Neutrophils drive accelerated tumor progression in the collagen-dense mammary tumor microenvironmentReport as inadecuate

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Breast Cancer Research

, 18:49

First Online: 11 May 2016Received: 18 November 2015Accepted: 12 April 2016DOI: 10.1186-s13058-016-0703-7

Cite this article as: García-Mendoza, M.G., Inman, D.R., Ponik, S.M. et al. Breast Cancer Res 2016 18: 49. doi:10.1186-s13058-016-0703-7


BackgroundHigh mammographic density has been correlated with a 4-fold to 6-fold increased risk of developing breast cancer, and is associated with increased stromal deposition of extracellular matrix proteins, including collagen I. The molecular and cellular mechanisms responsible for high breast tissue density are not completely understood.

MethodsWe previously described accelerated tumor formation and metastases in a transgenic mouse model of collagen-dense mammary tumors type I collagen-α1 Col1α1 and mouse mammary tumor virus - polyoma virus middle T antigen MMTV-PyVT compared to wild-type mice. Using ELISA cytokine arrays and multi-color flow cytometry analysis, we studied cytokine signals and the non-malignant, immune cells in the collagen-dense tumor microenvironment that may promote accelerated tumor progression and metastasis.

ResultsCollagen-dense tumors did not show any alteration in immune cell populations at late stages. The cytokine signals in the mammary tumor microenvironment were clearly different between wild-type and collagen-dense tumors. Cytokines associated with neutrophil signaling, such as granulocyte monocyte-colony stimulated factor GM-CSF, were increased in collagen-dense tumors. Depleting neutrophils with anti-Ly6G 1A8 significantly reduced the number of tumors, and blocked metastasis in over 80 % of mice with collagen-dense tumors, but did not impact tumor growth or metastasis in wild-type mice.

ConclusionOur study suggests that tumor progression in a collagen-dense microenvironment is mechanistically different, with pro-tumor neutrophils, compared to a non-dense microenvironment.

KeywordsExtracellular matrix Tumor microenvironment Collagen Tumor associated neutrophils Breast cancer MMTV-PyVT Stroma Cytokines AbbreviationsAPCallophycocyanin

ABCavidin-biotin complex

BSAbovine serum albumin

CCL3chemokine C-C motif ligand 3

CCL5chemokine C-C motif ligand 5

COLtumor mice expressing the polyoma virus antigen and heterozygote for the collagen-1α chain mutation

Col1α1type I collagen-α1

CTcomputed tomography


DDR2discoidin domain receptor 2

DMEMDulbecco’s modified Eagle’s medium


ECMextracellular matrix

EDTAethylenediaminetetraacetic acid

ELISAenzyme-linked immunosorbent assay

EPLUniversity of Wisconsin Carbone Cancer Center Experimental Pathology Laboratory

FBSfetal bovine serum


FITCfluorescein isothiocyanate

FMOfluorescent minus one

FVBFriend virus B type

FGFfibroblast growth factor

GM-CSFgranulocyte monocyte-colony stimulated factor

HandEhematoxylin and eosin

HRPhorseradish peroxidase

IFN-γinterferon gamma


JAKJanus kinase

LOCIUniversity of Wisconsin – Madison Laboratory of Computational Instrumentation

MAPKmitogen-activated protein kinase

MDSCmyeloid derived suppressor cells

MFImedium fluorescent intensity

MIPmaximum intensity projection

MIP-1αmacrophage inflammatory protein-1α

MMPmatrix metalloproteinase

MMTV-PyVTmouse mammary tumor virus - polyoma virus middle T antigen

N1anti-tumor neutrophil

N2pro-tumor neutrophil

NEneutrophil elastase

NK cellnatural killer cell

NRLneutrophil to lymphocyte ratio

OSEMordered-subset expectation maximization

PCRpolymerase chain reaction

pDCplasmacytoid predendritic cells

PDGF-BBplatelet-derived growth factor subunit B homodimer


PETpositron emission tomography

RANTESregulation on activation, normal T-cell expressed and secreted

ROIregion of interest

ROSreactive oxygen species

STATsignal transducer and activator of transcription

TAMtumor-associated macrophage

TANtumor-associated neutrophil

TBSTris-buffered saline

TGFtransforming growth factor

TNFtumor necrosis factor

UWCCCUniversity of Wisconsin Carbone Cancer Center

VEGFvascular endothelial growth factor

WTtumor mice expressing the polyoma virus antigen, but negative for the collagen-1α chain mutation

Electronic supplementary materialThe online version of this article doi:10.1186-s13058-016-0703-7 contains supplementary material, which is available to authorized users.

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Author: María G. García-Mendoza - David R. Inman - Suzanne M. Ponik - Justin J. Jeffery - Dagna S. Sheerar - Rachel R. Van D


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