Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers

Roni Allaoui; Caroline Bergenfelz; Sofie Mohlin; Catharina Hagerling; Kiarash Salari; Zena Werb; Robin L Anderson; Stephen P Ethier; Karin Jirström; Sven Påhlman; Daniel Bexell; Balázs Tahin; Martin E Johansson; Christer Larsson; Karin Leandersson

doi:10.1038/ncomms13050

Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers

Nat Commun. 2016 Oct 11:7:13050. doi: 10.1038/ncomms13050.

Authors

Roni Allaoui¹, Caroline Bergenfelz¹, Sofie Mohlin², Catharina Hagerling^{1

3}, Kiarash Salari³, Zena Werb³, Robin L Anderson⁴, Stephen P Ethier⁵, Karin Jirström⁶, Sven Påhlman², Daniel Bexell², Balázs Tahin⁷, Martin E Johansson^{1

7}, Christer Larsson², Karin Leandersson¹

Affiliations

¹ Department of Translational Medicine, Cancer Immunology, Lund University, Malmö 205 02, Sweden.
² Department of Laboratory Medicine, Translational Cancer Research, Lund University, Lund 223 63, Sweden.
³ Department of Anatomy and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143-0452, USA.
⁴ Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne 8006, Australia.
⁵ Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
⁶ Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund 221 85, Sweden.
⁷ Department of Translational Medicine, Clinical Pathology, Skånes Universitetssjukhus, Malmö 205 02, Sweden.

Abstract

Triple-negative (TN) breast cancers (ER^-PR^-HER2^-) are highly metastatic and associated with poor prognosis. Within this subtype, invasive, stroma-rich tumours with infiltration of inflammatory cells are even more aggressive. The effect of myeloid cells on reactive stroma formation in TN breast cancer is largely unknown. Here, we show that primary human monocytes have a survival advantage, proliferate in vivo and develop into immunosuppressive myeloid cells expressing the myeloid-derived suppressor cell marker S100A9 only in a TN breast cancer environment. This results in activation of cancer-associated fibroblasts and expression of CXCL16, which we show to be a monocyte chemoattractant. We propose that this migratory feedback loop amplifies the formation of a reactive stroma, contributing to the aggressive phenotype of TN breast tumours. These insights could help select more suitable therapies targeting the stromal component of these tumours, and could aid prediction of drug resistance.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cancer-Associated Fibroblasts / drug effects
Cancer-Associated Fibroblasts / metabolism*
Cancer-Associated Fibroblasts / pathology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Chemokine CXCL16 / metabolism*
Chemotactic Factors / pharmacology*
Coculture Techniques
Collagen / metabolism
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
Humans
Immunosuppression Therapy
Mice, Nude
Monocytes / drug effects
Monocytes / metabolism
Monocytes / pathology*
Myeloid Cells / metabolism
Myeloid Cells / pathology
Solubility
Stromal Cells / pathology
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / metabolism*
Triple Negative Breast Neoplasms / pathology*
Tumor Microenvironment / drug effects
Xenograft Model Antitumor Assays

Substances

CXCL16 protein, human
Chemokine CXCL16
Chemotactic Factors
Collagen

Abstract

Publication types

MeSH terms

Substances

Grants and funding