Comparative Analysis of Cell-Cell Contact Abundance in Ovarian Carcinoma Cells Cultured in Two- and Three-Dimensional In Vitro Models.

Abstract

Simple SummaryTumor resistance to therapy is a crucial problem of today’s oncology. The emerging data indicate that tumor microenvironment is the key participant in the resistance development. One of the most basic aspect of tumor microenvironment is intercellular adhesion. Our data obtained using monolayer culture, matrix-free and matrix-based three-dimensional in vitro models indicate that the abundance of cell-cell contact proteins is varying depending on the microenvironment. These differences coincided with the degree of the resistance to therapeutics. The importance of adhesion proteins in tumor resistance may provide the fundamental basis for improving cancer treatment approaches and must be taken into account when screening candidate drugs. Tumor resistance to therapy is associated with the 3D organization and peculiarities of the tumor microenvironment, of which intercellular adhesion is a key participant. In this work, the abundance of contact proteins was compared in SKOV-3 and SKOV-3.ip human ovarian adenocarcinoma cell lines, cultivated in monolayers, tumor spheroids and collagen hydrogels. Three-dimensional models were characterized by extremely low expression of basic molecules of adherens junctions E-cadherin and demonstrated a simultaneous decrease in desmosomal protein desmoglein-2, gap junction protein connexin-43 and tight junction proteins occludin and ZO-1. The reduction in the level of contact proteins was most pronounced in collagen hydrogel, accompanied by significantly increased resistance to treatment with doxorubicin and targeted anticancer toxin DARPin-LoPE. Thus, we suggest that 3D models of ovarian cancer, especially matrix-based models, tend to recapitulate tumor microenvironment and treatment responsiveness to a greater extent than monolayer culture, so they can be used as a highly relevant platform for drug efficiency evaluation.