Abstract
BackgroundCells of the tumor microenvironment are recognized as important determinants of the tumor biology. The adjacent non-malignant cells can regulate drug responses of the cancer cells by secreted paracrine factors and direct interactions with tumor cells.ResultsHuman mesenchymal stromal cells (MSC) actively contribute to tumor microenvironment. Here we focused on their response to chemotherapy as during the treatment these cells become affected. We have shown that the secretory phenotype and behavior of mesenchymal stromal cells influenced by cisplatin differs from the naïve MSC. MSC were more resistant to the concentrations of cisplatin, which was cytotoxic for tumor cells. They did not undergo apoptosis, but a part of MSC population underwent senescence. However, MSC pretreatment with cisplatin led to changes in phosphorylation profiles of many kinases and also increased secretion of IL-6 and IL-8 cytokines. These changes in cytokine and phosphorylation profile of MSC led to increased chemoresistance and stemness of breast cancer cells.ConclusionTaken together here we suggest that the exposure of the chemoresistant cells in the tumor microenvironment leads to substantial alterations and might lead to promotion of acquired microenvironment-mediated chemoresistance and stemness.
Highlights
Cells of the tumor microenvironment are recognized as important determinants of the tumor biology
Mesenchymal stromal cells (MSC) exposed to cisplatin did not undergo apoptosis but underwent senescence Based on the sensitivity of breast cancer cell lines (Fig. 1a) we have chosen the concentration of 1 μg/ml cisplatin (IC80 for almost all used cell lines) for pretreatment of mesenchymal stromal cells (MSC)
We have shown that MSC are resistant to 1 μg/ ml cisplatin by measuring Caspase-3/7 activity corresponding to the induction of apoptosis in treated cells
Summary
Cells of the tumor microenvironment are recognized as important determinants of the tumor biology. Tumor microenvironment is composed of many different types of non-malignant cells including mesenchymal stromal cells (MSC) [7]. Gilbert et al [12] suggested that the chemotherapeutic drug doxorubicin leads to an acute stress response in the cells of the tumor microenvironment which results in the induction of chemoresistance in multiple myeloma. Similar processes, such as a stress response in the cells from the stromal tumor compartment including the MSC, might be involved in solid tumors as well. Cancer stem cells (CSCs) can be identified and characterized using different methodologies focusing on chemoresistance, multipotency, tumorigenicity, stem cell gene expression and aldehyde dehydrogenase (ALDH) activity [17, 18]
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