Michael Klagsbrun has made major contributions to the field of growth factors and their receptors, particularly those that regulate the vascular system. He is credited with the first purifications of basic fibroblast growth factor (FGF-2), a potent angiogenesis factor, and of heparin-binding EGF-like growth factor (HB-EGF), a potent smooth muscle mitogen.
More recently, Dr. Klagsbrun's laboratory has purified vascular growth factor receptors. One of these, neuropilin, is a novel receptor for the angiogenesis factor, VEGF. Neuropilin was originally described as a receptor for semaphorin, a protein involved in regulating axon guidance. These studies have suggested that similar molecular mechanisms regulate angiogenesis and neuronal guidance, both of which are networking processes.
The Klagsbrun lab has demonstrated that Semaphorin 3F (SEMA3F) is a potent inhibitor of tumor angiogenesis, tumor progression and metastasis. The mechanism of SEMA3F inhibition involves rapid collapse of the F-actin cytoskeleton due to inactivation of RhoA, a small GTPase that regulates stress fiber formation. As a consequence of the cytoskeletal collapse, cell migration, a hallmark of tumor progression and metastasis, is inhibited.
Tumor-associated endothelial cells (EC) are the actual targets for anti-angiogenesis therapy. They were originally thought to be normal diploid cells. However, it is now apparent that EC are heterogeneous cell types with different functions in different organs. The Klagsbrun lab has isolated mouse EC from human tumor xenografts in mice. Unexpectedly, some tumor EC are cytogenetically abnormal and are more drug-resistant. In addition, tumor EC isolated from the TRAMP mouse model of prostate carcinoma are multi-potent and stem cell-like. They can differentiate into cartilage and bone and express EC cartilage and bone markers. In human patient samples, tumor EC are associated with calcification. Taken together, these results indicate that it may be more difficult to successfully target tumor blood vessels than originally thought.
About Michael Klagsbrun
Michael Klagsbrun received a Ph.D. in Biochemistry from the University of Wisconsin with research carried out at The Massachusetts Institute of Technology. He did his postdoctoral studies at the National Institutes of Health and was subsequently recruited to Boston Children's Hospital/Harvard Medical School. He has risen through the ranks and presently holds the Patricia K. Donahoe Chair in Surgery (Pathology). His research efforts have been rewarded by two nine-year MERIT Awards from the National Cancer Institute.
- Shing Y, Folkman J, Sullivan R, Butterfield C, Murray J, Klagsbrun M. Heparin affinity: Purification of a tumor-derived capillary endothelial cell growth factor. Science 1984; 223:1196-1299.
- Folkman J, Klagsbrun M. Angiogenic factors. Science 1987; 235:442-447.
- Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 1991; 64:841-848.
- Higashiyama S, Abraham JA, Miller J, Fiddes JC, Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science 1991; 251:936-939.
- Soker S, Takashima S, Miao H-Q, Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998; 92:735-745.
- Dudley AC, Khan ZA, Shih S-C, Kang S-Y, Zwaans BM, Klagsbrun M. Calcification of multipotent prostate tumor endothelium. Cancer Cell 2008; 14:201-211.