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Blood, 15 February 2008, Vol. 111, No. 4, pp. 1755-1756. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Griffioen, A. W. Search for Related Content PubMed Articles by Griffioen, A. W. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Dimberg et al, page 2015 New entry for angiostatic cancer treatment Arjan W. Griffioen MAASTRICHT UNIVERSITY SCHOOL FOR ONCOLOGY AND DEVELOPMENTAL BIOLOGY A member of the small heat shock protein family is found to regulate the formation of vasculature. A study by Dimberg and colleagues combines novel insights into the mechanisms of tumor angiogenesis with therapeutic opportunities for the treatment of cancer. In their study, Dimberg and colleagues present B-crystallin as a promoter of tumor angiogenesis, working through increasing endothelial-cell survival. An approach involving the proteomic screening of endothelial cells in a tubular morphogenesis assay led to the identification of this molecule, which was never before found to be involved in vessel formation or angiogenesis. B-crystallin is up-regulated during tube formation of cultured endothelial cells in a 3-dimensional sprouting assay. Besides enhanced expression, there is also activation of the molecule through phosphorylation during tube formation. siRNA knock-down experiments proved the specific role of B-crystallin in tube formation through enhanced cleavage of caspase-3, leading to induction of apoptosis. B-crystallin was shown to be overexpressed in a subset of blood vessels in human tumors, and knock-out mice were shown to have reduced angiogenesis and impaired function of the endothelium. The identification of specific markers of tumor endothelium is an important field of research that may reveal novel therapeutic targets based on angiogenesis inhibition. The neutralization of a central angiogenic factor, vascular endothelial growth factor (VEGF), has been shown to prolong the life expectancy of patients with colon, breast, and lung cancer. Although this approach has demonstrated proof-of-concept for clinical application of antiangiogenesis compounds, targeting VEGF is a way of treating the tumor cells, which may be difficult due to different means of resistance that can be acquired by virtue of the plasticity of those cells.1,2 A better strategy for angiogenesis inhibition is therefore the direct targeting of (pivotal determinants of the biology of) endothelial cells, leading to growth inhibition or cell death without tumor-cell interference. Such an approach would take advantage of the inherent attraction of angiogenesis inhibition—that is, that the endothelial-cell compartment is genetically stable and therefore unlikely to mutate into drug resistant variants, and thus could be a superior target compared with the tumor cell. The identification of B-crystallin as a target for therapy may provide a tool for directly targeting the tumor endothelium. The proteomic screen as performed by Dimberg and coworkers, as well as previously published genomic screenings of tumor endothelium,3,4 may help pinpoint even more markers for direct targeting of tumor endothelium. It is interesting to note that B-crystallin is also overexpressed in other cells that are under continuous stress. This includes the tumor cells, in which the molecule was earlier described as a novel oncogene and, when present in human tumors, a predictor of poor survival. The dual targeting of endothelium and tumor cells is an attractive approach that may be possible with a single molecule that blocks B-crystallin. The present challenge is to develop small-molecule, peptide, or antibody-based B-crystallin blocking compounds and test them in animal models of cancer. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Griffioen AW. Therapeutic approaches of angiogenesis inhibition: are we tackling the problem at the right level? Trends Cardiovasc Med 2007; 17:171–176.[CrossRef][Medline] [Order article via Infotrieve] Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005; 438:932–936.[CrossRef][Medline] [Order article via Infotrieve] St Croix B, Rago C, Velculescu V, et al. Genes expressed in human tumor endothelium. Science 2000; 289:1197–1202.[Abstract/Free Full Text] van Beijnum J, Dings RP, van der Linden E, et al. Gene expression of tumor angiogenesis dissected; specific targeting of colon cancer angiogenic vasculature. Blood 2006; 108:2339–2348.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: 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 Blood 2008 111: 2015-2023. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Griffioen, A. W. Search for Related Content PubMed Articles by Griffioen, A. W. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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