The bone marrow (BM) has been suggested to serve as a protective environment for disseminated breast cancer cells (BCCs). The precise molecular signals that circulating BCCs use to identify and adhere to BM vasculature are unknown, yet these interactions are essential for the development of bone metastases. To address this question, we used in vivo fluorescence microscopy to track the interactions of estrogen receptor (ER)+ and ER- BCC lines with bone in real time in an intracardiac injection xenograft mouse model. Our data show that circulating tumor cells enter the bone through unique vascular niches where endothelial cell expression of the adhesive molecule E-selectin and of the chemokine SDF-1 are both upregulated. These vascular niches are the same sinusoidal capillary beds that serve as the site of entry for peripherally circulating hematopoietic stem and progenitor cells (HSPCs) returning to the BM. Similar to HSPCs, BCCs aberrantly express the major cell surface molecules known to regulate hematopoietic cell entry and exit through the BM, including CXCR4 (SDF-1 receptor) and multiple E-selectin ligands. While neither CXCR4 blockade nor general chemokine signaling inhibition in BCCs prevented BM dissemination, E-selectin blockade by the specific glycomimetic antagonist GMI-1271 decreased BCC entry in the BM by approximately three fold at 2 and 24 hours after treatment. Moreover, in studies comparing FACS isolated stem and non-stem MCF-7 BCCs, GMI-1271 inhibition of E-selectin specifically targeted CD44+CD24- breast cancer stem cell homing. Non-stem CD44+CD24+ BCCs demonstrated significantly less BM homing compared to stem BCCs, and their BM trafficking was less E-selectin dependent. These data reveal for the first time a molecular mediator of bone metastases at the point-of-entry for BCCs in the BM. In addition, the ability of BCCs to hijack HSPC trafficking pathways to metastasize to bone correlates with E-selectin ligand expression and may be a specific characteristic of the BCC stem cell subpopulation.
Citation Format: Trevor Price, Monika Burness, Ayelet Sivan, Renee Cheng, John L. Magnani, Dorothy A. Sipkins. Breast cancer cells metastasize to bone through E-selectin+ vascular gateways. [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 4831. doi:10.1158/1538-7445.AM2014-4831