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Genetic Contributions of the Tumor Microenvironment in Breast Cancer Metastasis

Please use this identifier to cite or link to this item: http://hdl.handle.net/1811/38809

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Title: Genetic Contributions of the Tumor Microenvironment in Breast Cancer Metastasis
Creators: Werbeck, Jillian
Advisor: Rosol, Thomas
Issue Date: 2009-04
Abstract: Metastasis is a multistage process involving many complex genetic events which facilitate the spread and growth of cancer cells at a secondary site. In vivo models of metastasis are invaluable to our understanding of the interactions between cancer cells and a variety of cell types at the metastatic microenvironment. The objective of this study is to first understand how different in vivo models of metastasis can affect the site of secondary growth and second, to identify the genetic changes that occur in a single population of cancer cells at various metastatic microenvironments. For this study, we used a cell line derived from the commonly used and highly metastatic MMTV-PymT murine breast cancer model. In order to accurately model metastasis as a multi-step process we injected the PymT breast cancer cells via 5 different routes of inoculation. Subcutaneous, orthotopic (mammary fat pad), intravascular (tail vein and intracardiac), and intratibial injections allow us to assess the metastatic pattern of this cell line along different stages in the metastatic cascade. In order to evaluate patterns of dissemination, tumor cells were tracked over time using a Xenogen In Vivo Imaging System (IVIS). Termination criteria were based on clinical symptoms of metastasis and therefore mice were sacrificed accordingly based on tumor burden and/or other signs of pain or distress. Metastases were evaluated based on histopathology, radiographic evaluation, and gross necropsy. The genetic profile of the tumor was compared at various organ sites (subcutis, mammary fat pad, lung, ovary, adrenal gland, tibia) using a RT2 Profiler™ PCR Array System, Superarray Bioscience Corporation (N=3). We found that the route of injection did affect the dissemination of PymT tumor cells. We found no metastasis after mammary fat pad injection (N= 0/10), or subcutaneous injection (N= 0/10). Lung metastases were commonly detected after tail vein injection (N= 9/11), along with ovary metastases in a smaller percentage of mice (N= 2/11). Interestingly, alternative intravascular routes of injection (intracardiac) resulted in a different pattern of dissemination: ovary (N= 13/20), adrenal gland (N= 6/20), and bone (N= 3/20). Finally, no metastases were observed following intratibial injections although mild osteolysis was visible via radiographic and histologic evaluation. In addition, the MMTV-PymT tumor cells had different genetic profiles depending on their site of growth (p<0.01). Specifically, E-cadherin, FGFR1, EGF, and MMP9 expression were greater than 3 fold different in PymT metastases when compared to the cells in the mammary gland control. We demonstrated that the tumor microenvironment has a site-specific effect on the gene expression profile of the PymT cell line. Interestingly, we have also shown that the injection route may significantly affect the metastatic potential of tumor cells, and therefore the pathology of secondary lesions. This study has significant implications in trying to understand the mechanism by which tumor cells disseminate, and also the genetic interactions between tumor cells and stroma in various organs of metastasis.
Embargo: A five-year embargo was granted for this item.
Series/Report no.: 2009 Edward F. Hayes Graduate Research Forum. 23rd
Keywords: breast cancer
tumor microenvironment
metastasis
Description: Biological Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
URI: http://hdl.handle.net/1811/38809
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