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 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.
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors: Virna
authors: V
authors: Cortez-Retamozo
authors: Martin
authors: M
authors: Etzrodt
authors: Andita
authors: A
authors: Newton
authors: Russell
authors: R
authors: Ryan
authors: Ferdinando
authors: F
authors: Pucci
authors: Selena W
authors: SW
authors: Sio
authors: Wilson
authors: W
authors: Kuswanto
authors: Philipp J
authors: PJ
authors: Rauch
authors: Aleksey
authors: A
authors: Chudnovskiy
authors: Yoshiko
authors: Y
authors: Iwamoto
authors: Rainer
authors: R
authors: Kohler
authors: Brett
authors: B
authors: Marinelli
authors: Rostic
authors: R
authors: Gorbatov
authors: Gregory
authors: G
authors: Wojtkiewicz
authors: Peter
authors: P
authors: Panizzi
authors: Mari
authors: M
authors: Mino-Kenudson
authors: Reza
authors: R
authors: Forghani
authors: Jose-Luiz
authors: JL
authors: Figueiredo
authors: John W
authors: JW
authors: Chen
authors: Ramnik
authors: R
authors: Xavier
authors: Filip K
authors: FK
authors: Swirski
authors: Matthias
authors: M
authors: Nahrendorf
authors: Ralph
authors: R
authors: Weissleder
authors: Mikael J
authors: MJ
authors: Pittet
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000804:Angiotensin II / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication; D002465:Cell Movement; D049109:Cell Proliferation; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013154:Spleen / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden
chemical_list: D008246:Lysophospholipids; D000804:Angiotensin II; C060506:sphingosine 1-phosphate; D013110:Sphingosine