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

Departments of ¹ Medical Cell Biology and ² Genetics and Pathology, Uppsala University, Uppsala, Sweden; ³ Department of Biology, Masaryk University, Brno, Czech Republic; ⁴ Department of Pathology, School of Stomatology, JiLin University, China; ⁵ Department of Medical Genetics, Charles University, Prague, Czech Republic; and ⁶ Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Requests for reprints: Michael Welsh, Department of Medical Cell Biology, Uppsala University, Box 571, Husargatan 3, 75123, Uppsala, Sweden. Phone: 46-184714447; Fax: 46-184714059; E-mail: Michael.welsh{at}mcb.uu.se.

Key Words: Shb • VEGFR-2 • angiogenesis • knockout • microvasculature • vascular permeability • 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 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. [Cancer Res 2009;69(5):2141–8]

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