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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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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
 B-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis
Anna Dimberg1,
Svetlana Rylova1,
Lothar C. Dieterich1,
Anna-Karin Olsson1,
Petter Schiller1,
Charlotte Wikner1,
Svante Bohman1,
Johan Botling1,
Agneta Lukinius1,
Eric F. Wawrousek2, and
Lena Claesson-Welsh1
1 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; and
2 National Eye Institute, National Institutes of Health, Bethesda, MD
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 antiangiogenic 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. Small interfering RNA–mediated knockdown of B-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic 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. Ultrastructural 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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