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Use of Molecular Imaging and Genetic Approaches to Investigate the Role of Tumor Lymphangiogenesis in Breast Cancer Metastasis
Several advances have been made to improve diagnostic tools and treatment options, however little therapeutic hope exists for patients with advanced, metastatic disease. Thus tumor metastasis remains the major cause of mortality in cancer patients, and it is predicted that more than 40 000 women will die of breast cancer in 2004 in the US. Tumor growth is dependent on angiogenesis and the degree of vascularization of a primary tumor has been found to correlate with the establishment of distant metastases. However, one of the early signs of aggressive invasive growth is tumor spread to local lymph nodes, indicating that the lymphatic drainage system also may play an important part in the process of metastasis. Recently, due to the development of the necessary molecular tools it has been made possible to investigate tumor lymphangiogenesis. There exist evidence that increased lymph vessel density in and around the primary lesion correlates positively with the degree of lymph node involvement. Further, the presence of tumor cells in local lymph nodes is considered a predictive factor for worse clinical outcome. In order to identify novel potential targets for drug development against metastasis we aim to investigate the direct role of lymphangiogenesis in animal models of breast cancer. We plan to determine if increased lymphangiogenic potential in the primary tumor correlates with augmented metastatic spread. We will analyse the progression of the disease by a tumor-selective in vivo imaging approach. Based on the principle of our previously developed tissue-specific reporter gene system, using lenti- or adenoviral vectors for the delivery of a reporter gene such as firefly luciferase, we will monitor the growth and progression of human breast cancer cells in xenograft animal models.The selective expression of the reporter gene in the cancer cells allows for repetitive, non-invasive imaging whereby we can study in vivo the development of metastatic lesions. This will be correlated with the lymphangiogenic potential of the tumor cells (lymphangiogenic factors examined by RT-PCR) and the degree of lymph vessel growth in area of the primary tumor (tumor immunohistochemistry for different lymphatic markers). Further, we plan to investigate the potential therapeutic effect of anti-lymphangiogenic treatment on the development of metastasis. We hope that the proposed project will provide a better understanding of the role of tumor lymphangiogenesis in the metastatic process, that may aid in the development of novel therapeutic approaches for metastatic disease.
Breast cancer is the most common cancer type in women, in the US it is estimated that 1 out of 8 women will develop breast cancer during their lifetimes. It is the second most common cause of cancer-related death in women, it has been predicted that more than 40 000 american women will succumb to the disease in 2004. Although several recent advances have been made in order to improve the possibilities for early diagnosis as well as to increase treatment options, generally little therapeutic hope exists for patients with advanced disease when the tumor has spread to distant sites. It is most often these secondary lesions, the metastases, that kill the patient. Tumors are dependent for their growth on the formation of new blood vessels that carry nutrition and oxygen to the rapidly dividing tumor cells. This process of neovascularization is called angiogenesis and its regulation has been extensively studied during the last 20 years. Another related process, which involves the growth of lymphatic vessels, called lymphangiogenesis, remains much less well-characterized. It has been found that tumor cells exit the primary site through the blood circulation as well as via the lymphatic system. Thus stimulation of lymphangiogenesis may be an important step in the process of metastasis. We aim to study the involvement of the lymphatics using a mouse model of metastatic human breast cancer. We will take advantage of novel imaging technologies to monitor in real time the development of metastatic lesions. This information will be correlated with studies of the molecular changes that occur in the tumor tissue. Specifically we will analyse the samples for signs of lymphangiogenesis and for increased production of molecules known to be involved in this process. Further we aim to test the effect of anti-lymphangiogenic agents to investigate if prevention of lymphangiogenesis may block metastasis. We hope that our project will bring important new clues about the significance of the lymphatic system and its dynamic regulation in relation to tumor metastasis, thereby offering some novel opportunities for the treatment of breast cancer.