Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome

Katherine Drews-Elger, Elizabeth Iorns, Alexandra Dias, Philip Miller, Toby M. Ward, Sonja Dean, Jennifer Clarke, Adriana Campion-Flora, Daniel Nava Rodrigues, Jorge S. Reis-Filho, James M. Rae, Dafydd Thomas, Deborah Berry, Dorraya El-Ashry, Marc E Lippman

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)41-59
Number of pages19
JournalBreast Cancer Research and Treatment
Volume148
Issue number1
DOIs
StatePublished - Jan 1 2014

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Myeloid Cells
Breast Neoplasms
Neoplasms
Heterografts
Survival
Calgranulin A
Macrophages
Neoplasm Metastasis
T-Lymphocytes
Cellular Microenvironment
Gene Expression
Messenger RNA
Aptitude
Tumor Microenvironment
Coculture Techniques
Flow Cytometry
Proteins
Cohort Studies
Immunohistochemistry
Cell Proliferation

Keywords

  • Cytokines
  • Inflammation and tumor development
  • Molecular markers of metastasis and progression
  • Myeloid-derived suppressor cells (MDSCs)
  • S100A8

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome. / Drews-Elger, Katherine; Iorns, Elizabeth; Dias, Alexandra; Miller, Philip; Ward, Toby M.; Dean, Sonja; Clarke, Jennifer; Campion-Flora, Adriana; Rodrigues, Daniel Nava; Reis-Filho, Jorge S.; Rae, James M.; Thomas, Dafydd; Berry, Deborah; El-Ashry, Dorraya; Lippman, Marc E.

In: Breast Cancer Research and Treatment, Vol. 148, No. 1, 01.01.2014, p. 41-59.

Research output: Contribution to journalArticle

Drews-Elger, K, Iorns, E, Dias, A, Miller, P, Ward, TM, Dean, S, Clarke, J, Campion-Flora, A, Rodrigues, DN, Reis-Filho, JS, Rae, JM, Thomas, D, Berry, D, El-Ashry, D & Lippman, ME 2014, 'Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome', Breast Cancer Research and Treatment, vol. 148, no. 1, pp. 41-59. https://doi.org/10.1007/s10549-014-3122-4
Drews-Elger, Katherine ; Iorns, Elizabeth ; Dias, Alexandra ; Miller, Philip ; Ward, Toby M. ; Dean, Sonja ; Clarke, Jennifer ; Campion-Flora, Adriana ; Rodrigues, Daniel Nava ; Reis-Filho, Jorge S. ; Rae, James M. ; Thomas, Dafydd ; Berry, Deborah ; El-Ashry, Dorraya ; Lippman, Marc E. / Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome. In: Breast Cancer Research and Treatment. 2014 ; Vol. 148, No. 1. pp. 41-59.
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