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Nat Cell Biol. 2014 Nov;16(11):1105-17. doi: 10.1038/ncb3041. Epub 2014 Sep 28.

A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages.

Author information

1
1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] MIT Ludwig Center for Molecular Oncology, Cambridge, Massachusetts 02139, USA.
2
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA.
3
1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] MIT Ludwig Center for Molecular Oncology, Cambridge, Massachusetts 02139, USA [3] Genome Institute of Singapore, 60 Biopolis Street Singapore 138672, Singapore.
4
1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [3] University of Heidelberg, 69120 Heidelberg, Germany.
5
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
6
1] Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA [2] Department of Cardiothoracic Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
7
Magee-Womens Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
8
1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] MIT Ludwig Center for Molecular Oncology, Cambridge, Massachusetts 02139, USA [3] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.

Abstract

The cell-biological program termed the epithelial-mesenchymal transition (EMT) confers on cancer cells mesenchymal traits and an ability to enter the cancer stem cell (CSC) state. However, the interactions between CSCs and their surrounding microenvironment are poorly understood. Here we show that tumour-associated monocytes and macrophages (TAMs) create a CSC niche through juxtacrine signalling with CSCs. We performed quantitative proteomic profiling and found that the EMT program upregulates the expression of CD90, also known as Thy1, and EphA4, which mediate the physical interactions of CSCs with TAMs by directly binding with their respective counter-receptors on these cells. In response, the EphA4 receptor on the carcinoma cells activates Src and NF-κB. In turn, NF-κB in the CSCs induces the secretion of a variety of cytokines that serve to sustain the stem cell state. Indeed, admixed macrophages enhance the CSC activities of carcinoma cells. These findings underscore the significance of TAMs as important components of the CSC niche.

PMID:
25266422
PMCID:
PMC4296514
DOI:
10.1038/ncb3041
[Indexed for MEDLINE]
Free PMC Article

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