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.
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.
Biomaterials. 2017 Apr;124:211-224. doi: 10.1016/j.biomaterials.2017.02.004. Epub 2017 Feb 5.
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.
巨噬细胞经常在实体肿瘤中被发现，在癌症进展中发挥着重要作用。它们显著的可塑性使它们对环境因素非常敏感，包括细胞外基质（ECM）。在本工作中，我们研究了人结直肠肿瘤基质对巨噬细胞极化和巨噬细胞介导的癌细胞侵袭的影响。相应地，我们开发了一种基于正常和肿瘤组织脱细胞化的创新的 3D 器官型模型，这些组织来源于结直肠癌患者的手术切除。对这些支架的广泛表征表明，DNA 和其他细胞成分被有效地去除，而天然组织特征，即主要的 ECM 成分、结构和机械性能，得以保留。值得注意的是，正常和肿瘤脱细胞基质明显促进了巨噬细胞的极化，肿瘤基质中的巨噬细胞向抗炎 M2 样表型分化（更高的 IL-10、TGF-β 和 CCL18，以及更低的 CCR7 和 TNF 表达）。基质胶侵袭实验表明，肿瘤 ECM 诱导的巨噬细胞通过涉及 CCL18 的机制有效地刺激癌细胞侵袭。值得注意的是，这种趋化因子在人结直肠肿瘤侵袭前沿的高表达与肿瘤的晚期分期相关。我们的方法证明，正常和肿瘤脱细胞基质在试图重建复杂的微环境以了解疾病的基本机制或治疗抵抗时，是极好的支架。
