Pleural mesothelioma side populations have a precursor phenotype

DyeCycleViolet was used to set up the side population (SP) functional assay aimed at identifying subpopulations of malignant pleural mesothelioma (MPM) tumor cells with chemoresistance phenotype associated with ABCG2 transporter activity. Self-renewal, chemoresistance and tumorigenicity were tested for SP and non-side population (NSP) cells. Tumors were characterized by mesothelin, calretinin, N-cadherin, D2-40 and Wilms tumor 1 (WT1) immunohistochemistry. Surface expression of mesenchymal stem cell markers CD90, CD73 and CD105 was investigated in SP and NSP cells. We identified SP cells with self-renewal properties and increased chemoresistance in MPM cell lines and tumor-derived primary cell cultures. Compared with the non-SP fraction (NSP), the SP fraction led to the development of tumors including cells with mesothelium precursor phenotype characterized by mesenchymal morphology, being WT1 negative but cytoplasmic D2-40 positive and having a tendency of increased tumorigenicity. The same phenotypic shift was observed in patients with relapsing tumors after chemotherapy. Furthermore, the SP cells were enriched in CD105−/low expressing cells, which were small sized and had increased tumorigenicity compared with CD105high cells. Taken together, our results support the hypothesis that MPM CD105−/low, chemoresistant small sized SP cells may constitute the cellular pool out of which recurrence develops. Further characterization of mechanisms of chemoresistance and self-renewal should lead to targets specific for this subpopulation in MPM patient

Number and cost of claims linked to minor cervical trauma in Europe: results from the comparative study by CEA, AREDOC and CEREDOC

Comparative epidemiological study of minor cervical spine trauma (frequently referred to as whiplash injury) based on data from the Comité Européen des Assurances (CEA) gathered in ten European countries. To determine the incidence and expenditure (e.g., for assessment, treatment or claims) for minor cervical spine injury in the participating countries. Controversy still surrounds the basis on which symptoms following minor cervical spine trauma may develop. In particular, there is considerable disagreement with regard to a possible contribution of psychosocial factors in determining outcome. The role of compensation is also a source of constant debate. The method followed here is the comparison of the data from different areas of interest (e.g., incidence of minor cervical spine trauma, percentage of minor cervical spine trauma in relationship to the incidence of bodily trauma, costs for assessment or claims) from ten European countries. Considerable differences exist regarding the incidence of minor cervical spine trauma and related costs in participating countries. France and Finland have the lowest and Great Britain the highest incidence of minor cervical spine trauma. The number of claims following minor cervical spine trauma in Switzerland is around the European average; however, Switzerland has the highest expenditure per claim at an average cost of €35,000.00 compared to the European average of €9,000.00. Furthermore, the mandatory accident insurance statistics in Switzerland show very large differences between German-speaking and French- or Italian-speaking parts of the country. In the latter the costs for minor cervical spine trauma expanded more than doubled in the period from 1990 to 2002, whereas in the German-speaking part they rose by a factor of five. All the countries participating in the study have a high standard of medical care. The differences in claims frequency and costs must therefore reflect a social phenomenon based on the different cultural attitudes and medical approach to the problem including diagnosis. In Switzerland, therefore, new ways must be found to try to resolve the problem. The claims treatment model known as “Case Management” represents a new approach in which accelerated social and professional reintegration of the injured party is attempted. The CEA study emphasizes the fundamental role of medicine in that it postulates a clear division between the role of the attending physician and the medical expert. It also draws attention to the need to train medical professionals in the insurance business to the extent that they can interact adequately with insurance professionals. The results of this study indicate that the usefulness of the criterion of so-called typical clinical symptoms, which is at present applied by the courts to determine natural causality and has long been under debate, is inappropriate and should be replaced by objective assessment (e.g. accident and biomechanical analysis). In addition, the legal concept of adequate causality should be interpreted in the same way in both third party liability and social security law, which is currently not the case

When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro, however BMS-777607 was far superior to LCRF-0004. The in vivo and in vitro data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone

P3.03-021 When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Untreated, MPM has a median survival time of 6 months, and most patients die within 24 months of diagnosis. Therefore an urgent need exists to identify new therapies for treating MPM patients. \ud \ud The potential for therapeutically targeting receptor tyrosine kinase (RTK) signalling networks is emerging as a critical mechanism in ‘oncogene addicted’ cancer, with RTK inhibitors evolving as areas of considerable importance in cancer therapy. Furthermore, RTK hetero-dimerization has emerged as a key element in the development of resistance to cancer therapy. As such TKIs which target several RTKs may have superior efficacy compared with TKIs targeting individual RTKs. \ud \ud We and others have identified c-MET, RON, Axl and Tyro3 as RTKs frequently overexpressed and activated in MPM, making these attractive candidate therapeutic targets. A number of orally bioavailable small molecule inhibitors have been developed which can target these receptors. LCRF0004 specifically targets RON, whereas ASLAN002 (BMS-777607) or Merestinib (LY2801653) are orally bioavailable small molecule inhibitors which inhibit c-MET, RON, Axl and Tyro3 at nanomolar concentrations. These drugs may therefore have applicability in the treatment/management of MPM

Pleural mesothelioma side populations have a precursor phenotype

DyeCycleViolet was used to set up the side population (SP) functional assay aimed at identifying subpopulations of malignant pleural mesothelioma (MPM) tumor cells with chemoresistance phenotype associated with ABCG2 transporter activity. Self-renewal, chemoresistance and tumorigenicity were tested for SP and non-side population (NSP) cells. Tumors were characterized by mesothelin, calretinin, N-cadherin, D2-40 and Wilms tumor 1 (WT1) immunohistochemistry. Surface expression of mesenchymal stem cell markers CD90, CD73 and CD105 was investigated in SP and NSP cells. We identified SP cells with self-renewal properties and increased chemoresistance in MPM cell lines and tumor-derived primary cell cultures. Compared with the non-SP fraction (NSP), the SP fraction led to the development of tumors including cells with mesothelium precursor phenotype characterized by mesenchymal morphology, being WT1 negative but cytoplasmic D2-40 positive and having a tendency of increased tumorigenicity. The same phenotypic shift was observed in patients with relapsing tumors after chemotherapy. Furthermore, the SP cells were enriched in CD105(-)(/low) expressing cells, which were small sized and had increased tumorigenicity compared with CD105(high) cells. Taken together, our results support the hypothesis that MPM CD105(-)(/low), chemoresistant small sized SP cells may constitute the cellular pool out of which recurrence develops. Further characterization of mechanisms of chemoresistance and self-renewal should lead to targets specific for this subpopulation in MPM patients