Inhibition by lenalidomide of growth factor and hypoxia-induced signaling in endothelial and epithelial tumor cells, and effects within the tumor cell microenvironment

Abstract

e14620 Background: Lenalidomide, an immunomodulatory and anti-angiogenic agent, has activity in many hematological malignancies. It has direct anti-proliferative activity in hematological cells but there is no evidence of direct activity in solid tumor cells. In solid tumors, lenalidomide is being advanced in combination with other agents to take advantage of its immune-enhancing properties in combination with direct anti-tumor agents. Lenalidomide studies in CLL and MM suggest that it may also attenuate pro-survival signals generated by interaction of stroma with the malignant cell itself. Lysophosphatidic acid (LPA) is a key pro-survival factor present at high levels within the ascites of ovarian cancer patients which confers increased tumor invasiveness and reduced survival. Hypoxia-induced factor (HIF)-1α is the key initiator of angiogenesis and tumor invasiveness. Methods: The effect of lenalidomide on growth factor-induced Akt phosphorylation was investigated in endothelial cells, NHL cells, and ovarian cancer cells in vitro. Ovarian cancer cell lines SKOV-3 and OVCAR-3 were treated with LPA and the effect of lenalidomide on invasiveness via enhanced p-Akt was investigated. The effect of lenalidomide on HIF-1α expression by endothelial cells and epithelial cells was also investigated. Results: Lenalidomide inhibited growth factor-induced Akt phosphorylation. Treatment of ovarian tumor cells with LPA increased tumor cell invasiveness via enhanced p-Akt. Lenalidomide strongly inhibited invasion and p-Akt (at S308 but not T473) in a dose-dependent manner. Hypoxic endothelial cells and epithelial tumor cells showed enhanced HIF-1α expression. Lenalidomide inhibited hypoxia-induced HIF-1α expression by endothelial cells and by epithelial tumor cells, including prostate, breast, pancreatic, renal and ovarian tumor cells. Conclusions: Lenalidomide may act within the tumor microenvironment to inhibit key signals of tumor cells survival, growth, and invasiveness. These studies support the potential utility of lenalidomide in combination with other agents in the treatment of patients with solid tumors. [Table: see text]