Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in <i>Shb</i>-Deficient Endothelial Cells Increases Tumor Lung Metastasis

Metastasis reflects both the inherent properties of tumor cells and the response of the stroma to the presence of the tumor. Vascular barrier properties, either due to endothelial cell (EC) or pericyte function, play an important role in metastasis in addition to the contribution of the immune syste...

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Autores principales:	Qi He, Maria Jamalpour, Eric Bergquist, Robin L. Anderson, Karin Gustafsson, Michael Welsh
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	breast carcinoma metastasis angiogenesis immune suppression SHB Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/d7c47950013d40fab68f9bcfa2d029e2
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spelling	oai:doaj.org-article:d7c47950013d40fab68f9bcfa2d029e22021-11-11T16:56:46ZMouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in <i>Shb</i>-Deficient Endothelial Cells Increases Tumor Lung Metastasis10.3390/ijms2221114781422-00671661-6596https://doaj.org/article/d7c47950013d40fab68f9bcfa2d029e22021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11478https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Metastasis reflects both the inherent properties of tumor cells and the response of the stroma to the presence of the tumor. Vascular barrier properties, either due to endothelial cell (EC) or pericyte function, play an important role in metastasis in addition to the contribution of the immune system. The <i>Shb</i> gene encodes the Src homology-2 domain protein B that operates downstream of tyrosine kinases in both vascular and immune cells. We have investigated E0771.lmb breast carcinoma metastasis in mice with conditional deletion of the <i>Shb</i> gene using the <i>Cdh5-Cre<sup>ERt2</sup></i> transgene, resulting in inactivation of the <i>Shb</i>-gene in EC and some hematopoietic cell populations. Lung metastasis from orthotopic tumors, tumor vascular and immune cell characteristics, and immune cell gene expression profiles were determined. We found no increase in vascular leakage that could explain the observed increase in metastasis upon the loss of <i>Shb</i> expression. Instead, <i>Shb</i> deficiency in EC promoted the recruitment of monocytic/macrophagic myeloid-derived suppressor cells (mMDSC), an immune cell type that confers a suppressive immune response, thus enhancing lung metastasis. An MDSC-promoting cytokine/chemokine profile was simultaneously observed in tumors grown in mice with EC-specific <i>Shb</i> deficiency, providing an explanation for the expanded mMDSC population. The results demonstrate an intricate interplay between tumor EC and immune cells that pivots between pro-tumoral and anti-tumoral properties, depending on relevant genetic and/or environmental factors operating in the microenvironment.Qi HeMaria JamalpourEric BergquistRobin L. AndersonKarin GustafssonMichael WelshMDPI AGarticlebreast carcinomametastasisangiogenesisimmune suppressionSHBBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11478, p 11478 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	breast carcinoma metastasis angiogenesis immune suppression SHB Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	breast carcinoma metastasis angiogenesis immune suppression SHB Biology (General) QH301-705.5 Chemistry QD1-999 Qi He Maria Jamalpour Eric Bergquist Robin L. Anderson Karin Gustafsson Michael Welsh Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in <i>Shb</i>-Deficient Endothelial Cells Increases Tumor Lung Metastasis
description	Metastasis reflects both the inherent properties of tumor cells and the response of the stroma to the presence of the tumor. Vascular barrier properties, either due to endothelial cell (EC) or pericyte function, play an important role in metastasis in addition to the contribution of the immune system. The <i>Shb</i> gene encodes the Src homology-2 domain protein B that operates downstream of tyrosine kinases in both vascular and immune cells. We have investigated E0771.lmb breast carcinoma metastasis in mice with conditional deletion of the <i>Shb</i> gene using the <i>Cdh5-Cre<sup>ERt2</sup></i> transgene, resulting in inactivation of the <i>Shb</i>-gene in EC and some hematopoietic cell populations. Lung metastasis from orthotopic tumors, tumor vascular and immune cell characteristics, and immune cell gene expression profiles were determined. We found no increase in vascular leakage that could explain the observed increase in metastasis upon the loss of <i>Shb</i> expression. Instead, <i>Shb</i> deficiency in EC promoted the recruitment of monocytic/macrophagic myeloid-derived suppressor cells (mMDSC), an immune cell type that confers a suppressive immune response, thus enhancing lung metastasis. An MDSC-promoting cytokine/chemokine profile was simultaneously observed in tumors grown in mice with EC-specific <i>Shb</i> deficiency, providing an explanation for the expanded mMDSC population. The results demonstrate an intricate interplay between tumor EC and immune cells that pivots between pro-tumoral and anti-tumoral properties, depending on relevant genetic and/or environmental factors operating in the microenvironment.
format	article
author	Qi He Maria Jamalpour Eric Bergquist Robin L. Anderson Karin Gustafsson Michael Welsh
author_facet	Qi He Maria Jamalpour Eric Bergquist Robin L. Anderson Karin Gustafsson Michael Welsh
author_sort	Qi He
title	Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in <i>Shb</i>-Deficient Endothelial Cells Increases Tumor Lung Metastasis
title_short	Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in <i>Shb</i>-Deficient Endothelial Cells Increases Tumor Lung Metastasis
title_full	Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in <i>Shb</i>-Deficient Endothelial Cells Increases Tumor Lung Metastasis
title_fullStr	Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in <i>Shb</i>-Deficient Endothelial Cells Increases Tumor Lung Metastasis
title_full_unstemmed	Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in <i>Shb</i>-Deficient Endothelial Cells Increases Tumor Lung Metastasis
title_sort	mouse breast carcinoma monocytic/macrophagic myeloid-derived suppressor cell infiltration as a consequence of endothelial dysfunction in <i>shb</i>-deficient endothelial cells increases tumor lung metastasis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d7c47950013d40fab68f9bcfa2d029e2
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Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in <i>Shb</i>-Deficient Endothelial Cells Increases Tumor Lung Metastasis

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