The angiogenic factor midkine is aberrantly expressed in NF1-deficient Schwann cells and is a mitogen for neurofibroma-derived cells

Loss of the tumor suppressor gene NF1 in neurofibromatosis type 1 (NF1) con tributes to the development of a variety of tumors, including malignant per ipheral nerve sheath tumors (MPNST) and benign neurofibromas, Of the differ ent cell types found in neurofibromas, Schwann cells usually provide betwee n 40 and 80%, and are thought to be critical for tumor growth. Here we desc ribe the identification of growth factors that are upregulated in NF1-/- mo use Schwann cells and are potential regulators of angiogenesis and cell gro wth. Basic fibroblast growth factor (FGF-2), platelet-derived growth factor (PDGF) and midkine (MK) were found to be induced by loss of neurofibromin and MK was further characterized. MK was induced in human neurofibromas, sc hwannomas, and various nervous system tumors associated with NF1 or NF2; mi dkine showed an expression pattern overlapping but distinct from its homolo g pleiotrophin (PTN), Immunohistochemistry revealed expression of MK in S-1 00 positive Schwann cells of dermal and plexiform neurofibromas, and in end othelial cells of tumor blood vessels, but not in normal blood vessels, Fur thermore, MK demonstrated potent mitogenic activity for human systemic and brain endothelial cells in vitro and stimulated proliferation and soft agar colony formation of human MPNST derived S100 positive cells and fibroblast oid cells derived from an NF1 neurofibroma, The data support a possible cen tral role for MK as a mediator of angiogenesis and neurofibroma growth in N F1.