New entry for angiostatic cancer treatment

In their study, Dimberg and colleagues present αB-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. αB-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 αB-crystallin in tube formation through enhanced cleavage of caspase-3, leading to induction of apoptosis. αB-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 αB-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 αB-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 αB-crystallin. The present challenge is to develop small-molecule, peptide, or antibody-based αB-crystallin blocking compounds and test them in animal models of cancer.