Angiotensin II Drives the Production of Tumor-Promoting Macrophages

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• 作者：Virna Cortez-Retamozo¹ ; ⁵ ; Martin Etzrodt¹ ; ⁵ ; Andita Newton¹ ; Russell Ryan³ ; Ferdinando Pucci¹ ; Selena W. Sio¹ ; Wilson Kuswanto¹ ; Philipp J. Rauch¹ ; Aleksey Chudnovskiy¹ ; Yoshiko Iwamoto¹ ; Rainer Kohler¹ ; Brett Marinelli¹ ; Rostic Gorbatov¹ ; Gregory Wojtkiewicz¹ ; Peter Panizzi¹ ; Mari Mino-Kenudson³ ; Reza Forghani¹ ; Jose-Luiz Figueiredo¹ ; John W. Chen¹ ; Ramnik Xavier² ; Filip K. Swirski¹ ; Matthias Nahrendorf¹ ; Ralph Weissleder¹ ; ⁴ ; Mikael J. Pittet¹ ; ^{mpittet@mgh.harvard.edu}
• 刊名：Immunity
• 出版年：2013
• 出版时间：21 February, 2013
• 年：2013
• 卷：38
• 期：2
• 页码：296-308
• 全文大小：1960 K

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lass=""h3"">Summary

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.