Angiotensin II Drives the Production of Tumor-Promoting Macrophages

• DOI: 10.1016/j.immuni.2012.10.015
• Publication Date: 2013-01-17T15:46:09Z
• Authors: Virna Cortez-Reta...; 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
• Keywords: 0301 basic medicine; 570; Lung Neoplasms; Immunology; 610; Gene Expression; Adenocarcinoma of Lung; Mice, Transgenic; Cell Communication; Adenocarcinoma; Mice; 03 medical and health sciences; Cell Movement; Sphingosine; Carcinoma, Non-Small-Cell Lung; Immunology and Allergy; Animals; Humans; Cell Proliferation; Angiotensin II; Macrophages; Hematopoietic Stem Cells; Tumor Burden; 3. Good health; Infectious Diseases; Lysophospholipids; Spleen; Signal Transduction

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 S1P(1) 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.