Abstract 4043: Prevention of breast cancer lung metastasis via the blockade of the adhesion cascade

Abstract

Abstract Organ metastasis is a major cause of mortality from breast cancer. In particular, the lung and pleura are common metastatic sites. It occurs when cancer cells escape from the primary tumor, adhere to blood vessels, and extravasate through the vascular endothelium of distant target organs, where they can establish a secondary tumor. Therefore, the vascular endothelium is the crucial gateway for disseminated cancer cells to enter the target organ, and this process is governed by the adhesion cascade. E-selectin (or CD62E, ELAM-1 or LECAM-2) is the initiator of the vascular adhesion cascade. The physical interaction of E-selectin with its ligand present on the disseminated cancer cells (CD44, sLeX, sLeA) results in a rolling adhesion of the circulating cells to firm adhesion to the vascular endothelium. Therefore, the adhesion cascade may represent an excellent therapeutic target for the blockade of metastasis. In this study, we aimed to dissect the mechanism of cancer cell adhesion to the endothelium and develop a new therapeutic strategy to block the adhesion cascade by using an antagonistic aptamer against E-selectin (ESTA) for the inhibition of lung metastasis development. First, to understand the mechanism underlying E-selectin-mediated vascular adhesion, we examined the adhesion of four different breast cancer cell lines to E-selectin expressing endothelial cells. E-selectin expression on endothelial cells enhanced the adhesion and transendothelial migration of two basal like ER-/PR-/Her2-/CD44high breast cancer cell lines (MDA-MB-231 and MDA-MB-468), whereas this effect was not observed in two luminal like ER+/PR+/Her2+/CD44-/low breast cancer cell lines (MCF-7 and T-47D). To further confirm the role of CD44 on the cancer cell adhesion, three independent assays were performed. We showed that 1) CD44 isolated from breast cancer cells physically binds to E-selectin, 2) E-selectin antagonists (monoclonal antibody or ESTA) reduces the adhesion of CD44high breast cancer cells to the E-selectin-expressing endothelial cells, and 3) a CD44 blocking antibody and shRNA against CD44 inhibit the adhesion of the cells to E-selectin-expressing endothelial cells. These data suggest that E-selectin preferentially permits the adhesion of CD44high breast cancer cells. Finally, we demonstrated that a single intravenous administration of ESTA reduced the formation of lung metastases in two independent mouse models derived from CD44+ breast cancer cell lines (MDA-MB-231 and 4T-1) with no overt toxicity. The effect of ESTA, however, was minimal on lung metastasis formation of CD44 knocked-down cells. In summary, CD44 is a key mediator for E-selectin-mediated vascular adhesion. ESTA effectively inhibited the formation of lung metastases of CD44high breast cancer cells possibly due to the blockade of the adhesion cascade. This highlights a feasibility of targeting the adhesion cascade for the prevention of breast cancer lung metastasis. Citation Format: Shin-Ae Kang, Nafis Hasan, Stephen K. Suh, Hallgeir Rui, Takemi Tanaka. Prevention of breast cancer lung metastasis via the blockade of the adhesion cascade. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4043. doi:10.1158/1538-7445.AM2014-4043