VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis.
In the RIP1-Tag2 mouse model of pancreatic islet carcinoma, angiogenesis is switched on in a discrete premalignant stage of tumor development, persisting thereafter. Signaling through VEGF receptor tyrosine kinases is a well-established component of angiogenic regulation. We show that five VEGF ligand genes are expressed in normal islets and throughout islet tumorigenesis. To begin dissecting their contributions, we produced an islet beta cell specific knockout of VEGF-A, resulting in islets with reduced vascularity but largely normal physiology. In RIP1-Tag2 mice wherein most oncogene-expressing cells had deleted the VEGF-A gene, both angiogenic switching and tumor growth were severely disrupted, as was the neovasculature. Thus, VEGF-A is crucial for angiogenesis in a prototypical model of carcinogenesis, whose loss is not readily compensated.
Inoue
Masahiro
M
Department of Biochemistry & Biophysics, Diabetes and Comprehensive Cancer Centers, University of California at San Francisco, San Francisco, CA 94143, USA.
Hager
Jeffrey H
JH
Ferrara
Napoleone
N
Gerber
Hans-Peter
HP
Hanahan
Douglas
D
D000818:Animals; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006801:Humans; D007515:Islets of Langerhans / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D020690:GTPase-Activating Proteins; D008222:Lymphokines; C490620:Ralbp1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors