Small, microscopic, avascular and therefore asymptomatic tumors can remain in their dormant stage for a considerable period of time depending on numerous processes. One crucial mechanism underlying the transformation from a dormant to a fast-growing phenotype is the ability of tumor cells to induce angiogenesis, a phenomenon termed as the "angiogenic switch". We have identified and isolated a dormant tumor-generating clone, derived from the aggressive tumor-forming U-87 MG human glioblastoma cell line (1), using gene expression signature of dormant tumors (2). The two cell lines exhibit profound differences in their angiogenic potential and gene expression involved in angiogenesis regulation. One of the major dissimilarities was found in thrombospondin-1 (TSP-1) expression levels. The dormant avascular tumor-generating cell line (U-87-D) expresses significantly higher levels of TSP-1 compared to the fast-growing angiogenic tumor-generating parental cell line (U-87-F). It has been previously demonstrated that TSP-1 is a key endogenous angiogenesis inhibitor. Therefore, it has been established as an attractive potential therapy for angiogenesis-dependent diseases.
In this study, we evaluated the ability of TSP-1-peptidomimetic to regress the fast-growing angiogenic phenotype of U-87-F to the dormant avascular phenotype of U-87-D. Mice bearing established U-87-F tumors received daily treatment (50 mg/kg/day), by intra-peritoneal injection concomitantly by slow-release ALZET® osmotic pump (0.5 µl/h). TSP-1-peptidomimetic attenuated tumor progression in treated mice compared with control mice. Immunohistochemistry analysis of treated tumors revealed reduced abnormal vasculature, increased αSMA expression and decreased VEGF expression. We concluded that TSP-1-peptidomimetic in combination with chemotherapy may present a promising treatment for advanced glioblastoma.
