Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer

Karin Binnemars-Postma, Ruchi Bansal, Gert Storm, Jai Prakash (Corresponding Author)

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Abstract

Tumor-associated macrophages (TAMs) are the key effector cells in the tumor microenvironment and induce neoangiogenesis, matrix remodeling, and metastasis while suppressing the tumor immune system. These protumoral macrophages display an M2 phenotype induced by IL-4 and IL-13 cytokines. In this study, we hypothesized that the inhibition of the signal transducer and activator of transcription 6 (Stat6) pathway, a common downstream signaling pathway of IL-4 and IL-13, may be an interesting strategy by which to inhibit TAM differentiation and, thus, their protumorigenic activities. In vitro inhibition of the Stat6 pathway by using small interfering RNA or the pharmacologic inhibitor, AS1517499, inhibited the differentiation of mouse RAW264.7 macrophages into the M2 phenotype, as demonstrated by the reduction of Arg-1 (arginase-1) and Mrc-1 (mannose receptor 1) expression and arginase activity. In vivo, AS1517499 significantly attenuated tumor growth and early liver metastasis in an orthotopic 4T1 mammary carcinoma mouse model. Furthermore, in another experiment, we observed an increase in the intrahepatic mRNA expression of F4/80 (EGF-like module-containing mucin-like hormone receptor-like 1; total macrophages) and M2 macrophage markers [Ym-1 (chitinase 3–like protein 3) and Mrc-1] and metastatic niche markers [Mmp-2 (matrix metalloproteinase-2), Postn (periostin), and Cd34] in mice with increasing growth of primary tumors. Of interest, these markers were found to be reduced after treatment with AS1517499. In summary, inhibition of the Stat6 pathway in TAMs is a vital therapeutic approach to attenuate tumor growth and metastasis by inhibiting TAM-induced protumorigenic and prometastatic activities
Original languageEnglish
Article numberfj.201700629R
Pages (from-to)969-978
Number of pages10
JournalFASEB journal
Volume32
Issue number2
Early online date24 Oct 2017
DOIs
Publication statusPublished - Feb 2018

Fingerprint

STAT6 Transcription Factor
Macrophages
Tumors
Breast Neoplasms
Growth
Neoplasms
Arginase
Interleukin-13
Neoplasm Metastasis
Interleukin-4
Phenotype
Chitinases
Tumor Microenvironment
Matrix Metalloproteinase 2
Mucins
Immune system
Epidermal Growth Factor
Small Interfering RNA
Immune System
Liver

Cite this

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title = "Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer",
abstract = "Tumor-associated macrophages (TAMs) are the key effector cells in the tumor microenvironment and induce neoangiogenesis, matrix remodeling, and metastasis while suppressing the tumor immune system. These protumoral macrophages display an M2 phenotype induced by IL-4 and IL-13 cytokines. In this study, we hypothesized that the inhibition of the signal transducer and activator of transcription 6 (Stat6) pathway, a common downstream signaling pathway of IL-4 and IL-13, may be an interesting strategy by which to inhibit TAM differentiation and, thus, their protumorigenic activities. In vitro inhibition of the Stat6 pathway by using small interfering RNA or the pharmacologic inhibitor, AS1517499, inhibited the differentiation of mouse RAW264.7 macrophages into the M2 phenotype, as demonstrated by the reduction of Arg-1 (arginase-1) and Mrc-1 (mannose receptor 1) expression and arginase activity. In vivo, AS1517499 significantly attenuated tumor growth and early liver metastasis in an orthotopic 4T1 mammary carcinoma mouse model. Furthermore, in another experiment, we observed an increase in the intrahepatic mRNA expression of F4/80 (EGF-like module-containing mucin-like hormone receptor-like 1; total macrophages) and M2 macrophage markers [Ym-1 (chitinase 3–like protein 3) and Mrc-1] and metastatic niche markers [Mmp-2 (matrix metalloproteinase-2), Postn (periostin), and Cd34] in mice with increasing growth of primary tumors. Of interest, these markers were found to be reduced after treatment with AS1517499. In summary, inhibition of the Stat6 pathway in TAMs is a vital therapeutic approach to attenuate tumor growth and metastasis by inhibiting TAM-induced protumorigenic and prometastatic activities",
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Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer. / Binnemars-Postma, Karin; Bansal, Ruchi; Storm, Gert; Prakash, Jai (Corresponding Author).

In: FASEB journal, Vol. 32, No. 2, fj.201700629R, 02.2018, p. 969-978.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer

AU - Binnemars-Postma, Karin

AU - Bansal, Ruchi

AU - Storm, Gert

AU - Prakash, Jai

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AB - Tumor-associated macrophages (TAMs) are the key effector cells in the tumor microenvironment and induce neoangiogenesis, matrix remodeling, and metastasis while suppressing the tumor immune system. These protumoral macrophages display an M2 phenotype induced by IL-4 and IL-13 cytokines. In this study, we hypothesized that the inhibition of the signal transducer and activator of transcription 6 (Stat6) pathway, a common downstream signaling pathway of IL-4 and IL-13, may be an interesting strategy by which to inhibit TAM differentiation and, thus, their protumorigenic activities. In vitro inhibition of the Stat6 pathway by using small interfering RNA or the pharmacologic inhibitor, AS1517499, inhibited the differentiation of mouse RAW264.7 macrophages into the M2 phenotype, as demonstrated by the reduction of Arg-1 (arginase-1) and Mrc-1 (mannose receptor 1) expression and arginase activity. In vivo, AS1517499 significantly attenuated tumor growth and early liver metastasis in an orthotopic 4T1 mammary carcinoma mouse model. Furthermore, in another experiment, we observed an increase in the intrahepatic mRNA expression of F4/80 (EGF-like module-containing mucin-like hormone receptor-like 1; total macrophages) and M2 macrophage markers [Ym-1 (chitinase 3–like protein 3) and Mrc-1] and metastatic niche markers [Mmp-2 (matrix metalloproteinase-2), Postn (periostin), and Cd34] in mice with increasing growth of primary tumors. Of interest, these markers were found to be reduced after treatment with AS1517499. In summary, inhibition of the Stat6 pathway in TAMs is a vital therapeutic approach to attenuate tumor growth and metastasis by inhibiting TAM-induced protumorigenic and prometastatic activities

U2 - 10.1096/fj.201700629R

DO - 10.1096/fj.201700629R

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EP - 978

JO - FASEB journal

JF - FASEB journal

SN - 0892-6638

IS - 2

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