Involvement of the Syk-mTOR Pathway in Follicular Lymphoma Cell Invasion and Angiogenesis,

Abstract 3656

Follicular lymphoma is the second most common non-Hodgkin's lymphoma. The disease affects the lymph nodes and 50% of patients present with bone marrow infiltration, however the mechanisms involved in dissemination of the disease are not yet known. We previously reported that follicular lymphoma cells display an over-expression of Syk, a tyrosine kinase involved in many cellular processes including cell migration. Therefore we sought to explore its role in the invasive process. Here we show that follicular lymphoma patients display higher MMP-9 and VEGF levels than healthy donors. Moreover, using Syk siRNA and the Syk inhibitor R406, we demonstrate that, in follicular lymphoma cells, Syk is involved in the regulation of MMP-9 and VEGF expression, and that invasion and angiogenesis is mediated through a PI3K-mTOR module. Finally, using a follicular lymphoma xenograft mouse model we observe that R406, the active metabolite of fostamatinib (R788), inhibits MMP-9 expression and angiogenesis in vivo. Altogether, this study provides strong evidence that Syk represents an encouraging therapeutic target in follicular lymphoma and suggests the potential use of fostamatinib as an anti-invasive and anti-angiogenic drug.