Mesenchymal Stem Cells in the Bone Marrow Provide a Supportive Niche for Early Disseminated Breast Tumor-Initiating Cells

The study of breast cancer tumorigenesis and metastasis depends on the use of established breast cancer cell lines, which don t accurately represent the heterogeneity and complexity of human breast tumors. We developed a tumor model using primary breast tumor-initiating cells isolated from patient core biopsies which would more accurately reflect human breast cancer and its metastasis. Tumorspheres were successfully isolated from all patient core biopsies, independent of the ERPRHer2 status or grade. Tumorspheres demonstrated a cell surface expression phenotype CD44CD24lowESA and were shown to secrete MMP-2 and MMP-9 in vitro. Injection of 503 cells in combination with matrigel into the mammary fat pad of NUDE mice resulted in the formation of small, palpable tumors, which were sustained up to 12 months post-injection. Micrometastasis was detected 3 months post-injection of tumorspheres into the mammary fat pad by PCR for human chromosome 17 in the lung, liver, kidneys, brain and femur. Macrometastatic lesions were detected as early as 6 months postinjection of tumorspheres into the mammary fat pad in the lung, liver and kidneys. Despite aberrant E-cadherin expression in the primary tumors, re-expression of E-cadherin was observed in the membrane of metastatic cells in close proximation to hepatocytes in the liver. Additionally, re-expression of E-cadherin was observed in the membrane of the majority of metastatic cells in the lung.