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

摘要

Tumorspheres were isolated from core biopsies collected from five patients with clinical diagnosis of invasive ductal carcinoma (IDC). Isolated tumorspheres were transplanted into the mammary fat pad of NUDE mice to establish tumorigenicity in vivo. At 3 months post-injection, micrometastases to the lung, liver, kidneys, brain and femur were detected by measuring content of human chromosome 17. Primary tumors variably expressed cytokeratins, Her2/neu, cytoplasmic E-cadherin, nuclear catenin and fibronectin but were negative for ER and vimentin. The injection of bone marrow isolated from mice previously injected with tumorspheres into the mammary fat pad, resulted in large tumor formation in the mammary fat pad 2 months post-injection. The tumors exhibited accelerated development of metastatic lesions within the lung, liver and kidney. The resultant tumors and the majority of metastatic lesions within the lung and liver exhibited a mesenchymal-like phenotype. Conclusions: Micrometastases in mouse organs demonstrated a dormancy period prior to outgrowth of macrometastases. Dormant disseminated tumor cells (DTCs) within the bone marrow were highly malignant upon injection into the mammary fat pad, with the accelerated development of metastatic lesions. These results indicate the acquisition of a more aggressive phenotype of DTCs during metastatic latency within the bone marrow microenvironment.