Matrix metalloproteases as maestros for the dual role of LPS- and IL-10-stimulated macrophages in cancer cell behaviour

BMC Cancer

Research Article

Alberto Mantovani¹  Marc Mareel²  João B. Relvas³  Marta I. Oliveira⁴  Cátia Monteiro⁴  Maria J. Oliveira⁵  Ana T. Pinto⁶  Susana G. Santos⁶  Ana P. Cardoso⁶  Mário A. Barbosa⁷  Marta L. Pinto⁷  Marta T. Pinto⁸  Raquel Seruca⁹ 

[1] Humanitas Clinical and Research Centre, Rozzano, Italy;BIOMETRA Department, University of Milan, Milan, Italy;Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, Belgium;i3S-Instituto de Investigação e Inovação em Saúde/IBMC-Institute for Cell and Molecular Biology, University of Porto, Porto, Portugal;i3S-Instituto de Investigação e Inovação em Saúde/INEB-Institute of Biomedical Engineering, University of Porto, Porto, Portugal;i3S-Instituto de Investigação e Inovação em Saúde/INEB-Institute of Biomedical Engineering, University of Porto, Porto, Portugal;Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal;i3S-Instituto de Investigação e Inovação em Saúde/INEB-Institute of Biomedical Engineering, University of Porto, Porto, Portugal;FEUP-Faculty of Engineering, University of Porto, Porto, Portugal;i3S-Instituto de Investigação e Inovação em Saúde/INEB-Institute of Biomedical Engineering, University of Porto, Porto, Portugal;ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal;i3S-Instituto de Investigação e Inovação em Saúde/IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal;i3S-Instituto de Investigação e Inovação em Saúde/IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal;Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal;

关键词: Tumour microenvironment;    M1 and M2-like macrophages;    Invasion;    Angiogenesis;    Gastrointestinal cancer;    MMPs;   

DOI  :  10.1186/s12885-015-1466-8

 received in 2014-10-12, accepted in 2015-05-21,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe interactions established between macrophages and cancer cells are largely dependent on instructions from the tumour microenvironment. Macrophages may differentiate into populations with distinct inflammatory profiles, but knowledge on their role on cancer cell activities is still very scarce. In this work, we investigated the influence of pro-inflammatory (LPS-stimulated) and anti-inflammatory (IL-10-stimulated) macrophages on gastric and colorectal cancer cell invasion, motility/migration, angiogenesis and proteolysis, and the associated molecular mechanisms.MethodsFollowing exposure of gastric and colon cancer cell lines to LPS- and IL-10-stimulated human macrophages, either by indirect contact or conditioned media, we analyzed the effect of the different macrophage populations on cancer cell invasion, migration, motility and phosphorylation status of EGFR and several interacting partners. Cancer-cell induced angiogenesis upon the influence of conditioned media from both macrophage populations was assessed using the chick embryo chorioallantoic membrane assay. MMP activities were evaluated by gelatin zymograhy.ResultsOur results show that IL-10-stimulated macrophages are more efficient in promoting in vitro cancer cell invasion and migration. In addition, soluble factors produced by these macrophages enhanced in vivo cancer cell-induced angiogenesis, as opposed to their LPS-stimulated counterparts. We further demonstrate that differences in the ability of these macrophage populations to stimulate invasion or angiogenesis cannot be explained by the EGFR-mediated signalling, since both LPS- and IL-10-stimulated macrophages similarly induce the phosphorylation of cancer cell EGFR, c-Src, Akt, ERK1/2, and p38. Interestingly, both populations exert distinct proteolytic activities, being the IL-10-stimulated macrophages the most efficient in inducing matrix metalloprotease (MMP)-2 and MMP-9 activities. Using a broad-spectrum MMP inhibitor, we demonstrated that proteolysis was essential for macrophage-mediated cancer cell invasion and angiogenesis.ConclusionsWe propose that IL-10- and LPS-stimulated macrophages distinctly modulate gastric and colorectal cancer cell behaviour, as result of distinct proteolytic profiles that impact cell invasion and angiogenesis.

【 授权许可】

Unknown   
© Cardoso et al. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.