Stromal Gene Expression and Function in Primary Breast Tumors that Metastasize to Bone Cancer

摘要

Tumor progression and metastasis is mediated not only by tumor cells but by the surrounding stroma as well, including the vascular endothelium. Knowledge of the molecular and cellular interactions that promote metastasis is required to determine prognostic markers and therapeutic targets for metastatic breast cancer. A clinically relevant syngeneic model of breast cancer metastasis has been used to determine gene expression alterations that occur in both tumor epithelial cells and the associated vascular endothelium throughout metastatic progression. A number of candidates have been identified as over- expressed or suppressed in tumor endothelium and in the tumor cells themselves during metastatic progression. Some of these have been verified and are being analysed further for their functional role in metastasis, and for their role in human breast cancer. Of particular interest are 3 groups of genes- the increased expression and activity of cathepsin proteases and their inhibitor Stefin A, suppression of interleukin receptors IL13r 1 and IL4r and the interferon regulatory factor IRF7 (genes involved in immune defence) and also suppression of a novel gene that may have promise as a metastasis suppressor, Lrch2. In the human disease, our studies have shown that a lack of Stefin A primary tumor expression decreased risk of recurrence and improved patient outcome in a small cohort study.