Malignant Pleural Mesothelioma Cell Proliferation Research Articles

The therapeutic efficacy of S-1 against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice

PurposeMalignant pleural mesothelioma (MPM) is a highly lethal neoplasm. S-1 has been developed as a novel oral antineoplastic agent based on the modulation of 5-fluorouracil (5-FU) bioactivity. This study was conducted to investigate the preclinical therapeutic effect of S-1 on MPM.MethodsWe used three human MPM cell lines, Y-MESO-14, NCI-H290 and MSTO-211H. In vitro proliferation of human MPM cells was determined by MTT assay. Human MPM cells were orthotopically implanted into thoracic cavity of SCID mice. Tumor-bearing mice were treated with S-1 or vehicle.ResultsThe combination of 5-FU and 5-chloro-2,4-dihydroxypyridine (CDHP) was more effective than 5-FU alone in inhibiting MPM cell proliferation in vitro. This combination was most effective in Y-MESO-14 cells, which co-expressed high protein level of dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP). In vivo data showed that treatment with S-1 significantly reduced thoracic tumors and pleural effusion produced by Y-MESO-14 cells. Moreover, treatment with S-1 prolonged the survival of Y-MESO-14 cell-bearing SCID mice.ConclusionsWe demonstrated that S-1 was effective for inhibiting the proliferation of MPM cells, particularly with both DPD and TP expressions, suggesting that S-1 might be therapeutically effective for control of MPM.

Serum levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) as prognostic factors in malignant pleural mesothelioma (MPM)

10080 Background: MPM is an uncommon but extremely aggressive tumor of the serosal surfaces, which has been closely linked to asbestos exposure. Several in-vitro studies have demonstrated that HGF enhances MPM cell proliferation, migration, and invasiveness and the presence of EGF is closely related to the process of cell differentiation and the synthesis of glycosaminoglycans in MPM cells. Few studies have measured the blood levels of these growth factors in tumor patients and assessed their correlation with clinical outcome. This pilot study was designed to investigate the potential value of serum EGF and HGF measurements for the diagnosis and the prediction of survival in MPM patients. Methods: Baseline serum EGF and HGF levels (ng/ml) were determined using an ELISA method in 81 newly diagnosed MPM patients (mean age 67.5±11.0 years) and 48 patients with benign respiratory diseases (BRD; mean age 64.3±13.5 years). Results: HGF and EGF median concentrations in MPM (1.6 ng/ml and 0.5 ng/ml, respectively) were not statistically different from concentrations in BRD (1.2 ng/ml and 0.4 ng/ml). Median follow-up for MPM patients was 27 months, while overall median survival was 11.8 months. At univariate analysis, only high EGF serum levels were associated with an unfavorable survival outcome. Using a cut-off point for EGF of 0.5 ng/ml (corresponding to the median of marker concentration in MPM), the survival rate in patients with higher serum EGF was significantly worse than that in patients with lower levels (median 10.7 vs. 13.0 months, p=0.01). Multivariate analysis, after adjusting for age, sex, histology and platelet count, confirmed the independent predictive value of serum EGF concentration as a negative prognostic factor (p=0.01). Conclusions: High pre-treatment levels of serum EGF are associated with an adverse prognostic impact on survival in MPM patients. No significant financial relationships to disclose.

Inhibition of the Met Receptor in Mesothelioma

Expression of the Met receptor and its ligand, hepatocyte growth factor (HGF), has been observed in 74% to 100% and 40% to 85% of malignant pleural mesothelioma (MPM) specimens, respectively. HGF stimulation has been shown to enhance MPM cell proliferation, migration, cell scattering, and invasiveness. To investigate a potential therapeutic role for the Met receptor in MPM, we examined the effects of PHA-665752, a specific small-molecule inhibitor of the Met receptor tyrosine kinase, in a panel of 10 MPM cell lines. Two of the cell lines, H2461 and JMN-1B, exhibited autocrine HGF production as measured by ELISA (3.9 and 10.5 ng/mL, respectively, versus <0.05 ng/mL in other cell lines). Evaluation of PHA-665752 across the 10 MPM cell lines indicated that despite Met expression in all cell lines, only in cell lines that exhibited a Met/HGF autocrine loop, H2461 and JMN-1B, did PHA-665752 inhibit growth with an IC(50) of 1 and 2 micromol/L, respectively. No activating mutations in Met were detected in any of the cell lines. Consistent with observed growth inhibition, PHA-665752 caused cell cycle arrest at G(1)-S boundary accompanied by a dose-dependent decrease in phosphorylation of Met, p70S6K, Akt, and extracellular signal-regulated kinase 1/2. Growth of H2461 cells was also inhibited by neutralizing antibodies to HGF and by RNA interference knockdown of the Met receptor, confirming that growth inhibition observed was through a Met-dependent mechanism. PHA-665752 also reduced MPM in vitro cell migration and invasion. Taken together, these findings suggest that inhibition of the Met receptor may be an effective therapeutic strategy for patients with MPM and provides a mechanism, the presence of a HGF/Met autocrine loop, by which to select patients for PHA-665752 treatment.