title: Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome.
abstract: 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.
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, 1120 N.W. 14th Street, CRB 620, Miami, FL, 33136, USA, drewselger@gmail.com.
authors.forename: Katherine
authors.initials: K
authors.lastname: Drews-Elger
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Iorns
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dias
authors.forename: Philip
authors.initials: P
authors.lastname: Miller
authors.forename: Toby M
authors.initials: TM
authors.lastname: Ward
authors.forename: Sonja
authors.initials: S
authors.lastname: Dean
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clarke
authors.forename: Adriana
authors.initials: A
authors.lastname: Campion-Flora
authors.forename: Daniel Nava
authors.initials: DN
authors.lastname: Rodrigues
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.forename: Dafydd
authors.initials: D
authors.lastname: Thomas
authors.forename: Deborah
authors.initials: D
authors.lastname: Berry
authors.forename: Dorraya
authors.initials: D
authors.lastname: El-Ashry
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lippman
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D040501:Calgranulin A / Q000096:biosynthesis; D002277:Carcinoma / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D022423:Myeloid Cells / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D046888:Tissue Array Analysis; D059467:Transcriptome; D059016:Tumor Microenvironment
chemical_list: D040501:Calgranulin A