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Breast Cancer Res. 2016 May 11;18(1):49. doi: 10.1186/s13058-016-0703-7.

Neutrophils drive accelerated tumor progression in the collagen-dense mammary tumor microenvironment.

Author information

1
Department of Cell and Regenerative Biology, University of Wisconsin - Madison, Madison, WI, USA.
2
UW Carbone Cancer Center, University of Wisconsin - Madison, Madison, WI, USA.
3
Present Address: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
4
Department of Cell and Regenerative Biology, University of Wisconsin - Madison, Madison, WI, USA. pjkeely@wisc.edu.
5
UW Carbone Cancer Center, University of Wisconsin - Madison, Madison, WI, USA. pjkeely@wisc.edu.
6
Wisconsin Institutes of Medical Research, 1111 Highland Ave., Madison, WI, 53705, USA. pjkeely@wisc.edu.

Abstract

BACKGROUND:

High 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.

METHODS:

We previously described accelerated tumor formation and metastases in a transgenic mouse model of collagen-dense mammary tumors (type I collagen-α1 (Col1α1)(tm1Jae) 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.

RESULTS:

Collagen-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.

CONCLUSION:

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

KEYWORDS:

Breast cancer; Collagen; Cytokines; Extracellular matrix; MMTV-PyVT; Stroma; Tumor associated neutrophils; Tumor microenvironment

PMID:
27169366
PMCID:
PMC4864897
DOI:
10.1186/s13058-016-0703-7
[Indexed for MEDLINE]
Free PMC Article

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