Stromal Gene Expression and Function in Primary Tumors That Metastasize to Bone Cancer
Abstract
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. Expression profiles of immunopurified cell populations derived from primary tumors of varying metastatic potential have identified aberrant gene expression in endothelial (Cathepsin D, SNAIL and FoxPI) and tumor/epithelial (Stefin A1 and Breast Cancer Metastasis Suppressor gene 1, BRMS1) cells. Analysis of matched primary tumors and spine metastases revealed the additional up-regulation of the cathepsin inhibitor Stefin Al at sites of distant metastasis, including lung and bone. Further, we have preliminary evidence of prognostic significance of Stefin A expression in primary human breast tumors, with a significant increase in Stefin A positivity in tumors derived from patients that developed soft tissue and bone metastases (N=24). In a small study, human breast cancer bone metastases were positive for Stefin A, indicating the clinical validity of the murine model and the potential significance of Stefin A in bone metastasis. In co-cultures, Stefin Al expression is induced in vitro in highly metastatic cells when co-cultured with stroma. The role of cathepsins and the inhibitor Stefin A1 in breast cancer metastasis are under investigation by examining the effect of stefin A over-expression on metastasis and the associated role of the cathepsins.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2005
- Accession Number
- ADA443872
Entities
People
- Belinda S. Parker
- Robin L. Anderson
Organizations
- University of Melbourne