cells and proliferation of normal and neoplastic epithelium. These effects of VEGF, largely occurring prior to the canonical angiogenic switch in tumors, may be in part independent of angiogenesis.
Boquoi
Amelie
A
Department of Medicine, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Jover
Rodrigo
R
Chen
Tina
T
Pennings
Marieke
M
Enders
Greg H
GH
D011125:Adenomatous Polyposis Coli / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003106:Colon / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D007414:Intestinal Neoplasms / Q000378:metabolism* / Q000473:pathology; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D042461:Vascular Endothelial Growth Factor A