Mesenchymal stromal cells respond to necrotic material within tumor microenvironment with regard to proliferation and chemotaxis

Abstract

Necrosis with subsequent release of damage associated molecular patterns (DAMPs) is a characteristic feature shared by advanced solid tumors. DAMPs impact tumor microenvironment by initiating wound healing processes like angiogenesis or modulating the immune response. The presence of tumor-infiltrating immunoregulatory mesenchymal stromal cells (MSCs) is associated with higher risk of tumor progression and metastasis. Aim of the presented study was to characterize the impact of DAMPs on MSCs and furthermore to identify specific DAMPs which influence MSC biology in the setting of tumor necrosis. Additionally, the question concerning the importance of redox conditions for the biologic activity of DAMPs on MSCs was addressed here. Necrotic material (DAMPs), regardless of its tissue of origin, promoted migration and proliferation of MSCs. This effect could be diminished once the DAMPs were oxidized. High mobility group box 1 (HMGB1), S100A4 and uric acid could be identified as crucial members of the DAMP family that influence MSC biology within the tumor microenvironment. Reducing and hypoxic conditions characterize the tumor microenvironment and possibly protect sensitive DAMPs from oxidation. According to these results, oxidizing conditions should be preferred for therapeutic strategies that target the tumor microenvironment.