Abstract 5939: Dissemination of breast cancer

Abstract

Abstract Breast cancer is the second leading cause of death in US women. Despite advances in early detection, diagnosis and treatment of breast cancer, metastasis and tumor recurrence persist leading to continued morbidity and mortality. Several breast cancer studies have highlighted the role of cyclooxygenase-2 (COX-2) and its interaction with the tumor microenvironment (TME) in breast cancer progression. The TME consists of stromal cells that include fibroblasts, macrophages, the extracellular matrix (ECM), and several secreted factors that contribute to aggressiveness of the cancer and resistance to therapy. Increased density of collagen 1 (Col1) fibers, a major structural component of the ECM in solid tumors, and their alignment in tumors frequently result in increased invasion and metastasis of cancer cells. To understand the role of COX-2 at the lung metastatic site, and its relationship with Col1 fibers, COX-2 overexpressing triple negative SUM-149 human breast cancer cells (SUM-149-COX-2) or empty vector SUM-149 cells (EV) were injected through tail vein in SCID mice to compare Col1 fiber patterns in metastatic lesions. We isolated the lungs, processed the tissue, and imaged for Col1 fiber by second harmonic generation microscopy on H&E stained sections. The number of cancer associated fibroblasts (CAFs) were detected in adjacent sections by immunostaining for α-SMA. COX-2 overexpression did not increase the size of the cancer cell emboli in blood vessels or the size of pulmonary metastasis formed in the lungs. However, COX-2 overexpression did significantly increase the number of pulmonary metastases. Significantly higher Col1 fiber volume was observed in emboli compared to pulmonary metastases independent of COX-2 overexpression. Interestingly, the Col1 fibers were significantly more aligned in the COX-2 overexpressing pulmonary metastases compared to COX-2 overexpressing and EV emboli. The COX-2 overexpressing emboli had significantly higher amounts of CAFs detected by α-SMA expression compared to the EV emboli and the EV and COX-2 overexpressing pulmonary metastases. Pulmonary metastases from COX-2 overexpressing cells were detected further away from the nearest blood vessel compared to the metastases from EV cells suggesting that COX-2 may facilitate the formation of distant metastases. These data provide new insights into the role of COX-2, Col1 fibers, and CAFs in enabling emboli to extravasate to form pulmonary metastatic foci. These insights are important as COX-2 upregulation during treatment may potentiate metastasis. This work was supported by NIH R01 CA82337. Citation Format: Samata Kakkad, Mikayla Hanna, Desmond Jacob, Balaji Krishnamachary, Zaver M. Bhujwalla. Dissemination of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5939. doi:10.1158/1538-7445.AM2017-5939