TY - JOUR
T1 - Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome
AU - Drews-Elger, Katherine
AU - Iorns, Elizabeth
AU - Dias, Alexandra
AU - Miller, Philip
AU - Ward, Toby M.
AU - Dean, Sonja
AU - Clarke, Jennifer
AU - Campion-Flora, Adriana
AU - Rodrigues, Daniel Nava
AU - Reis-Filho, Jorge S.
AU - Rae, James M.
AU - Thomas, Dafydd
AU - Berry, Deborah
AU - El-Ashry, Dorraya
AU - Lippman, Marc E.
N1 - Publisher Copyright:
© 2014, Springer Science+Business Media New York.
PY - 2014/10/14
Y1 - 2014/10/14
N2 - 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.
AB - 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.
KW - Cytokines
KW - Inflammation and tumor development
KW - Molecular markers of metastasis and progression
KW - Myeloid-derived suppressor cells (MDSCs)
KW - S100A8
UR - http://www.scopus.com/inward/record.url?scp=84919903194&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84919903194&partnerID=8YFLogxK
U2 - 10.1007/s10549-014-3122-4
DO - 10.1007/s10549-014-3122-4
M3 - Article
C2 - 25270120
AN - SCOPUS:84919903194
SN - 0167-6806
VL - 148
SP - 41
EP - 59
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 1
ER -