Dysfunctional Microvasculature as a Consequence of Shb Gene Inactivation Causes Impaired Tumor Growth

Shb (Src homology 2 protein B) is an adapter protein downstream of the vascular endothelial growth factor receptor receptor-2 (VEGFR-2). Previous experiments have suggested a role for Shb in endothelial cell function. Recently, the Shb gene was inactivated and Shb null mice were obtained on a mixed...

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Published in:	Cancer research (Chicago, Ill.) Vol. 69; no. 5; pp. 2141 - 2148
Main Authors:	FUNA, Nina S, KRIZ, Vitezslav, GUANGXIANG ZANG, CALOUNOVA, Gabriela, AKERBLOM, Bjöm, MARES, Jaroslav, LARSSON, Erik, YING SUN, BETSHOLTZ, Christer, WELSH, Michael
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-03-2009
Subjects:	Animals Antigens, CD - analysis Antineoplastic agents Biological and medical sciences Cadherins - analysis Capillary Permeability Endothelial Cells - physiology Endothelial Cells - ultrastructure Liver - blood supply Liver - ultrastructure Medical sciences MEDICIN Medicin och hälsovetenskap MEDICINE Mice Mice, Inbred C57BL Myocardium - ultrastructure Neoplasms, Experimental - blood supply Neoplasms, Experimental - pathology Neoplasms, Experimental - therapy Pharmacology. Drug treatments Platelet Endothelial Cell Adhesion Molecule-1 - analysis Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - physiology Tumors Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor Receptor-2 - genetics Genetics Malignant tumor Tumor growth Gene Inactivation Cancer
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Summary:	Shb (Src homology 2 protein B) is an adapter protein downstream of the vascular endothelial growth factor receptor receptor-2 (VEGFR-2). Previous experiments have suggested a role for Shb in endothelial cell function. Recently, the Shb gene was inactivated and Shb null mice were obtained on a mixed genetic background, but not on C57Bl6 mice. The present study was performed to address endothelial function in the Shb knockout mouse and its relevance for tumor angiogenesis. Tumor growth was retarded in Shb mutant mice, and this correlated with decreased angiogenesis both in tumors and in Matrigel plugs. Shb null mice display an abnormal endothelial ultrastructure in liver sinusoids and heart capillaries with cytoplasmic extensions projecting toward the lumen. Shb null heart VE-cadherin staining was less distinct than that of control heart, exhibiting in the former case a wavy and punctuate pattern. Experiments on isolated endothelial cells suggest that these changes could partly reflect cytoskeletal abnormalities. Vascular permeability was increased in Shb null mice in heart, kidney, and skin, whereas VEGF-stimulated vascular permeability was reduced in Shb null mice. It is concluded that Shb plays an important role in maintaining a functional vasculature in adult mice, and that interference with Shb signaling may provide novel means to regulate tumor angiogenesis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-5472 1538-7445 1538-7445
DOI:	10.1158/0008-5472.CAN-08-3797