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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2015-2023.
Prepublished online as a Blood First Edition Paper on December 6, 2007; DOI 10.1182/blood-2007-04-087841.
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Submitted April 30, 2007
Accepted November 24, 2007
 B-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis
Anna Dimberg*, Svetlana Rylova, Lothar C Dieterich, Anna-Karin Olsson, Petter Schiller, Charlotte Wikner, Svante Bohman, Johan Botling, Agneta Lukinius, Eric F Wawrousek, and Lena Claesson-Welsh
Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
National Eye Institute, National Institutes of Health, Bethesda, MD, United States
* Corresponding author; email: anna.dimberg{at}genpat.uu.se.
Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in anti-angiogenic tumor therapy. The molecular chaperone  B-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation and subcellular localization, during tubular morphogenesis of endothelial cells. SiRNA-mediated knock-down of B-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of pro-apoptotic caspase-3 and increased apoptosis. B-crystallin was expressed in a subset of human tumor vessels, but not in normal capillaries. Tumors grown in B-crystallin -/- mice were significantly less vascularized than wild-type tumors, and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in B-crystallin -/- mice were leaky and showed signs of caspase-3 activation, and extensive apoptosis. Ultra-structural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate B-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of angiogenic modulators.
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