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Regulatory roles for vascular peptidases involved in breast cancer
Angiogenesis is a complex multi-step process that can occur in development and diseases with a vascular component in response to various stimuli. Several lines of evidence indicate that angiogenesis plays a central role in both local tumor growth and distant metastasis in breast cancer. Different studies indicate that proteases are upregulated during pathological angiogenesis; therefore these molecules represent potential targets for elucidating the molecular mechanisms of tumor growth and invasive breast cancer. By using genetic elimination and biochemical inhibition, we have uncovered an as yet unrecognized mechanistic role for aminopeptidase A (APA) and aminopeptidase N (APN) in pathological angiogenesis. Hypothesis/Objectives: We hypothesize that APA and APN activities contribute to important regulatory pathways for blood vessel formation. Here, we propose to investigate the mechanisms by which APA and APN expression and activity control the physiological and pathological proliferation of activated endothelial cells forming blood vessels. First, (1) we will study the induction and activity of APA and APA during angiogenesis, and evaluate the expression of APN and APA in angiogenic vasculature of breast cancer tumors. Moreover, (2) we will determine the nature of the angiogenic stimuli leading to upregulation and activation of APA and APN in endothelial cells and perivascular cells (pericytes). Finally, (3) we will evaluate the phenotype of APN-deficient, and APA/APN (double)-deficient mice with respect to angiogenesis by using cytokine-, oxygen- and tumor-induced angiogenesis models. Central to our hypothesis is that these peptidases may play complementary roles in angiogenesis. These studies are likely to establish a mechanistic basis for the role of pro-angiogenic peptidases in the formation and maintenance of neovasculature, an aspect of high relevance in vascular and cancer biology. The proposed experiments in this application may also lead to development of new therapeutic strategies for breast cancer and metastasis.
The major cause of death in patients with breast cancer is not the growth of the primary tumor, but rather the spreading of the tumor cells to other sites of the body forming metastasis. When tumor cells detach from the primary tumor and circulate in the blood stream, they need to attach and dig their way into a new site in the body forming metastasis. In contrast to conventional chemotherapy and radiotherapy currently in use against breast cancer, we want to use biological agents that specifically prevent tumor growth and metastasis without toxic side effects of conventional therapies. We want to develop new agents to stop the metastasis of breast cancer. The first agent is is a polymer of a molecule called fibronectin, which is an important component of the blood. This polymer appears to trap the malignant cells released into the blood stream by the tumor. Trapped cells are then rapidly eliminated from the body, even before they have time to travel and attach to distant sites and start dividing again. The other agent will inhibit the function of two enzymes (APA and APN) that are crucial in the digging of tumor cells and cells that line tumor blood vessels into a new site in the body. By inhibiting these enzymes our group has been able to arrest tumor growth in a mouse. We expect that by combining these two agents, we will be able to provide more efficient means of blocking the growth of a tumor and development of metastasis in breast cancer patients. If successful, this project will lead to the development of a novel non-toxic method to treat breast cancer.