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Nat Commun. 2015 Nov 2;6:8695. doi: 10.1038/ncomms9695.

BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages.

Author information

1
BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.
2
Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno 84081, Italy.
3
Department of Pharmacy, Division of Biomedicine "A. Leone", University of Salerno, Fisciano, Salerno 84084, Italy.
4
Pathology Unit, Istituto Nazionale Tumouri Fondazione "G. Pascale", Naples 81100, Italy.
5
Animal facility, Istituto Nazionale Tumouri Fondazione "G. Pascale", Naples 81100, Italy.
6
Reconstructive Microsurgery, Department of Oncology, Careggi University Hospital, Florence 50139, Italy.
7
Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, Montpellier 34293, France.
8
Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105AZ, The Netherlands.
9
Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, Chieti 66100, Italy.
10
Division of Surgical Oncology, "S.S. Annunziata"Hospital, Chieti 66100, Italy.
11
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD, School of Medicine, San Diego, California 92093-0723, USA.
12
CALIXAR, Bioparc, Bâtiment Laënnec, Lyon 69008, France.
13
Department of Surgery, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
14
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.

Abstract

The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential.

PMID:
26522614
PMCID:
PMC4659838
DOI:
10.1038/ncomms9695
[Indexed for MEDLINE]
Free PMC Article
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