TGFβ Signaling in Myeloid Cells Promotes Lung and Liver Metastasis Through Different Mechanisms

TGFβ overexpression is commonly detected in cancer patients and correlates with poor prognosis and metastasis. Cancer progression is often associated with an enhanced recruitment of myeloid-derived cells to the tumor microenvironment. Here we show that functional TGFβ-signaling in myeloid cells is r...

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Autores principales:	Cristina Stefanescu, Merel Van Gogh, Marko Roblek, Mathias Heikenwalder, Lubor Borsig
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	tumor microenvironment metastasis TGFβ mouse model lung liver Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/de470c0be9224bdbbb3aae21b447f81c
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spelling	oai:doaj.org-article:de470c0be9224bdbbb3aae21b447f81c2021-11-18T09:20:05ZTGFβ Signaling in Myeloid Cells Promotes Lung and Liver Metastasis Through Different Mechanisms2234-943X10.3389/fonc.2021.765151https://doaj.org/article/de470c0be9224bdbbb3aae21b447f81c2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.765151/fullhttps://doaj.org/toc/2234-943XTGFβ overexpression is commonly detected in cancer patients and correlates with poor prognosis and metastasis. Cancer progression is often associated with an enhanced recruitment of myeloid-derived cells to the tumor microenvironment. Here we show that functional TGFβ-signaling in myeloid cells is required for metastasis to the lungs and the liver. Myeloid-specific deletion of Tgfbr2 resulted in reduced spontaneous lung metastasis, which was associated with a reduction of proinflammatory cytokines in the metastatic microenvironment. Notably, CD8+ T cell depletion in myeloid-specific Tgfbr2-deficient mice rescued lung metastasis. Myeloid-specific Tgfbr2-deficiency resulted in reduced liver metastasis with an almost complete absence of myeloid cells within metastatic foci. On contrary, an accumulation of Tgfβ-responsive myeloid cells was associated with an increased recruitment of monocytes and granulocytes and higher proinflammatory cytokine levels in control mice. Monocytic cells isolated from metastatic livers of Tgfbr2-deficient mice showed increased polarization towards the M1 phenotype, Tnfα and Il-1β expression, reduced levels of M2 markers and reduced production of chemokines responsible for myeloid-cell recruitment. No significant differences in Tgfβ levels were observed at metastatic sites of any model. These data demonstrate that Tgfβ signaling in monocytic myeloid cells suppresses CD8+ T cell activity during lung metastasis, while these cells actively contribute to tumor growth during liver metastasis. Thus, myeloid cells modulate metastasis through different mechanisms in a tissue-specific manner.Cristina StefanescuMerel Van GoghMarko RoblekMarko RoblekMathias HeikenwalderLubor BorsigLubor BorsigFrontiers Media S.A.articletumor microenvironmentmetastasisTGFβmouse modellungliverNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tumor microenvironment metastasis TGFβ mouse model lung liver Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	tumor microenvironment metastasis TGFβ mouse model lung liver Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cristina Stefanescu Merel Van Gogh Marko Roblek Marko Roblek Mathias Heikenwalder Lubor Borsig Lubor Borsig TGFβ Signaling in Myeloid Cells Promotes Lung and Liver Metastasis Through Different Mechanisms
description	TGFβ overexpression is commonly detected in cancer patients and correlates with poor prognosis and metastasis. Cancer progression is often associated with an enhanced recruitment of myeloid-derived cells to the tumor microenvironment. Here we show that functional TGFβ-signaling in myeloid cells is required for metastasis to the lungs and the liver. Myeloid-specific deletion of Tgfbr2 resulted in reduced spontaneous lung metastasis, which was associated with a reduction of proinflammatory cytokines in the metastatic microenvironment. Notably, CD8+ T cell depletion in myeloid-specific Tgfbr2-deficient mice rescued lung metastasis. Myeloid-specific Tgfbr2-deficiency resulted in reduced liver metastasis with an almost complete absence of myeloid cells within metastatic foci. On contrary, an accumulation of Tgfβ-responsive myeloid cells was associated with an increased recruitment of monocytes and granulocytes and higher proinflammatory cytokine levels in control mice. Monocytic cells isolated from metastatic livers of Tgfbr2-deficient mice showed increased polarization towards the M1 phenotype, Tnfα and Il-1β expression, reduced levels of M2 markers and reduced production of chemokines responsible for myeloid-cell recruitment. No significant differences in Tgfβ levels were observed at metastatic sites of any model. These data demonstrate that Tgfβ signaling in monocytic myeloid cells suppresses CD8+ T cell activity during lung metastasis, while these cells actively contribute to tumor growth during liver metastasis. Thus, myeloid cells modulate metastasis through different mechanisms in a tissue-specific manner.
format	article
author	Cristina Stefanescu Merel Van Gogh Marko Roblek Marko Roblek Mathias Heikenwalder Lubor Borsig Lubor Borsig
author_facet	Cristina Stefanescu Merel Van Gogh Marko Roblek Marko Roblek Mathias Heikenwalder Lubor Borsig Lubor Borsig
author_sort	Cristina Stefanescu
title	TGFβ Signaling in Myeloid Cells Promotes Lung and Liver Metastasis Through Different Mechanisms
title_short	TGFβ Signaling in Myeloid Cells Promotes Lung and Liver Metastasis Through Different Mechanisms
title_full	TGFβ Signaling in Myeloid Cells Promotes Lung and Liver Metastasis Through Different Mechanisms
title_fullStr	TGFβ Signaling in Myeloid Cells Promotes Lung and Liver Metastasis Through Different Mechanisms
title_full_unstemmed	TGFβ Signaling in Myeloid Cells Promotes Lung and Liver Metastasis Through Different Mechanisms
title_sort	tgfβ signaling in myeloid cells promotes lung and liver metastasis through different mechanisms
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/de470c0be9224bdbbb3aae21b447f81c
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_version_	1718420933859868672

TGFβ Signaling in Myeloid Cells Promotes Lung and Liver Metastasis Through Different Mechanisms

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