Our major interests are in vascular and tumor biology, in particular, the role of vascular growth factors 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. For example, 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 and are competitive inhibitors. Exogenous B domain blocks VEGF binding and has anti-tumor potential. 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 adhesions and migration. Current studies include analysis of NRP and SEMA3F structure, regulation, signaling and activity in vitro. Furthermore, the potential of SEMA3F for blocking tumor angiogenesis and growth is being investigated in mouse brain glioma 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.
EGF receptors (EGFR): EGF receptors, also known as ErbBs, are targets for the EGF family of growth and differentiation factors. ErbB1 and ErbB2 have been implicated as major contributors to breast and other cancers. Currently, drugs such as EGFR kinase inhibitors (EGFR KI) are used to target tumor cells. However, we have found that tumor EC, unlike normal EC, express ErbB1. Thus, EGFR (ErbB1) kinase inhibitors targeted not only tumor cells but blood vessels as well. These EC, when isolated, were unable to respond to EGF. However, blocking the EGF/EGFR pathway resulted in enhanced sensitivity to VEGFR-2 kinase inhibitors. Thus, targeting Erbs also targets VEGF and its receptors.
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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.
- Amin DN, Bielenberg DR, Lifshits E, Heymach JV, Klagsbrun M. Targeting EGFR activity in blood vessels is sufficient to inhibit tumor growth and is accompanied by an increase in VEGFR-2 dependence in tumor endothelial cells. Microvasc Res 2008; 76:15-22.
- 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; in press.
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