title: Tumor angiogenesis in the absence of fibronectin or its cognate integrin receptors.
abstract: Binding of α5β1 and αvβ3/β5 integrin receptors on the endothelium to their fibronectin substrate in the extracellular matrix has been targeted as a possible means of blocking tumor angiogenesis and tumor growth. However, clinical trials of blocking antibodies and peptides have been disappointing despite promising preclinical results, leading to questions about the mechanism of the inhibitors and the reasons for their failure. Here, using tissue-specific and inducible genetics to delete the α5 and αv receptors in the endothelium or their fibronectin substrate, either in the endothelium or globally, we show that both are dispensable for tumor growth, in transplanted tumors as well as spontaneous and angiogenesis-dependent RIP-Tag-driven pancreatic adenocarcinomas. In the nearly complete absence of fibronectin, no differences in vascular density or the deposition of basement membrane laminins, ColIV, Nid1, Nid2, or the TGFβ binding matrix proteins, fibrillin-1 and -2, could be observed. Our results reveal that fibronectin and the endothelial fibronectin receptor subunits, α5 and αv, are dispensable for tumor angiogenesis, suggesting that the inhibition of angiogenesis induced by antibodies or small molecules may occur through a dominant negative effect, rather than a simple functional block.
authors: Howard Hughes Medical Institute, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States of America.
authors: Patrick A
authors: PA
authors: Murphy
authors: Howard Hughes Medical Institute, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States of America.
authors: Shahinoor
authors: S
authors: Begum
authors: Howard Hughes Medical Institute, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States of America.
authors: Richard O
authors: RO
authors: Hynes
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D004727:Endothelium / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D000071838:Fibrillin-1; D000071837:Fibrillins; D005353:Fibronectins / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054392:Adipokines
chemical_list: D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D000071838:Fibrillin-1; D000071837:Fibrillins; D005353:Fibronectins; D039081:Integrin alpha5beta1; D016023:Integrins; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C112846:Nid2 protein, mouse; C029967:nidogen