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Breast Cancer Stem Cells in the Formation of Bone Metastasis
BACKGROUND: 4%-45% of patients with early stage breast cancer already have occult disseminated breast cancer cells in the bone marrow by the time the primary tumors are surgically excised. Despite the successful treatment of the primary malignancy in these patients, relapse can occur between 18 months to 5 years, but even up to 15 years after surgery. The propensity with which breast cancer associates with the bone and the subsequent relapse many years later, suggests a specific molecular basis for breast cancer attraction to the bone marrow, and that the cells in the bone may represent a reservoir of cancer cells from which subsequent distant metastases may seed. HYPOTHESIS: Breast cancer stem cells are the metastatic cells in the tumor mass. In the bone marrow, the metastatic cells are maintained as stem cells, which is dependant on the bone marrow stromal cells. Upon changes in the bone microenvironment due to bone resorption or changes in the marrow as a response to inflammation, the breast cancer stem cells begin to proliferate and from macrometastases. SPECIFIC AIMS: 1) To demonstrate that metastatic breast cancer cell lines contain breast cancer stem cells and that this population is metastatic 2) To show that the breast cancer stem cells remain viable as stem cells in the bone marrow environment but differentiate into non-tumorigenic cells in other tissue environments 3) To demonstrate that local bone resorption or systemic inflammation promotes macro-metastasis. STUDY DESIGN: Metastatic human breast cancer cell lines, SUM159 and SUM1315, will be sorted to isolate the breast cancer stem cells and characterized for their ability to form primary tumors as well as micro and micrometastases in the bone. Breast cancer stem cells will be co-cultured with stromal cells from various tissues and examined for the ability to differentiate as well as the cells present in the bone marrow. Metastatic promotion will be examined by altering the bone marrow environment through locally or systemically induced bone resorption, or inflammation. POTENTIAL OUTCOMES: This study will identify which cells in a breast cancer are the metastatic cells. This is highly important in the treatment of breast cancer as they represent the true target of therapies. More importantly, this work will elucidate in part, the local or systemic triggers that may promote breast cancer metastasis.
BACKGROUND: It is estimated that nearly 216,000 women will be diagnosed with breast cancer in 2004 and despite the enhanced detection methods and improved surgical treatment, breast cancer relapse and subsequent metastatic spread remains the major obstacle in the clinic. 4%-45% of patients with early stage breast cancer already have disseminated breast cancer cells that do not appear to be growing in the bone marrow by the time the primary tumors are surgically removed, and despite the removal of the primary malignancy many years prior to relapse in these patients, metastases at distant sites such as bone, and lung still develop and the mechanism for this remains unclear.
One important property that the cancer cells must exhibit in order to form a metastasis much later after the primary tumor is removed, is the ability to survive in these distant sites for years. In normal tissues, tissue stem cells are the only cells that exist throughout the life of the organism. The stem cells that are the progenitors of all the blood cells in the body remain as stem cells in the bone marrow because of specific interactions with the bone cells.
HYPOTHESIS: The metastatic cells in breast cancer are the cancer stem cells. They remain as stem cells in the bone marrow because of the specific interactions with the bone cells and therefore can give rise to metastases at a later time point. The development of metastasis is due to the changes that happen in the bone marrow environment as a result of inflammation or localized bone turnover.
SPECIFIC AIMS/DESIGN: To determine if the breast cancer stem cells are the metastatic cells, several human metastatic breast cancer cell lines will be characterized for cancer stem cells and whether the cells can metastasize compared to the non-metastatic cell lines. Specific mouse models will be used to address whether the bone marrow environment can maintain the stem cell properties of the cancer cells and to demonstrate that the formation of overt metastases is dependant upon localized bone turnover or systemic inflammation, both of which induce changes in the bone marrow environment.
BENEFITS OF THE RESEARCH: These studies are important, as they will identify which cells in a breast cancer are metastatic. This is highly important in the treatment of breast cancer as they represent the true target of therapies.