TGF-β signaling in myeloid cells is required for tumor metastasis

Yanli Pang; Sudheer Kumar Gara; Bhagelu R Achyut; Zhaoyang Li; Hannah H Yan; Chi-Ping Day; Jonathan M Weiss; Giorgio Trinchieri; John C Morris; Li Yang

doi:10.1158/2159-8290.CD-12-0527

TGF-β signaling in myeloid cells is required for tumor metastasis

Yanli Pang, Sudheer Kumar Gara, Bhagelu R Achyut, Zhaoyang Li, Hannah H Yan, Chi-Ping Day, Jonathan M Weiss, Giorgio Trinchieri, John C Morris, Li Yang

Research output: Contribution to journal › Article › peer-review

116 Scopus citations

Abstract

TGF-β is overexpressed in advanced human cancers. It correlates with metastasis and poor prognosis. However, TGF-β functions as both a tumor suppressor and a tumor promoter. Here, we report for the first time that genetic deletion of Tgfbr2 specifically in myeloid cells (Tgfbr2(MyeKO)) significantly inhibited tumor metastasis. Reconstitution of tumor-bearing mice with Tgfbr2(MyeKO) bone marrow recapitulated the inhibited metastasis phenotype. This effect is mediated through decreased production of type II cytokines, TGF-β1, arginase 1, and inducible nitric oxide synthase, which promoted IFN-γ production and improved systemic immunity. Depletion of CD8 T cells diminished the metastasis defect in the Tgfbr2(MyeKO) mice. Consistent with animal studies, myeloid cells from patients with advanced-stage cancer showed increased TGF-β receptor II expression. Our studies show that myeloid-specific TGF-β signaling is an essential component of the metastasis-promoting puzzle of TGF-β. This is in contrast to the previously reported tumor-suppressing phenotypes in fibroblasts, epithelial cells, and T cells.

Original language	English (US)
Pages (from-to)	936-51
Number of pages	16
Journal	Cancer Discovery
Volume	3
Issue number	8
DOIs	https://doi.org/10.1158/2159-8290.CD-12-0527
State	Published - Aug 2013

Keywords

Animals
Arginase
Cell Line, Tumor
Disease Models, Animal
Epithelial Cells
Fibroblasts
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Knockout
Myeloid Cells
Neoplasm Metastasis
Nitric Oxide Synthase
Protein-Serine-Threonine Kinases
Receptors, Transforming Growth Factor beta
Signal Transduction
T-Lymphocytes
Transforming Growth Factor beta
Tumor Microenvironment
Journal Article
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/2159-8290.CD-12-0527

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title = "TGF-β signaling in myeloid cells is required for tumor metastasis",

abstract = "TGF-β is overexpressed in advanced human cancers. It correlates with metastasis and poor prognosis. However, TGF-β functions as both a tumor suppressor and a tumor promoter. Here, we report for the first time that genetic deletion of Tgfbr2 specifically in myeloid cells (Tgfbr2(MyeKO)) significantly inhibited tumor metastasis. Reconstitution of tumor-bearing mice with Tgfbr2(MyeKO) bone marrow recapitulated the inhibited metastasis phenotype. This effect is mediated through decreased production of type II cytokines, TGF-β1, arginase 1, and inducible nitric oxide synthase, which promoted IFN-γ production and improved systemic immunity. Depletion of CD8 T cells diminished the metastasis defect in the Tgfbr2(MyeKO) mice. Consistent with animal studies, myeloid cells from patients with advanced-stage cancer showed increased TGF-β receptor II expression. Our studies show that myeloid-specific TGF-β signaling is an essential component of the metastasis-promoting puzzle of TGF-β. This is in contrast to the previously reported tumor-suppressing phenotypes in fibroblasts, epithelial cells, and T cells.",

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author = "Yanli Pang and Gara, {Sudheer Kumar} and Achyut, {Bhagelu R} and Zhaoyang Li and Yan, {Hannah H} and Chi-Ping Day and Weiss, {Jonathan M} and Giorgio Trinchieri and Morris, {John C} and Li Yang",

year = "2013",

month = aug,

doi = "10.1158/2159-8290.CD-12-0527",

language = "English (US)",

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journal = "Cancer Discovery",

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publisher = "American Association for Cancer Research Inc.",

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T1 - TGF-β signaling in myeloid cells is required for tumor metastasis

AU - Pang, Yanli

AU - Gara, Sudheer Kumar

AU - Achyut, Bhagelu R

AU - Li, Zhaoyang

AU - Yan, Hannah H

AU - Day, Chi-Ping

AU - Weiss, Jonathan M

AU - Trinchieri, Giorgio

AU - Morris, John C

AU - Yang, Li

PY - 2013/8

Y1 - 2013/8

N2 - TGF-β is overexpressed in advanced human cancers. It correlates with metastasis and poor prognosis. However, TGF-β functions as both a tumor suppressor and a tumor promoter. Here, we report for the first time that genetic deletion of Tgfbr2 specifically in myeloid cells (Tgfbr2(MyeKO)) significantly inhibited tumor metastasis. Reconstitution of tumor-bearing mice with Tgfbr2(MyeKO) bone marrow recapitulated the inhibited metastasis phenotype. This effect is mediated through decreased production of type II cytokines, TGF-β1, arginase 1, and inducible nitric oxide synthase, which promoted IFN-γ production and improved systemic immunity. Depletion of CD8 T cells diminished the metastasis defect in the Tgfbr2(MyeKO) mice. Consistent with animal studies, myeloid cells from patients with advanced-stage cancer showed increased TGF-β receptor II expression. Our studies show that myeloid-specific TGF-β signaling is an essential component of the metastasis-promoting puzzle of TGF-β. This is in contrast to the previously reported tumor-suppressing phenotypes in fibroblasts, epithelial cells, and T cells.

AB - TGF-β is overexpressed in advanced human cancers. It correlates with metastasis and poor prognosis. However, TGF-β functions as both a tumor suppressor and a tumor promoter. Here, we report for the first time that genetic deletion of Tgfbr2 specifically in myeloid cells (Tgfbr2(MyeKO)) significantly inhibited tumor metastasis. Reconstitution of tumor-bearing mice with Tgfbr2(MyeKO) bone marrow recapitulated the inhibited metastasis phenotype. This effect is mediated through decreased production of type II cytokines, TGF-β1, arginase 1, and inducible nitric oxide synthase, which promoted IFN-γ production and improved systemic immunity. Depletion of CD8 T cells diminished the metastasis defect in the Tgfbr2(MyeKO) mice. Consistent with animal studies, myeloid cells from patients with advanced-stage cancer showed increased TGF-β receptor II expression. Our studies show that myeloid-specific TGF-β signaling is an essential component of the metastasis-promoting puzzle of TGF-β. This is in contrast to the previously reported tumor-suppressing phenotypes in fibroblasts, epithelial cells, and T cells.

KW - Animals

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KW - Cell Line, Tumor

KW - Disease Models, Animal

KW - Epithelial Cells

KW - Fibroblasts

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Mice

KW - Mice, Knockout

KW - Myeloid Cells

KW - Neoplasm Metastasis

KW - Nitric Oxide Synthase

KW - Protein-Serine-Threonine Kinases

KW - Receptors, Transforming Growth Factor beta

KW - Signal Transduction

KW - T-Lymphocytes

KW - Transforming Growth Factor beta

KW - Tumor Microenvironment

KW - Journal Article

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DO - 10.1158/2159-8290.CD-12-0527

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SN - 2159-8274

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SP - 936

EP - 951

JO - Cancer Discovery

JF - Cancer Discovery

IS - 8

ER -

TGF-β signaling in myeloid cells is required for tumor metastasis

Abstract

Keywords

UN SDGs

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