Abstract PR06: Formation of lymph node metastases is not angiogenesis dependent

Abstract

Abstract Background: To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting. The presence of lymph node metastases dictate treatment decisions, however their reliance on angiogenesis for growth has not been described. Furthermore, recent data show that radiation and chemotherapy can treat limited lymph node disease in breast cancer patients with equal efficacy to complete lymph node dissection. This has led to a reduction in the use of complete lymph node dissection as the primary treatment option in these patients. Thus, greater numbers of patients will have cancer in lymph nodes after surgery that requires adjuvant therapy. Methods: Here, we developed a novel chronic lymph node window (CLNW) model to longitudinally image the growth and spread of lymph node metastases using intravital optical microscopy techniques. We use the CLNW in multiple models of spontaneous lymphatic metastases in mice to study the vasculature of metastatic lymph nodes. We further test our results in murine and patient samples using molecular and biochemical methods. Finally, we test the ability of antiangiogenic therapy to inhibit metastatic growth in the CLNW. Results: We reveal the surprising lack of sprouting angiogenesis during metastatic growth in lymph nodes using both intravital microscopy and ex vivo methods. Vascular endothelial growth factor was not produced by the metastatic lesion despite the presence of hypoxia in some lesions. Treatment with two different antiangiogenic therapies showed no effect on the growth or vascular density of lymph node metastases in our models. We confirmed these findings in clinical specimens, including the lack of reduction in blood vessel density in lymph node metastases in patients treated with bevacizumab. Conclusion: We provide pre-clinical and clinical evidence that sprouting angiogenesis does not occur during the growth of lymph node metastases, which reveals a mechanism of treatment resistance to antiangiogenic therapy in adjuvant settings. The targets of clinically approved angiogenesis inhibitors are not active during early cancer progression in the lymph node, suggesting that inhibitors of sprouting angiogenesis as a class will not be effective in treating lymph node metastases. Based on longitudinal intravital imaging, it appears that metastatic cancer cells in the lymph node invade the lymph node parenchyma where the native blood vessels reside in order to secure a supply of oxygen and nutrients for the survival and growth of the metastatic lesion. Citation Format: Dennis Jones, Han-sin Jeong, Shan Liao, Timothy P. Padera. Formation of lymph node metastases is not angiogenesis dependent. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr PR06.