Endostatin from tumor cells contributes to low-dose paclitaxel-mediated tumor growth suppression via HIF-1 α -dependent mechanism.

Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006 A111 Progression of cancer is dependent on neoangiogenesis. Antiangiogenic (metronomic or low-dose) chemotherapy is a strategy for optimizing the effects of chemotherapeutics by administrating traditional cytotoxic drugs at lower concentration without rest period. We and others have shown that an endogenous angiogenesis inhibitor, thrombospondin-1 (TSP-1), contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis in the tumor microenvironment. Here, we investigate whether endogenous endostatin is involved in the antiangiogenic chemotherapy. Tumor cells (Lewis lung carcinoma (LLC) cells) treated with low-dose paclitaxel demonstrate the elevated expression of endostatin by 31% (p<0.01) with the minimal effect on endothelial cells and fibroblasts. Low-dose paclitaxel predominantly induces the expression of endostatin in the mice transplanted LLC cells. In contrast, the expression of sFlt-1, TSP-1 and tumstatin is not increased. Low-dose paclitaxel treatment reduces the mean tumor volume and blood vessel density by 33% (p=0.04) and by 49% (p<0.01), respectively. Lack of endostatin in B16F10 cells and the host leads to diminished capacity of low-dose paclitaxel to suppress tumor growth. Hypoxia blocks the elevated expression of endostatin / type XVIII collagen in LLC cells after the paclitaxel treatment, whereas the disruption of HIF-1 α increases their expression, suggesting endostatin is the predominant endogenous inhibitor of angiogenesis produced by some tumor cells, after the paclitaxel treatment via HIF-1 α -dependent mechanism. This study demonstrates that endostatin may be a key mediator of antiangiogenic effects observed with low-dose paclitaxel treatment and long-term anti-cancer therapy before tumors become symptomatic.