A New Model for the Study of Human Breast Cancer Metastasis

• Main Author: Marsden, Carolyn Gage
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2012
• Subjects: Cellular biology; Oncology
• ISBN: 9781267941138; 1267941138

Disseminated breast cancer cells may be present at distant sites at the time of primary diagnosis of breast cancer in patients that exhibit no outward signs of clinical metastasis. Current models of breast cancer metastasis have provided great insight into the contributing molecular mechanisms; however fail to recapitulate the dormancy period observed clinically. Exit from the dormant state is necessary for the development of macroscopic metastatic lesions in distant organs, yet the mechanisms involved are poorly understood. Primary breast tumor-initiating cells (bTICs) isolated as tumorspheres from breast cancer biopsies from patients, were hypothesized to more accurately recapitulate the metastatic process observed in human breast cancer metastasis in an immune-deficient mouse model. Breast cancer needle biopsies from primary tumors were mechanically and enzymatically dissociated, yielding a single cell suspension that was subsequently cultured under non-adherent and serum-free conditions to obtain tumorspheres. Injection of ≤100 tumorspheres into the mammary fat pad of NUDE mice resulted in the formation of small, palpable tumors. H+E staining and immunohistochemistry (IHC) of primary tumors revealed complex cellular organization and molecular heterogeneity. Upon primary tumor formation in the mammary fat pad, metastatic human breast cancer cells were detected within the lungs, liver, brain and bone marrow (femur). Micrometastatic lesions were detected by H+E staining throughout the organs prior to the development of macroscopic lesions that were observed ≥ 6 months post-injection. Organ-specific heterogeneity was observed between the macroscopic metastatic lesions. These results demonstrate a novel model for the study of human breast cancer metastasis, dormancy at the metastatic sites, and organ specific effects on the metastatic cells.