Defining the Rules of Breast Cancer Cell Traffic Through Bone

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ABSTRACT The major cause of death from breast cancer is metastatic relapse, which most commonly occurs first in the bone. Bone marrow (BM) biopsies performed on women with early stage breast cancer have shown that small, clinically unapparent “micrometastases” are actually present at the time of diagnosis in many patients. These micrometastases can survive in the face of adjuvant chemotherapy and lay dormant for years before they become proliferative, causing overt metastatic disease. At this stage, disease becomes incurable. Our increasing understanding of breast cancer biology has revealed to us the importance of the host tissue in creating a receptive and protective environment for metastases. Preliminary data from our lab using mouse xenograft models show that breast cancer cells (BCCs) metastasize to and lay dormant in unique perivascular hematopoietic progenitor and stem cell (HSPC) niches. The blood vessels in these regions are distinguished by their sinusoidal morphology and their high basal expression of the adhesion molecule E- selectin, and the cytokine SDF-1. Using highly specific E-selectin and CXCR4 inhibitors, we have identified that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. While E-selectin interactions are critical for allowing BCC entry in BM, SDF-1/CXCR4 anchors BCCs to the microenvironment and its inhibition induces mobilization of dormant micrometastases into circulation. Moreover, our immunohistochemical studies of biopsies performed on patients with micrometastatic BM involvement show that dormant metastases reside adjacent to SDF-1+ vasculature. Based on these data, we hypothesize that dormant BCCs shelter within unique peri-sinusoidal vascular BM niches from which they are able to dynamically transit back-and-forth to the peripheral circulation as well as to alternative, pro-proliferative microenvironments within the bone. We also hypothesize that interventions such as CXCR4 and E-selectin inhibition can flush dormant BCCs from the protective sinusoidal niche, making them susceptible to cytotoxic or hormonal therapies. To test these hypotheses, we will use single cell resolution, video rate in vivo microscopy in mouse xenograft models to track BCC migration through BM in real time. In combination with in vitro molecular and cellular biology approaches, we will 1) Investigate the signals that critically regulate BCC metastatic entry in bone; 2) Study the molecular mechanisms that regulate BCC exit from bone metastatic sites into peripheral circulation and the impact of mobilization on BCC signaling and viability; and 3) Understand how cross talk with the peri-sinusoidal BM vascular niche mediates BCC dormancy and sensitivity to chemo- and hormonal therapies. Knowledge gained from this work will identify fundamental mechanisms governing the dynamic movement of micrometastatic BCCs and will suggest therapeutic methods to target supportive crosstalk between BM and dormant breast cancer.