Multidrug resistance mediated by ABC transporters in osteosarcoma cell lines: mRNA analysis and functional radiotracer studies.

Drug resistance remains a significant impediment to successful chemotherapy and constitutes a major prognostic factor in osteosarcoma (OS) patients. This study was designed to identify the role and prognostic significance of multidrug-resistance (MDR)-related transporters, such as multidrug resistance protein 1 (MDR1), multidrug-resistance-associated protein (MRP1) and breast-cancer-related protein (BCRP), in OS using cationic lipophilic radiotracers. We evaluated the chemosensitivity of four OS cell lines (Saos-2, 143B, MNNG/HOS and U-2OS) to doxorubicin (DOX), cisplatin (CIS) and methotrexate. The expression of MDR-related transporters was analyzed at mRNA level by quantitative polymerase chain reaction and at functional level by 99mTc sestamibi and 99mTc tetrofosmin. The effectiveness of MDR modulators [cyclosporin A (CsA) and imatinib] on transporter inhibition and on the reversal of resistance was also assessed. MNNG/HOS and U-2OS cells expressing high levels of MDR1 were highly resistant to DOX and showed reduced accumulation and higher efflux for radiotracers. Although MRP1 was uniformly expressed in all cells, only U-2OS was resistant to CIS. CsA restored sensitivity to DOX and CIS, and enhanced the accumulation and efflux half-life of radiotracers in MDR1-expressing cell lines. The chemosensitivity of OS cells to DOX was strongly dependent on mRNA MDR1 expression and could be circumvented by adding CsA. The kinetic parameters of radiotracers correlated with MDR1 expression levels, hence predicting DOX resistance. We concluded that sensitivity to chemotherapy is strongly dependent on the expression of MDR1 transporter and that radiotracer studies could prove clinically useful in predicting chemotherapy response and in evaluating the efficacy of MDR-reversing agents.

The dual role of mesenchymal stem cells in tumor progression.

Mesenchymal stem cells (MSCs) have attracted increasing interest in the field of oncology because of their inherent capacity to migrate and home tumor tissues. The remarkable tropism of MSCs for tumor microenvironments has been exploited in order to use these cells as cellular vehicles to deliver gene therapies or anticancer agents. At functional levels, these cells display chemotactic properties similar to those of immune cells in response to tissue insult and inflammation and secrete a broad range of bioactive biomolecules with an impact on tumor development and a progression through direct actions on tumor cells and the stromal microenvironment. However, the exact contribution of such interactions in tumor progression has not yet been fully clarified, and some concerns remain regarding whether MSCs exert a tumor-suppressive effect or, on the contrary, favor tumor growth. The article by Keramidas and colleagues in this issue of Stem Cell Research & Therapy provides an interesting contribution to this hot topic.