Cancer Biology and Signal Transduction Differential Therapeutic Effects of Anti–VEGF-A Antibody in Different Tumor Models: Implications for Choosing Appropriate Tumor Models for Drug Testing

We previously reported that the host response to certain chemotherapies can induce primary tumor regrowth, angiogenesis, and even metastases in mice, but the possible impact of anti–VEGF-A therapy in this context has not been fully explored.We, therefore, used combinations of anti–VEGF-Awith chemotherapy on various tumor models in mice, including primary tumors, experimental lungmetastases, and spontaneous lung metastases of 4T1-breast and CT26-colon murine cancer cell lines. Our results show that a combined treatmentwith anti–VEGF-A and folinic acid/5-fluorouracil/oxaliplatin (FOLFOX) but notwith anti–VEGF-A and gemcitabine/cisplatinum (Gem/CDDP) enhances the treatment outcome partly due to reduced angiogenesis, in both primary tumors and experimental lungmetastasesmodels. However, neither treatment group exhibited an improved treatment outcome in the spontaneous lung metastases model, nor were changes in endothelial cell numbers found atmetastatic sites. As chemotherapy has recently been shown to induce tumor cell invasion, we tested the invasion properties of tumor cells when exposed to plasma from FOLFOX-treated mice or patientswith cancer.While plasma fromFOLFOX-treatedmice or patients induced invasionproperties of tumor cells, the combination of anti–VEGF-A and FOLFOX abrogated these effects, despite the reduced plasma VEGF-A levels detected in FOLFOX-treated mice. These results suggest that the therapeutic impact of antiangiogenic drugs varies in different tumor models, and that anti–VEGF-A therapy can block the invasion properties of tumor cells in response to chemotherapy. These results may implicate an additional therapeutic role for anti–VEGF-A when combined with chemotherapy. Mol Cancer Ther; 13(1); 1–12. 2013 AACR.