Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed

Abstract

Abstract. Malignant pleural mesothelioma (MPM) is a lethal cancer of the mesothelium with high chemotherapeutic resistance via unknown mechanisms. A prevailing hypothesis states that cancer stem cells (CSCs) persist in tumors causing relapse after chemotherapy, thus, rendering these cells as critical targets responsible for tumor resistance and recurrence. We selected candidate CSC markers based on expansion under hypoxic conditions, a hallmark for the selection of chemoresistant cells; and investigated the expression of CSC markers: CD133, Bmi-1, uPAR and ABCG2 in three MPM cell lines and normal mesothelial cells by quantitative RT-PCR. Furthermore, we evaluated the chemotherapeutic resistance associated with each CSC marker by determining the change in CSC marker-mRNA levels as an index of drugresistance following treatment with either cisplatin or pemetrexed. We demonstrate the expression of CSC markers: CD133, Bmi-1, uPAR and ABCG2 in both normal and MPM cell lines. Bmi-1 + , uPAR + and ABCG2 + cells show a distinct role in conferring chemoresistance to cisplatin and pemetrexed in the malignant setting. By contrast, these markers have no apparent participation in chemoresistance to drug treatments in normal mesothelial cells. Intriguingly, CD133 revealed chemoresistant properties in both normal mesothelial and malignant pleural mesothelioma cells. This study provides evidence of putative CSCs conferring drug-resistance to cisplatin and pemetrexed in MPM cell lines. Specific targeting of these drug-resistant cells, while considering the functional heterogeneity of the MPM subtypes, may contribute to more focused and effective chemotherapeutic regimens for malignant pleural mesothelioma.

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

“…CSCs theory is based on a hierarchical organization of cells in the tumor, where only a sub-set of cells with high tumor-forming properties can give rise to a heterogenous cancerous cell population associated with rapid recurrence [ 38 , 39 ]. Different studies identified the presence of CSCs within malignant mesothelioma (MM) tissue as responsible for tumor heterogeneity [ 40 ], chemoresistance and relapse after therapy [ 41 ]. MM, as with other tumor types, is strongly characterized by inter and intra-tumor heterogeneity and the persistence of resistant CSCs in tumor tissue represent the main cause of treatment failure in cancer therapy [ 42 , 43 ].…”