INVESTIGATION OF ANGIOGENIC FUNCTION IN CANCER BY MRI

University Of California Irvine, Irvine CA

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Abstract

In this proposal we will apply the MRI techniques in conjunction with the immuno histochemistry (IHC) to investigate the angiogenic function of breast lesions by using a carcinogen induced breast cancer model. When N-ethyl-N-nitrosourea (ENU) is infected into rats it can induce malignant and benign breast rumors which were similar to that of humans. The tumors also develop with various grades and growth rates, and with different degree of metastatic potential. We will apply the MRI acquisition and data analysis techniques that we have developed over the years (dynamic contrast enhanced MRI using two sequentially injected agents, an extracellular shown that such a technique could be used to differentiate benign from malignant as well as the grade of malignancy. After the MRI study is finished the primary tumor will be surgically removed for IHC studies. Several angiogenic IHC markers, including p53, TSP-1, vessel density counting (using CD31 or Factor VIII staining), and expression of VEGF will be measured. In addition, the 3-phase fraction (SPF) of the tumor cells will be measured. After removal of the primary tumor, the rats will be kept for another 6 months for observation of recurrence or metastasis. Then they will be sacrificed for lymph node examination to determine the metastatic genesis in aggressiveness of tumor's growth will be investigated. Finally the MRI parameters and IHC markers will be correlated with metastatic status of the primary to investigate whether they can serve as accurate predictors of metastasis as well as determining the angiogenic function of the primary tumor. If the developed techniques prove to be accurate, they can then be used to monitor therapies that affect the angiogenesis process. A thorough investigation of tumor biology and prognostic factors associated with breast cancer is important for the understanding of the angiogenesis in breast cancer and its alteration in response to anti- angiogenic therapies. The validation of prognostic factors which discriminate between high and low risks of metastasis would make it possible to administer chemotherapy only to those who would benefit in spite of the associated morbidity. The outcome of the current proposal should enhance the accuracy of the prognostic factors and reduce the treatment-associated morbidity while also reducing the long-term mortality by selecting the "correct treatment". All of these goals are major issues in health care of breast-cancer patients and the successful outcome of the proposed investigation will help reduce the human and economic costs of breast cancer.