Molecular Angiogenic Signaling in Angiofibromas After Embolization

Abstract

To examine (1) the molecular angiogenic relationship between endothelial and stromal cells of angiofibromas and how this may elucidate the pathogenesis of angiofibromas and (2) the effects of embolization on the expression of angiotrophic factors and proapoptotic and antiapoptotic factors within the tumor. The expression of mesenchymal and endothelial stem/progenitor cell-associated proteins (MECAPs) such as proangiogenic cytokine vascular endothelial growth factor (VEGF), VEGF receptors (VEGFR1, VEGFR2, and VEGFR3), angiopoietin receptors (Tie-1 and Tie-2), and stem cell subset marker CD133 was assessed by immunohistological staining in 7 embolized angiofibroma specimens. Expression of proapoptotic Bax, antiapoptotic Bcl-2 and Bcl-xL, nuclear proliferation protein MiB-1, and hypoxia-inducible factor 1alpha (Hif-1alpha) in peri-ischemic areas of the embolized angiofibromas was also assessed. A single pediatric institution. Seven patients (identified from medical records, January 1, 2001, through December 31, 2005) who were diagnosed as having juvenile angiofibroma and who underwent surgical treatment. Archival tissues were retrieved for immunostaining. The immunostaining results were evaluated by microscopy and the staining intensities were also recorded. All angiofibroma specimens expressed the stem cell subset marker CD133 and MECAPs except VEGFR3 (a few cases). In the only case tested, we found evidence of VEGF-induced angiogenic signaling as the expression of phosphorylated VEGFR2 (Tyr951). Endothelial cells expressed VEGFR1 and VEGFR2 and angiopoietin receptors Tie-1 and Tie-2 but not VEGF. In contrast, VEGF was expressed within stromal cells. Viable tumor adjacent to the ischemic areas demonstrated increased staining intensities to VEGFR2, Tie-1, Tie-2 (all cases), and VEGFR3 (2 cases) and increased nuclear proliferation (5%-20%). All cases expressed proapoptotic and antiapoptotic factors, and the expression of Hif-1alpha was unaffected by ischemia. Stromal cells appear to be similar to mesenchymal stem cells with endothelial differentiation potential in umbilical cord blood cells. Stromal cells support endothelial growth by providing VEGF as a paracrine factor. Under ischemic stress, the embolized tumor tissues show upregulation of angiogenic receptors, retention of Hif-1alpha, and increased nuclear proliferation rates. Specific angiogenesis blockers may represent a novel treatment strategy for angiofibromas.