Contact-dependent carcinoma aggregate dispersion by M2a macrophages via ICAM-1 and β2 integrin interactions
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Jing Bai1,2,*, Giulia Adriani1,*, Truong-Minh Dang3, Ting-Yuan Tu1, Hwei-Xian Leong Penny3, Siew-Cheng Wong3, Roger D. Kamm1,2, Jean-Paul Thiery1,4,5
1BioSystems and Micromechanics IRG, Singapore-MIT Alliance for Research and Technology, 138602, Singapore
2Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
3SIgN (Singapore Immunology Network), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648, Singapore
4Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
5Institute of Molecular and Cell Biology, Proteos, 138673, Singapore
*These authors have contributed equally to this work
Jean-Paul Thiery, e-mail: [email protected]
Keywords: epithelial-mesenchymal transition, microfluidics, macrophage phenotypes, macrophage polarization, cancer microenvironment
Received: June 25, 2015 Accepted: July 17, 2015 Published: July 30, 2015
Tumor-associated macrophages (TAMs) can constitute up to 50% of the tumor mass and have strong implications in tumor progression and metastasis. Macrophages are plastic and can polarize to various subtypes that differ in terms of surface receptor expression as well as cytokine and chemokine production and effector function. Conventionally, macrophages are grouped into two major subtypes: the classically activated M1 macrophages and the alternatively activated M2 macrophages. M1 macrophages are pro-inflammatory, promote T helper (Th) 1 responses, and show tumoricidal activity, whereas M2 macrophages contribute to tissue repair and promote Th2 responses. Herein, we present a microfluidic system integrating tumor cell aggregates and subtypes of human monocyte-derived macrophages in a three-dimensional hydrogel scaffold, in close co-culture with an endothelial monolayer to create an in vitro tumor microenvironment. This platform was utilized to study the role of individual subtypes of macrophages (M0, M1, M2a, M2b and M2c) in human lung adenocarcinoma (A549) aggregate dispersion, as a representation of epithelial-mesenchymal transition (EMT). A significant difference was observed when M2a macrophages were in direct contact with or separated from A549 aggregates, suggesting a possible mechanism for proximity-induced, contact-dependent dissemination via ICAM-1 and integrin β2 interactions. Indeed, M2a macrophages tended to infiltrate and release cells from carcinoma cell aggregates. These findings may help in the development of immunotherapies based on enhancing the tumor-suppressive properties of TAMs.
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