A Humanized Model of Breast Cancer Metastasis to Bone Revealing Unique Roles for the Primary Tumor and Bone Microenvironment.
Approximately 200,000 new cases of breast cancer and 40,000 breast cancer deaths occur
annually in the U.S., making breast cancer the most common malignancy and second leading
cause of cancer death in women. Metastasis of breast cancer cells from the primary
neoplasm to the bone marrow has been shown to occur in up to 70% of breast cancer cases
and development of this spread to clin... read moreically detectable macrometastases signals an
incurable progression of the disease. Many mechanisms behind the metastatic process
still remain unclear, particularly the roles of surrounding supportive tissue, but
strong evidence of a central role for stromal cells from distant locations such as the
bone marrow is building. Additionally, the contribution of specific genetic changes
within primary tumor cells has been studied in the context of metastasis. Recent reports
have demonstrated the ability of bone marrow-derived mesenchymal stem cells (BMSCs) to
diversely affect tumors of various origins, including the breast. The influence of
exogenously supplied human BMSCs (hBMSCs) on tumorigenesis, proliferation, and
metastasis has been extensively described, but, to our knowledge, no model has
accurately demonstrated the effect of a physiologic level of hBMSCs on cancer cells. Nor
have any xenograft models studied the contribution of BMSCs from a humanized bone
microenvironment. Herein is demonstrated, for the first time, that hBMSCs from the bone
environment can home to orthotopically implanted human breast cancer tumors and alter
tumor cell proliferation and visceral and skeletal metastasis frequency. This work
develops a novel model system to study the role of bone-derived cells on primary tumor
growth and migration and suggests that cancer cells with different tissue tropisms and
metastatic frequencies respond uniquely to hBMSC stimulation. Additionally, using a
humanized model of breast cancer metastasis to bone we have identified that
over-expression of il-17br can serve as a marker of skeletal metastasis, and along with
it's ligand, il-17b, can possibly mediate the response of breast cancer cells to hBMSCs
and lead to increased migration and
Thesis (Ph.D.)--Tufts University, 2012.
Submitted to the Dept. of Genetics.
Advisor: Michael Rosenblatt.
Committee: Naomi Rosenberg, Charlotte Kuperwasser, Phil Hinds, and David Kaplan.
Keyword: Genetics.read less