Heterocellular 3D scaffolds as biomimetic to recapitulate the tumor microenvironment of peritoneal metastases in vitro and in vivo

Emiel De Jaeghere; Elly De Vlieghere; Jasper Van Hoorick; Sandra Van Vlierberghe; Glenn Wagemans; Leen Pieters; Elodie Melsens; Marleen Praet; Jo Van Dorpe; Matthieu N Boone; Rouba Ghobeira; Nathalie De Geyter; Marc Bracke; Christian Vanhove; Sara Neyt; Geert Berx; Bruno G De Geest; Peter Dubruel; Heidi Declercq; Wim Ceelen; Olivier De Wever

doi:10.1016/j.biomaterials.2017.12.017

Heterocellular 3D scaffolds as biomimetic to recapitulate the tumor microenvironment of peritoneal metastases in vitro and in vivo

Biomaterials. 2018 Mar:158:95-105. doi: 10.1016/j.biomaterials.2017.12.017. Epub 2017 Dec 23.

Authors

Emiel De Jaeghere¹, Elly De Vlieghere¹, Jasper Van Hoorick², Sandra Van Vlierberghe², Glenn Wagemans³, Leen Pieters⁴, Elodie Melsens⁵, Marleen Praet⁶, Jo Van Dorpe⁷, Matthieu N Boone⁸, Rouba Ghobeira⁹, Nathalie De Geyter⁹, Marc Bracke¹, Christian Vanhove¹⁰, Sara Neyt¹¹, Geert Berx¹², Bruno G De Geest¹³, Peter Dubruel², Heidi Declercq¹⁴, Wim Ceelen¹⁵, Olivier De Wever¹⁶

Affiliations

¹ Laboratory Experimental Cancer Research (LECR), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
² Polymer Chemistry & Biomaterials Group, Centre of Macromolecular Chemistry, Ghent University, Krijgslaan 281, S4-Bis, 9000 Ghent, Belgium.
³ Laboratory Experimental Cancer Research (LECR), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
⁴ Department of Basic Medical Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
⁵ Experimental Surgery Lab, Department of Surgery, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
⁶ Department of Pathology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
⁷ Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Department of Pathology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
⁸ Department of Physics and Astronomy, Ghent University, Proeftuinstraat 86, 9000 Ghent, Belgium.
⁹ Department of Applied Physics, Research Unit Plasma Technology (RUPT), Ghent University, Sint-Pietersnieuwstraat 41, B4, 9000 Ghent, Belgium.
¹⁰ Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Institute Biomedical Technology, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
¹¹ MOLECUBES NV, Ottergemsesteenweg-Zuid 808, 325 Ghent, Belgium.
¹² Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Department of Biomedical Molecular Biology, Unit of Molecular and Cellular Oncology, Inflammation Research Center, VIB, Technologiepark Zwijnaarde 927, 9052 Ghent, Belgium.
¹³ Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Department of Pharmaceutics, Ghent University, Ottergemstesteenweg 460, 9000 Ghent, Belgium.
¹⁴ Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Department of Basic Medical Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
¹⁵ Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Experimental Surgery Lab, Department of Surgery, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
¹⁶ Laboratory Experimental Cancer Research (LECR), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: Olivier.dewever@ugent.be.

PMID: 29306747
DOI: 10.1016/j.biomaterials.2017.12.017

Abstract

Peritoneal metastasis is a major cause of death and preclinical models are urgently needed to enhance therapeutic progress. This study reports on a hybrid hydrogel-polylactic acid (PLA) scaffold that mimics the architecture of peritoneal metastases at the qualitative, quantitative and spatial level. Porous PLA scaffolds with controllable pore size, geometry and surface properties are functionalized by type I collagen hydrogel. Co-seeding of cancer-associated fibroblasts (CAF) increases cancer cell adhesion, recovery and exponential growth by in situ heterocellular spheroid formation. Scaffold implantation into the peritoneum allows long-term follow-up (>14 weeks) and results in a time-dependent increase in vascularization, which correlates with cancer cell colonization in vivo. CAF, endothelial cells, macrophages and cancer cells show spatial and quantitative aspects as similarly observed in patient-derived peritoneal metastases. CAF provide long-term secretion of complementary paracrine factors implicated in spheroid formation in vitro as well as in recruitment and organization of host cells in vivo. In conclusion, the multifaceted heterocellular interactions that occur within peritoneal metastases are reproduced in this tissue-engineered implantable scaffold model.

Keywords: Biomimetics; Cancer-associated fibroblasts; Hybrid scaffolds; Hydrogels; Tissue engineering; Tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomimetics
Cell Line, Tumor
Coculture Techniques
Female
Humans
Mice
Peritoneal Neoplasms*
Polyesters / chemistry
Tissue Engineering
Tissue Scaffolds* / chemistry
Tumor Microenvironment*

Substances

Polyesters
poly(lactide)