Abstract Although tumor cell dissemination via the lymphatic vasculature is thought to be a common pathway of metastasis for solid human cancers, the mechanisms of lymphatic mediated metastasis remain poorly understood1. For breast cancer patients, lymph node involvement remains a very important indicator of patient prognosis and is utilized clinically for therapeutic choices2,3. A recent study has shown that the incidence of being diagnosed with stage IV breast cancer, i.e. breast cancer that has spread outside the breast, is increasing in young women4. Furthermore, young women diagnosed with breast cancer within 5 years postpartum are ∼3 times as likely to have metastatic disease5-7. Given that 35-45% of young women's breast cancers are likely to be postpartum8, i.e. diagnosed within 5 years of giving birth, we predict that postpartum breast cancers may be partially driving the observed increase in metastasis of young women's breast cancer. Recently, we have shown that postpartum breast cancer patients have increased tumor associated lymphatic vessel density and increased incidence of lymph node metastasis9. We hypothesized that postpartum tumors promote lymphangiogenesis, which leads to breast tumor metastasis. To test this hypothesis we utilized xenograft and isograft mouse models of postpartum breast cancer, which show increased metastasis in postpartum animals10,11. We utilized these rodent models, along with human breast tissues, to investigate lymphangiogenesis and lymph vessel invasion in the postpartum period. We showed that 1) lymphangiogenesis is enhanced in the postpartum period, 2) that postpartum tumors display increased lymphatic vessel density and lymphatic vessel invasion in the tumor periphery, and 3) that postpartum tumor cells from our rodent models promote lymphangiogenesis via secretion of PGE2 ex vivo9. Recently, we extended our observations to show that lymphatic vessels in breast tissues from postpartum women are more dilated, and in rodent models more leaky, suggesting the lymphatics as a favorable route for breast tumor metastasis in the postpartum period. To test this, we orthotopically injected tumor cells into postpartum mice, or nulliparous controls, and harvested distant lymph nodes at 4 and 6 days post-injection. We observed evidence for tumor cells in distant lymph nodes at higher frequency in the postpartum group at days 4 and 6 compared to the nulliparous controls. Furthermore, in postpartum rodents we also observed increased lymph node size and lymph node vessel density suggesting that expansion of the lymphatic vasculature in postpartum mice may be systemic. Importantly, we have shown that both normal and tumor associated mammary lymphangiogenesis in vivo are dependent upon COX-2 and that COX-2 inhibitors can block metastasis of postpartum tumors in our rodent models. Thus, we are also investigating COX-2 dependent mechanisms that result in alteration of mammary lymphatics and overall lymph node biology. Overall, our results suggest that COX-2 inhibitor, or NSAID, use may reduce lymphogenous tumor cell spread in postpartum women. 1. Stacker, S.A., Baldwin, M.E. & Achen, M.G. The role of tumor lymphangiogenesis in metastatic spread. Faseb J 16, 922-934 (2002). 2. Alitalo, K. & Carmeliet, P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1, 219-227 (2002). 3. Pepper, M.S., Tille, J.C., Nisato, R. & Skobe, M. Lymphangiogenesis and tumor metastasis. Cell Tissue Res 314, 167-177 (2003). 4. Johnson, R.H., Chien, F.L. & Bleyer, A. Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009. Jama 309, 800-805 (2013). 5. Callihan, E.B., et al. Postpartum diagnosis demonstrates a high risk for metastasis and merits an expanded definition of pregnancy-associated breast cancer. Breast Cancer Res Treat (2013). 6. Johansson, A.L., Andersson, T.M., Hsieh, C.C., Cnattingius, S. & Lambe, M. Increased Mortality in Women with Breast Cancer Detected during Pregnancy and Different Periods Postpartum. Cancer Epidemiol Biomarkers Prev 20, 1865-1872 (2011). 7. Stensheim, H., Moller, B., van Dijk, T. & Fossa, S.D. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol 27, 45-51 (2009). 8. Schedin, P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer 6, 281-291 (2006). 9. Lyons, T.R., et al. Cyclooxygenase-2-dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer. The Journal of clinical investigation 124, 3901-3912 (2014). 10. McDaniel, S.M., et al. Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. Am J Pathol 168, 608-620 (2006). 11. Lyons, T.R., et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med 17, 1109-1115 (2011). Citation Format: Sarah Black, Virginia F. Borges, Pepper Schedin, Traci R. Lyons. Lymphangiogenesis drives breast tumor cell spread in postpartum women and in models of postpartum breast cancer. [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 A08.
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