Michael Klagsbrun
Department of Surgery and Pathology, Vascular Biology Program
Karp Family Research Laboratories, Room 12.210
300 Longwood Ave
Boston, MA 02115
Tel: 617-919-2157
Fax: 617-730-0233
Email: michael.klagsbrun@childrens.harvard.edu
Visit my lab page here.
Our laboratory studies the role of vascular growth factors and their receptors in developmental and tumor angiogenesis, with emphasis on their contribution to, and inhibition of, tumor growth and metastasis.
Novel inhibitors of tumor angiogenesis, progression and metastasis. Neuropilins (NRP1 and NRP2) are receptors both for members of the class-3 semaphorin (SEMA) family of axon guidance mediators and for the vascular endothelial growth factor (VEGF) family of angiogenic factors. NRP knockouts in mice and NRP knockdowns in zebrafish demonstrate that NRP expression regulates angiogenesis. Overexpression of SEMA3F in melanoma cells inhibits tumor angiogenesis and metastasis. SEMA3F acts by inactivating RhoA in both human endothelial and tumor cells, and, as a result, the F-actin cytoskeleton of these cells collapses, inhibiting their migration and invasion. SEMA3F expression is regulated by bHLH transcription factors. E47 enhances SEMA3F expression, whereas Id2, a dominant negative of E47, inhibits SEMA3F. Another angiogenesis inhibitor is the B-domain of NRP, which is the VEGF binding site. Exogenous B-domain peptide, a VEGF trap, blocks VEGF binding and inhibits tumor growth. Current studies are focused on using these novel angiogenesis inhibitors, SEMA3F and NRP B-domain, to control brain gliomas and prostate carcinomas. In addition, the vascular and tumor activities of other guidance factors, such as Netrin-1, are being investigated. Tumor-associated endothelial cells (EC) are the actual targets for antiangiogenesis drugs but have not been that well characterized. Tumor EC (TEC) were originally thought to be normal diploid cells; however, we have isolated TEC that are aneuploid and more drug resistant, unlike normal EC (NEC). In addition, TEC isolated from the TRAMP mouse model of spontaneous prostate carcinoma are multi-potent. They can differentiate into cartilage and bone and express EC, cartilage and bone markers. Thus, TEC may be stem cell-like and, accordingly, difficult to target.
References:
Dudley AC, Khan ZA, Shih S-C, Kang S-Y, Zwaans BM, Klagsbrun M. Prostate tumor-derived endothelial cells are multi-potent and can differentiate into cartilage and bone. Cancer Cell 2008; 14:201-211.
Geretti E, van Meeteren LA, Shimizu A, Dudley AC, Claesson-Welsh L, Klagsbrun M. A mutated soluble neuropilin-2 B domain antagonizes vascular endothelial growth factor bioactivity and inhibits tumor progression. Mol Cancer Res 2010; 8:1063-1073.
Coma S, Amin DN, Shimizu A, Lasorella A, Iavarone A, Klagsbrun M. Id2 promotes tumor cell migration and invasion through transcriptional repression of Semaphorin 3F. Cancer Res 2010; 70:3823-32.
For a complete listing of publications click here.
Last Update: 8/7/2012