Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-β in breast cancer progression

Zhaoyang Li, Yanli Pang, Sudheer Kumar Gara, B R Achyut, Christopher Heger, Paul K Goldsmith, Scott Lonning, Li Yang

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

One great challenge in our understanding of TGF-β cancer biology and the successful application of TGF-β-targeted therapy is that TGF-β works as both a tumor suppressor and a tumor promoter. The underlying mechanisms for its functional change remain to be elucidated. Using 4T1 mammary tumor model that shares many characteristics with human breast cancer, particularly its ability to spontaneously metastasize to the lungs, we demonstrate that Gr-1+CD11b+ cells or myeloid derived suppressor cells are important mediators in TGF-β regulation of mammary tumor progression. Depletion of Gr-1+CD11b+ cells diminished the antitumor effect of TGF-β neutralization. Two mechanisms were involved: first, treatment with TGF-β neutralization antibody (1D11) significantly decreased the number of Gr-1+CD11b+ cells in tumor tissues and premetastatic lung. This is mediated through increased Gr-1+CD11b+ cell apoptosis. In addition, 1D11 treatment significantly decreased the expression of Th2 cytokines and Arginase 1. Interestingly, the number and property of Gr-1+CD11b+ cells in peripheral blood/draining lymph nodes correlated with tumor size and metastases in response to 1D11 treatment. Our data suggest that the efficacy of TGF-β neutralization depends on the presence of Gr-1+CD11b+ cells, and these cells could be good biomarkers for TGF-β-targeted therapy.

Original languageEnglish (US)
Pages (from-to)2584-95
Number of pages12
JournalInternational Journal of Cancer
Volume131
Issue number11
DOIs
StatePublished - Dec 1 2012

Fingerprint

Breast Neoplasms
Neoplasms
Arginase
Lung
Carcinogens
Biomarkers
Lymph Nodes
Apoptosis
Cytokines
Neoplasm Metastasis
Antibodies
Therapeutics

Keywords

  • Animals
  • Antibodies, Neutralizing
  • Antigens, CD11b
  • Apoptosis
  • Arginase
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Cytokines
  • Disease Progression
  • Female
  • Lung
  • Lymph Nodes
  • Mammary Neoplasms, Experimental
  • Mice
  • Mice, Inbred BALB C
  • Myeloid Cells
  • Receptors, Chemokine
  • Th2 Cells
  • Transforming Growth Factor beta
  • Tumor Microenvironment
  • Journal Article
  • Research Support, N.I.H., Intramural

Cite this

Li, Z., Pang, Y., Gara, S. K., Achyut, B. R., Heger, C., Goldsmith, P. K., ... Yang, L. (2012). Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-β in breast cancer progression. International Journal of Cancer, 131(11), 2584-95. https://doi.org/10.1002/ijc.27572

Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-β in breast cancer progression. / Li, Zhaoyang; Pang, Yanli; Gara, Sudheer Kumar; Achyut, B R; Heger, Christopher; Goldsmith, Paul K; Lonning, Scott; Yang, Li.

In: International Journal of Cancer, Vol. 131, No. 11, 01.12.2012, p. 2584-95.

Research output: Contribution to journalArticle

Li, Z, Pang, Y, Gara, SK, Achyut, BR, Heger, C, Goldsmith, PK, Lonning, S & Yang, L 2012, 'Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-β in breast cancer progression', International Journal of Cancer, vol. 131, no. 11, pp. 2584-95. https://doi.org/10.1002/ijc.27572
Li, Zhaoyang ; Pang, Yanli ; Gara, Sudheer Kumar ; Achyut, B R ; Heger, Christopher ; Goldsmith, Paul K ; Lonning, Scott ; Yang, Li. / Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-β in breast cancer progression. In: International Journal of Cancer. 2012 ; Vol. 131, No. 11. pp. 2584-95.
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abstract = "One great challenge in our understanding of TGF-β cancer biology and the successful application of TGF-β-targeted therapy is that TGF-β works as both a tumor suppressor and a tumor promoter. The underlying mechanisms for its functional change remain to be elucidated. Using 4T1 mammary tumor model that shares many characteristics with human breast cancer, particularly its ability to spontaneously metastasize to the lungs, we demonstrate that Gr-1+CD11b+ cells or myeloid derived suppressor cells are important mediators in TGF-β regulation of mammary tumor progression. Depletion of Gr-1+CD11b+ cells diminished the antitumor effect of TGF-β neutralization. Two mechanisms were involved: first, treatment with TGF-β neutralization antibody (1D11) significantly decreased the number of Gr-1+CD11b+ cells in tumor tissues and premetastatic lung. This is mediated through increased Gr-1+CD11b+ cell apoptosis. In addition, 1D11 treatment significantly decreased the expression of Th2 cytokines and Arginase 1. Interestingly, the number and property of Gr-1+CD11b+ cells in peripheral blood/draining lymph nodes correlated with tumor size and metastases in response to 1D11 treatment. Our data suggest that the efficacy of TGF-β neutralization depends on the presence of Gr-1+CD11b+ cells, and these cells could be good biomarkers for TGF-β-targeted therapy.",
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AU - Heger, Christopher

AU - Goldsmith, Paul K

AU - Lonning, Scott

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AB - One great challenge in our understanding of TGF-β cancer biology and the successful application of TGF-β-targeted therapy is that TGF-β works as both a tumor suppressor and a tumor promoter. The underlying mechanisms for its functional change remain to be elucidated. Using 4T1 mammary tumor model that shares many characteristics with human breast cancer, particularly its ability to spontaneously metastasize to the lungs, we demonstrate that Gr-1+CD11b+ cells or myeloid derived suppressor cells are important mediators in TGF-β regulation of mammary tumor progression. Depletion of Gr-1+CD11b+ cells diminished the antitumor effect of TGF-β neutralization. Two mechanisms were involved: first, treatment with TGF-β neutralization antibody (1D11) significantly decreased the number of Gr-1+CD11b+ cells in tumor tissues and premetastatic lung. This is mediated through increased Gr-1+CD11b+ cell apoptosis. In addition, 1D11 treatment significantly decreased the expression of Th2 cytokines and Arginase 1. Interestingly, the number and property of Gr-1+CD11b+ cells in peripheral blood/draining lymph nodes correlated with tumor size and metastases in response to 1D11 treatment. Our data suggest that the efficacy of TGF-β neutralization depends on the presence of Gr-1+CD11b+ cells, and these cells could be good biomarkers for TGF-β-targeted therapy.

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KW - Lymph Nodes

KW - Mammary Neoplasms, Experimental

KW - Mice

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KW - Myeloid Cells

KW - Receptors, Chemokine

KW - Th2 Cells

KW - Transforming Growth Factor beta

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JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

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ER -