Angiotensin II Drives the Production of Tumor-Promoting Macrophages

Virna Cortez-Retamozo; Martin Etzrodt; Andita Newton; Russell Ryan; Ferdinando Pucci; Selena W. Sio; Wilson Kuswanto; Philipp J. Rauch; Aleksey Chudnovskiy; Yoshiko Iwamoto; Rainer Kohler; Brett Marinelli; Rostic Gorbatov; Gregory Wojtkiewicz; Peter Panizzi; Mari Mino-Kenudson; Reza Forghani; Jose Luiz Figueiredo; John W. Chen; Ramnik Xavier; Filip K. Swirski; Matthias Nahrendorf; Ralph Weissleder; Mikael J. Pittet

doi:10.1016/j.immuni.2012.10.015

Angiotensin II Drives the Production of Tumor-Promoting Macrophages

Virna Cortez-Retamozo, Martin Etzrodt, Andita Newton, Russell Ryan, Ferdinando Pucci, Selena W. Sio, Wilson Kuswanto, Philipp J. Rauch, Aleksey Chudnovskiy, Yoshiko Iwamoto, Rainer Kohler, Brett Marinelli, Rostic Gorbatov, Gregory Wojtkiewicz, Peter Panizzi, Mari Mino-Kenudson, Reza Forghani, Jose Luiz Figueiredo, John W. Chen, Ramnik XavierFilip K. Swirski, Matthias Nahrendorf, Ralph Weissleder, Mikael J. Pittet

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

143 Scopus citations

Abstract

Macrophages frequently infiltrate tumors and can enhance cancer growth, yet the origins of the macrophage response are not well understood. Here we address molecular mechanisms of macrophage production in a conditional mouse model of lung adenocarcinoma. We report that overproduction of the peptide hormone Angiotensin II (AngII) in tumor-bearing mice amplifies self-renewing hematopoietic stem cells (HSCs) and macrophage progenitors. The process occurred in the spleen but not the bone marrow, and was independent of hemodynamic changes. The effects of AngII required direct hormone ligation on HSCs, depended on S1P₁ signaling, and allowed the extramedullary tissue to supply new tumor-associated macrophages throughout cancer progression. Conversely, blocking AngII production prevented cancer-induced HSC and macrophage progenitor amplification and thus restrained the macrophage response at its source. These findings indicate that AngII acts upstream of a potent macrophage amplification program and that tumors can remotely exploit the hormone's pathway to stimulate cancer-promoting immunity.

Original language	English (US)
Pages (from-to)	296-308
Number of pages	13
Journal	Immunity
Volume	38
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2012.10.015
State	Published - Feb 21 2013
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2012.10.015

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Cortez-Retamozo, V., Etzrodt, M., Newton, A., Ryan, R., Pucci, F., Sio, S. W., Kuswanto, W., Rauch, P. J., Chudnovskiy, A., Iwamoto, Y., Kohler, R., Marinelli, B., Gorbatov, R., Wojtkiewicz, G., Panizzi, P., Mino-Kenudson, M., Forghani, R., Figueiredo, J. L., Chen, J. W., ... Pittet, M. J. (2013). Angiotensin II Drives the Production of Tumor-Promoting Macrophages. Immunity, 38(2), 296-308. https://doi.org/10.1016/j.immuni.2012.10.015

Cortez-Retamozo, V, Etzrodt, M, Newton, A, Ryan, R, Pucci, F, Sio, SW, Kuswanto, W, Rauch, PJ, Chudnovskiy, A, Iwamoto, Y, Kohler, R, Marinelli, B, Gorbatov, R, Wojtkiewicz, G, Panizzi, P, Mino-Kenudson, M, Forghani, R, Figueiredo, JL, Chen, JW, Xavier, R, Swirski, FK, Nahrendorf, M, Weissleder, R & Pittet, MJ 2013, 'Angiotensin II Drives the Production of Tumor-Promoting Macrophages', Immunity, vol. 38, no. 2, pp. 296-308. https://doi.org/10.1016/j.immuni.2012.10.015

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title = "Angiotensin II Drives the Production of Tumor-Promoting Macrophages",

abstract = "Macrophages frequently infiltrate tumors and can enhance cancer growth, yet the origins of the macrophage response are not well understood. Here we address molecular mechanisms of macrophage production in a conditional mouse model of lung adenocarcinoma. We report that overproduction of the peptide hormone Angiotensin II (AngII) in tumor-bearing mice amplifies self-renewing hematopoietic stem cells (HSCs) and macrophage progenitors. The process occurred in the spleen but not the bone marrow, and was independent of hemodynamic changes. The effects of AngII required direct hormone ligation on HSCs, depended on S1P1 signaling, and allowed the extramedullary tissue to supply new tumor-associated macrophages throughout cancer progression. Conversely, blocking AngII production prevented cancer-induced HSC and macrophage progenitor amplification and thus restrained the macrophage response at its source. These findings indicate that AngII acts upstream of a potent macrophage amplification program and that tumors can remotely exploit the hormone's pathway to stimulate cancer-promoting immunity.",

author = "Virna Cortez-Retamozo and Martin Etzrodt and Andita Newton and Russell Ryan and Ferdinando Pucci and Sio, {Selena W.} and Wilson Kuswanto and Rauch, {Philipp J.} and Aleksey Chudnovskiy and Yoshiko Iwamoto and Rainer Kohler and Brett Marinelli and Rostic Gorbatov and Gregory Wojtkiewicz and Peter Panizzi and Mari Mino-Kenudson and Reza Forghani and Figueiredo, {Jose Luiz} and Chen, {John W.} and Ramnik Xavier and Swirski, {Filip K.} and Matthias Nahrendorf and Ralph Weissleder and Pittet, {Mikael J.}",

note = "Funding Information: The authors thank Jessica Truelove (MGH) for imaging and Michael Waring and Adam Chicoine (Ragon Institute, MGH) for sorting cells. This work was supported in part by NIH grants P50-CA86355, R01-AI084880, R56-AI084880, and MGH-Center for Systems Biology (to M.J.P.) and U54-CA126515 (to R.W.). M.E. is part of the International PhD program “Cancer and Immunology” at the University of Lausanne, Switzerland, and was supported by the AACR Centennial Predoctoral Fellowship and the Boehringer Ingelheim Fonds. ",

year = "2013",

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doi = "10.1016/j.immuni.2012.10.015",

language = "English (US)",

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T1 - Angiotensin II Drives the Production of Tumor-Promoting Macrophages

AU - Cortez-Retamozo, Virna

AU - Etzrodt, Martin

AU - Newton, Andita

AU - Ryan, Russell

AU - Pucci, Ferdinando

AU - Sio, Selena W.

AU - Kuswanto, Wilson

AU - Rauch, Philipp J.

AU - Chudnovskiy, Aleksey

AU - Iwamoto, Yoshiko

AU - Kohler, Rainer

AU - Marinelli, Brett

AU - Gorbatov, Rostic

AU - Wojtkiewicz, Gregory

AU - Panizzi, Peter

AU - Mino-Kenudson, Mari

AU - Forghani, Reza

AU - Figueiredo, Jose Luiz

AU - Chen, John W.

AU - Xavier, Ramnik

AU - Swirski, Filip K.

AU - Nahrendorf, Matthias

AU - Weissleder, Ralph

AU - Pittet, Mikael J.

N1 - Funding Information: The authors thank Jessica Truelove (MGH) for imaging and Michael Waring and Adam Chicoine (Ragon Institute, MGH) for sorting cells. This work was supported in part by NIH grants P50-CA86355, R01-AI084880, R56-AI084880, and MGH-Center for Systems Biology (to M.J.P.) and U54-CA126515 (to R.W.). M.E. is part of the International PhD program “Cancer and Immunology” at the University of Lausanne, Switzerland, and was supported by the AACR Centennial Predoctoral Fellowship and the Boehringer Ingelheim Fonds.

PY - 2013/2/21

Y1 - 2013/2/21

N2 - Macrophages frequently infiltrate tumors and can enhance cancer growth, yet the origins of the macrophage response are not well understood. Here we address molecular mechanisms of macrophage production in a conditional mouse model of lung adenocarcinoma. We report that overproduction of the peptide hormone Angiotensin II (AngII) in tumor-bearing mice amplifies self-renewing hematopoietic stem cells (HSCs) and macrophage progenitors. The process occurred in the spleen but not the bone marrow, and was independent of hemodynamic changes. The effects of AngII required direct hormone ligation on HSCs, depended on S1P1 signaling, and allowed the extramedullary tissue to supply new tumor-associated macrophages throughout cancer progression. Conversely, blocking AngII production prevented cancer-induced HSC and macrophage progenitor amplification and thus restrained the macrophage response at its source. These findings indicate that AngII acts upstream of a potent macrophage amplification program and that tumors can remotely exploit the hormone's pathway to stimulate cancer-promoting immunity.

AB - Macrophages frequently infiltrate tumors and can enhance cancer growth, yet the origins of the macrophage response are not well understood. Here we address molecular mechanisms of macrophage production in a conditional mouse model of lung adenocarcinoma. We report that overproduction of the peptide hormone Angiotensin II (AngII) in tumor-bearing mice amplifies self-renewing hematopoietic stem cells (HSCs) and macrophage progenitors. The process occurred in the spleen but not the bone marrow, and was independent of hemodynamic changes. The effects of AngII required direct hormone ligation on HSCs, depended on S1P1 signaling, and allowed the extramedullary tissue to supply new tumor-associated macrophages throughout cancer progression. Conversely, blocking AngII production prevented cancer-induced HSC and macrophage progenitor amplification and thus restrained the macrophage response at its source. These findings indicate that AngII acts upstream of a potent macrophage amplification program and that tumors can remotely exploit the hormone's pathway to stimulate cancer-promoting immunity.

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JO - Immunity

JF - Immunity

IS - 2

ER -

Angiotensin II Drives the Production of Tumor-Promoting Macrophages

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