The mechanisms by which breast cancer (BrC) can successfully metastasize are complex and not yet fully understood. Our goal was to identify tumor-induced stromal changes that influence metastatic cell behavior, and may serve as better targets for therapy. To identify stromal changes in cancer-bearing tissue, dual-species gene expression analysis was performed for three different metastatic BrC xenograft models. Results were confirmed by immunohistochemistry, flow cytometry, and protein knockdown. These results were validated in human clinical samples at the mRNA and protein level by retrospective analysis of cohorts of human BrC specimens. In pre-clinical models of BrC, systemic recruitment of S100A8+ myeloid cells—including myeloid-derived suppressor cells (MDSCs)—was promoted by tumor-derived factors. Recruitment of S100A8+ myeloid cells was diminished by inhibition of tumor-derived factors or depletion of MDSCs, resulting in fewer metastases and smaller primary tumors. Importantly, these MDSCs retain their ability to suppress T cell proliferation upon co-culture. Secretion of macrophage inhibitory factor (MIF) activated the recruitment of S100A8+ myeloid cells systemically. Inhibition of MIF, or depletion of MDSCs resulted in delayed tumor growth and lower metastatic burden. In human BrC specimens, increased mRNA and protein levels of S100A8+ infiltrating cells are highly associated with poor overall survival and shorter metastasis free survival of BrC patients, respectively. Furthermore, analysis of nine different human gene expression datasets confirms the association of increased levels of S100A8 transcripts with an increased risk of death. Recruitment of S100A8+ myeloid cells to primary tumors and secondary sites in xenograft models of BrC enhances cancer progression independent of their suppressive activity on T cells. In clinical samples, infiltrating S100A8+ cells are associated with poor overall survival. Targeting these molecules or associated pathways in cells of the tumor microenvironment may translate into novel therapeutic interventions and benefit patient outcome.
Bibliographical noteFunding Information:
Acknowledgments The authors would like to thank the members of the Oncogenomics Core Facility, Flow Cytometry Core Facility, and the Division of Veterinary Resources at the University of Miami Miller School of Medicine for their assistance during the course of the study. The authors would also like to thank Nanette Bishopric, MD and Barry I. Hudson PhD for helpful discussion of the manuscript. This Project was funded by Breast Cancer Research Foundation (BrCRF) awards to MEL and JMR. Part of these studies was conducted at the Lombardi Comprehensive Cancer Center Histopathology and Tissue Shared Resource which is supported in part by NIH/ NCI Grant P30-CA051008. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
© 2014, Springer Science+Business Media New York.
- Inflammation and tumor development
- Molecular markers of metastasis and progression
- Myeloid-derived suppressor cells (MDSCs)