Biological and Biomedical Science
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Michael Klagsbrun

Department of Surgery and Pathology, Vascular Biology Program
Children's Hospital
Karp Building, Room 12.210
300 Longwood Ave.
Boston, MA 02115
Tel: (617) 919-2157
Fax: (617) 730-0233
Email: Michael.klagsbrun@childrens.harvard.edu
Web Page: The Klagsbrun Lab Page
5 postdoctoral fellows, 1 student

Our major interests are in vascular and tumor biology, in particular, the role of vascular growth stimulators and inhibitors and their receptors in developmental and tumor angiogenesis, and their contribution to tumor growth and metastasis.

Neuropilin and semaphorin activity in angiogenesis, cancer and axon guidance: Neuropilins (NRP1 and NRP2) are receptors both for members of the class-3 semaphorin (SEMAs) family of axon guidance mediators and for the vascular endothelial growth factor (VEGF) family of angiogenic factors. NRPs play a prominent role in neuronal wiring, normal blood vessel development, tumor angiogenesis and tumor growth. In neurons, SEMAs, NRPs and plexins form a complex leading to repulsion of axons and collapse of growth cones. In EC, VEGF binds NRP and VEGFR-2 to form a complex that enhances VEGF angiogenic activity. NRP knockouts in mice and knockdowns in zebrafish demonstrate that NRPs are necessary for angiogenesis. On the other hand, whereas VEGF165 promotes angiogenesis, SEMAs inhibit angiogenesis. In EC, a complex of SEMA, NRP and plexin repel blood vessels and collapse the F-actin cytoskeleton. Overexpression of SEMA3F in melanoma cells inhibits tumor angiogenesis and metastasis, suggesting that SEMA3F may be an angiogenesis and metastasis suppressor. SEMA3F and VEGF bind to the B-domain of NRPs. Exogenous B domain peptide blocks VEGF binding and inhibits tumor growth. In terms of mechanism, SEMA3F inactivates RhoA in both human EC and human glioma cells and, as a result, the F-actin cytoskeleton of these cells collapses, inhibiting migration and invasion. Current studies include analysis of NRP and SEMA3F structure, transcriptional regulation of SEMA3F and NRP2 gene expression and identification of signaling pathways. Furthermore, the potential of SEMA3F for blocking tumor angiogenesis and growth is being investigated in spontaneous mouse tumor models. 

Tumor endothelial cells:   Tumor-associated endothelial cells (EC) are the actual targets for antiangiogenesis therapy. They were originally thought to be normal diploid cells; yet these EC have not been fully characterized. It is now apparent that EC are heterogenous cell types with different functions in different organs. We have isolated mouse EC from human tumor xenografts in mice and have compared them to normal EC counterparts. Surprisingly, some tumor EC are cytogenetically abnormal, unlike normal EC, and are more drug resistant. In addition, tumor EC isolated from the TRAMP mouse model of prostate carcinoma are multi-potent. They can differentiate into cartilage and bone and express EC, cartilage and bone markers. In human patient samples, tumor EC are associated with calcification.

 

References:

  • Geretti E, Shimizu A, Kurschat P, Klagsbrun M. Site-directed mutagenesis in the B-neuropilin-2 domain selectively enhances its affinity to VEGF165, but not to SEMA3F. J Biol Chem 2007; 282:25698-25707.

  • Shimizu A, Mammoto A, Italiano Jr J, Pravda E, Dudley AC, Ingber DI, Klagsbrun M. ABL2/ARG tyrosine kinase mediates SEMA3F-induced RhoA inactivation and cytoskeleton collapse in human tumor cells. J Biol Chem 2008; 283:27230-8.

  • 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.