title: Decellularized human colorectal cancer matrices polarize macrophages towards an anti-inflammatory phenotype promoting cancer cell invasion via CCL18.
abstract: Macrophages are frequently identified in solid tumors, playing important roles in cancer progression. Their remarkable plasticity makes them very sensitive to environmental factors, including the extracellular matrix (ECM). In the present work, we investigated the impact of human colorectal tumor matrices on macrophage polarization and on macrophage-mediated cancer cell invasion. Accordingly, we developed an innovative 3D-organotypic model, based on the decellularization of normal and tumor tissues derived from colorectal cancer patients' surgical resections. Extensive characterization of these scaffolds revealed that DNA and other cell constituents were efficiently removed, while native tissue characteristics, namely major ECM components, architecture and mechanical properties, were preserved. Notably, normal and tumor decellularized matrices distinctly promoted macrophage polarization, with macrophages in tumor matrices differentiating towards an anti-inflammatory M2-like phenotype (higher IL-10, TGF-β and CCL18 and lower CCR7 and TNF expression). Matrigel invasion assays revealed that tumor ECM-educated macrophages efficiently stimulated cancer cell invasion through a mechanism involving CCL18. Notably, the high expression of this chemokine at the invasive front of human colorectal tumors correlated with advanced tumor staging. Our approach evidences that normal and tumor decellularized matrices constitute excellent scaffolds when trying to recreate complex microenvironments to understand basic mechanisms of disease or therapeutic resistance.
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-135, Portugal; ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, 4050-313, Portugal.
authors.forename: M L
authors.initials: ML
authors.lastname: Pinto
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, 4200-465, Portugal; Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, 4200-319, Portugal; Department of Pathology, Centro Hospitalar São João, Porto, 4200-319, Portugal.
authors.forename: E
authors.initials: E
authors.lastname: Rios
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-135, Portugal; ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, 4050-313, Portugal; Gladstone Institutes, University of California San Francisco, San Francisco, 94158, United States.
authors.forename: A C
authors.initials: AC
authors.lastname: Silva
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-135, Portugal; FEUP-Faculty of Engineering, University of Porto, Porto, 4200-465, Portugal.
authors.forename: S C
authors.initials: SC
authors.lastname: Neves
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-135, Portugal; ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, 4050-313, Portugal.
authors.forename: H R
authors.initials: HR
authors.lastname: Caires
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-135, Portugal; FEUP-Faculty of Engineering, University of Porto, Porto, 4200-465, Portugal.
authors.forename: A T
authors.initials: AT
authors.lastname: Pinto
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, 4200-465, Portugal.
authors.forename: C
authors.initials: C
authors.lastname: Durães
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, 1649-028, Portugal.
authors.forename: F A
authors.initials: FA
authors.lastname: Carvalho
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-135, Portugal; FEUP-Faculty of Engineering, University of Porto, Porto, 4200-465, Portugal.
authors.forename: A P
authors.initials: AP
authors.lastname: Cardoso
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, 1649-028, Portugal.
authors.forename: N C
authors.initials: NC
authors.lastname: Santos
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-135, Portugal; ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, 4050-313, Portugal.
authors.forename: C C
authors.initials: CC
authors.lastname: Barrias
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-135, Portugal.
authors.forename: D S
authors.initials: DS
authors.lastname: Nascimento
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-135, Portugal; Faculty of Medicine, University of Porto, Porto, 4200-319 Portugal.
authors.forename: P
authors.initials: P
authors.lastname: Pinto-do-Ó
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-135, Portugal; ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, 4050-313, Portugal.
authors.forename: M A
authors.initials: MA
authors.lastname: Barbosa
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, 4200-465, Portugal; Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, 4200-319, Portugal; Department of Pathology, Centro Hospitalar São João, Porto, 4200-319, Portugal.
authors.forename: F
authors.initials: F
authors.lastname: Carneiro
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-135, Portugal; Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, 4200-319, Portugal. Electronic address: mariajo@ineb.up.pt.
authors.forename: M J
authors.initials: MJ
authors.lastname: Oliveira
mesh_terms: D016764:Cell Polarity; D002474:Cell-Free System; D019742:Chemokines, CC / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000276:immunology* / Q000473:pathology*; D005109:Extracellular Matrix / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D009361:Neoplasm Invasiveness; D054457:Tissue Scaffolds; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: C111792:CCL18 protein, human; D019742:Chemokines, CC
keywords: CCL18; Colorectal cancer; Decellularization; Extracellular matrix; Macrophage polarization