Microenvironmental Regulation of Mammary Carcinogenesis
Abstract
Chronic inflammation is now regarded as a promoting force for cancer development. We have previously demonstrated that inhibition of leukocyte migration and/or leukocyte-derived protease activities during squamous carcinogenesis significantly decrease tumor incidence; thus, supporting the contention that inflammation can be targeted pharmacologically to affect cancer outcome. Using the MMTV-PymT mouse model of mammary carcinogenesis, we now demonstrate that mammary carcinogenesis is similarly susceptible to immuno-modulation as genetic deletion of CD4+ T lymphocytes and/or a leukocyte cysteine protease (cathepsin C), significantly diminishes pulmonary metastasis formation. Utilizing a 3D organotypic culture system with primary cells, we have revealed that activated CD4+ T cells alter the mammary microenvironment in such a way that mammary epithelial cell migration into matrix is favored. Moreover, the paracrine mechanisms whereby T cells mediate these effects are in part due to M2-activation of macrophages in an IL-4-dependent manner. Together, these studies provide insight into the role adaptive immune cells play in regulating myeloid cell behavior and how leukocyte proteases together regulate cancer development, and will reveal novel mechanisms with which to target tumor cells with anti-cancer therapeutics and/or image inflammation associated with breast cancer development.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2008
- Accession Number
- ADA489771
Entities
People
- Lisa Coussens
Organizations
- University of California, San Francisco