A Viral Cytokine as a Promoter of Tumor Progression -
DESCRIPTION (provided by applicant): Nearly 200,000 new cases of breast cancer will be diagnosed in 2010, and over 40,000 women will succumb to the disease this year. Most cancer patients do not die from local complications of their primary tumor growth, but rather from the development of metastases and malignant spread of the tumor. While there are many known risk factors for breast cancer, one area that remains largely unexplored is the impact of infectious disease. Human cytomegalovirus (HCMV) is a widespread pathogen that infects 70-90% of the general population. HCMV usually causes clinical disease only in immune compromised individuals, but recent evidence has linked HCMV infection to several types of cancer. While previous studies have focused on the potential of HCMV gene products to increase malignancy of virus infected tumor cells, this study examines the effect of a secreted viral cytokine on uninfected tumor cells. The specific hypothesis is that cmvIL-10 contributes to tumor progression by enhancing invasiveness and promoting the growth and survival of cancer cells. This hypothesis is supported by preliminary data showing that cmvIL-10 triggers increased expression of matrix-metalloproteinases (MMPs) in breast cancer cells and is further based on several key observations about human IL-10. First, elevated levels of IL-10 are found in several types of cancer and correlate with poor prognosis. Second, IL-10 has been shown to inhibit apoptosis and promote metastasis of cancer cells. Finally, IL-10 stimulates activation of Stat3, a transcription factor which is strongly associated with enhanced metastatic potential and chemoresistance. Because cmvIL-10 is a virally encoded homolog that retains many biological functions of human IL-10, including stimulation of B cell growth and activation of Stat3, it seems likely that the viral cytokine may also stimulate metastasis. Breast cancer cells will be cultured in the presence or absence of cmvIL-10 to determine effects on MMP enzyme activity, cell motility, and invasiveness. In addition, the ability of cmvIL-10 to stimulate breast cancer cell growth and protect tumor cells from apoptosis will be evaluated. This work will provide an enhanced understanding of the impact of HCMV infection on breast cancer progression. The results are expected to clarify the effect of a secreted viral cytokine on uninfected tumor cells, and could have broad implications in the diagnosis and treatment of cancer.
PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer deaths for women in the United States. Opportunistic pathogens like human cytomegalovirus (HCMV), which infect 70-90% of the general population, may play a role in the acceleration and malignant spread of breast cancer. By studying the molecular interactions between this pathogen and its human host, novel therapeutic targets may be identified, potentially leading to improved cancer treatments and decreased human mortality.
