Contact-dependent carcinoma aggregate dispersion by M2a macrophages via ICAM-1 and β2 integrin interactions

Abstract

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.

A 3D microfluidic model for preclinical evaluation of TCR-engineered T cells against solid tumors

“…The detailed design and fabrication procedure of the poly(dimethylsiloxane) (PDMS) device (Figure 1), comprising a gel region with adjoining media channels separated from the gel channel by trapezoidal posts (100 μm spacing) was tested and validated in our previous publications (16,29,30). The height of the microfluidic channels is 120 μm, the culture media channel width is 500 μm, and the gel region width is 1 mm.…”

Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma

“…3 consisting of a central gel channel flanked by two fluidic channels was utilized. Similar microfluidic platforms have been used for investigating angiogenesis, 13,14 EMT, 15,16 cancer cell-macrophage interactions, 17 intravasation 18 and extravasation. 19,20 For the present work, GFPexpressing HUVECs were seeded into one of the fluidic channels to form a uniform monolayer mimicking a blood vessel wall (Fig.…”

Role of LFA-1 and ICAM-1 in Cancer

“…The metastasis-promoting effect of macrophages is exerted through cytokine secretion such as TGFß [23]. In an in vitro model of EMT, it was shown that M2-type macrophages in direct contact with carcinoma cells facilitated the dispersion of the latter via ICAM-1 and integrin CD18 interaction [26]. Similarly, in a mouse ovarian cancer model, the initial steps of spheroid formation and transcoelomic metastasis were facilitated by the attachment of cancer cells to macrophages via CD11b/CD18 -ICAM-1 adhesion [25].…”