Microenvironmental Regulation of Mammary Carcinogenesis
Annual rept. 1 Jun 2008-31 May 2009
CALIFORNIA UNIV SAN FRANCISCO
Pagination or Media Count:
During breast cancer development, increased presence of leukocytes in stroma parallels disease progression however, functional significance of leukocytes in regulating pro- versus anti-tumor immunity in the breast remains poorly understood. Utilizing the MMTV-PyMT model of mammary carcinogenesis, we have demonstrated that cathepsin C-expressing macrophages and IL-4-expressing CD4 T cells indirectly promote invasion and subsequent metastasis of mammary adenocarcinomas. CD4 T cells regulate the phenotype and effector function of macrophages that in turn enhance metastasis through activation of EGF receptor signaling in malignant epithelial cells. Together, these data indicate that anti-tumor acquired immune programs can be usurped in pro-tumor microenvironments and instead promote malignancy by engaging cellular components of the innate immune system functionally involved in regulating epithelial cell behavior. Based on this data, we revealed a unique immune signature that predicts overall survival of women with breast cancer. Moreover, we have revealed that transient blockade of Alk5 enhances delivery of high molecular weight compounds into mammary tumors. We will employ this capability and evaluate cell-based delivery systems and targeted-iron oxide imaging compounds to non-invasively evaluate inflammation in mammary carcinomas, to not only target leukocytes to minimize their tumor-promoting activities, but also to develop imaging modalities to predict outcome for patients and help guide therapy.
- Medicine and Medical Research