Antiangiogenesis in neurofibromatosis 1.
Antiangiogenesis therapy has become a potentially promising tool to inhibit tumor growth by targeting an essential yet untransformed tissue component. Identifying the factors involved and understanding the mechanisms required for tumor angiogenesis will facilitate efficient and specific targeting. In neurofibromas, tumor growth is facilitated by a genetically and cytologically diverse mixture of cell types, including Schwann cells, fibroblast, mast cells, and neurons where nf-/- Schwann cells are most likely the tumorigenic cell type. The matrix forming nf+/- cells may provide a permissive environment, facilitating tumor development, perhaps by providing landscaping factors such as the angiogenic molecules fibroblast growth factor-2, platelet-derived growth factor, endothelial growth factor, vascular endothelial growth factor, and midkine, which have been detected in neurofibromas. Systemic overexpression of specific factors such as midkine owing to loss of one nf allele might further lower the overall threshold for tumorigenesis and development of a tumor vasculature. Targeting these heparin-binding growth factors might inhibit not only angiogenesis but also proliferation of tumor cells because most of these factors also stimulate proliferation of neurofibroma-derived Schwann cells. We discuss the role of specific secreted molecules for angiogenesis in tumors of neurofibromatosis 1 and possible Approaches for their targeting. Furthermore, results are discussed that demonstrate the efficacy of antiangiogenesis targeting to inhibit growth of neurofibrosarcomas in experimental animal models.
Kurtz
Andreas
A
Department of Neurosurgery, Massachusets General Hospital, Harvard Medical School, Boston, USA. kurtza@helix.mgh.harvard.edu
Martuza
Robert L
RL
D000483:Alleles; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D002648:Child; D016207:Cytokines; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000078792:Midkine; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics; D017253:Neurofibromatoses / Q000188:drug therapy* / Q000235:genetics; D025542:Neurofibromin 1 / Q000235:genetics
D020533:Angiogenesis Inhibitors; D002352:Carrier Proteins; D016207:Cytokines; D025542:Neurofibromin 1; D000078792:Midkine