Vascular endothelial growth factor (VEGF), a potent mitogen for vascular endothelium, is expressed in malignant pleural mesothelioma (MM). The present report examines the effect of VEGF on MM growth. Four MM cell lines produced significantly higher VEGF levels than normal mesothelial cells (1946+/-14 pg/ml vs. 180+/-17 pg/ml; p<0.001). In addition, MM cells expressed the tyrosine kinase-related VEGF receptors Flt-1 and KDR. Recombinant human VEGF phosphorylated both Flt-1 and KDR and increased proliferation of all four MM cell lines in a dose-dependent fashion. Neutralizing antibodies against either VEGF, Flt-1 or KDR significantly reduced MM cellular proliferation. In addition, expression of VEGF, Flt-1, and KDR was observed in MM biopsies. Moreover, higher VEGF levels were found in the pleural effusions of MM patients than in the effusions of patients with non-malignant pleural disease (1885.7+/-894.9 pg/ml vs. 266.9+/-180.5 pg/ml; p<0.001). Linear regression analysis showed a significant inverse correlation between serum VEGF levels and MM patient survival (r=0.72; p<0.01). No correlation was found between tumour vessel density and either serum (r=0.26; p=0.42) or pleural effusion (r=0.35; p=0.26) VEGF levels. These results indicate that VEGF, via activation of its tyrosine kinase receptors, may be a key regulator of MM growth. In addition, VEGF production could have an impact on patient survival, not only by promoting tumour angiogenesis but also by directly stimulating tumour growth.

A case-control study was conducted in high- and low-risk areas of Italy to evaluate reasons for the striking geographic variation in gastric cancer (GC) mortality within the country. Personal interviews with 1,016 histologically confirmed GC cases and 1,159 population controls of similar age and sex revealed that the patients were more often of lower social class and resident in rural areas and more frequently reported a familial history of gastric (but not other) cancer. After adjusting for these effects, case-control differences were found for several dietary variables, assessed by asking about the usual frequency of consumption of 146 food items and beverages. A significant trend of increasing GC risk was found with increasing consumption of traditional soups, meat, salted/dried fish and a combination of cold cuts and seasoned cheeses. The habit of adding salt and the preference for salty foods were associated with elevated GC risk, while more frequently storing foods in the refrigerator, the availability of a freezer and use of frozen foods lowered risk. Reduced GC risk were associated with increasing intake of raw vegetables, fresh fruit and citrus fruits. Lowered risk was also related to consumption of spices, olive oil and garlic. Neither cigarette smoking nor alcoholic beverage drinking were significantly related to GC risk. The case-control differences tended to be consistent across geographic areas, despite marked regional variations in intake levels of certain foods. The high-risk areas tended to show higher consumption of food associated with elevated risk (traditional soups, cold cuts) and lower consumption of foods associated with reduced risks (raw vegetables, citrus fruits, garlic). Our findings indicate that dietary factors contribute to the regional variation of stomach cancer occurrence in Italy, and offer clues for further etiologic and prevention research.

c-Met receptor tyrosine kinase (RTK) has not been extensively studied in malignant pleural mesothelioma

No abstract

Purpose: High levels of serum-soluble mesothelin family proteins (SMRP) have been found to be associated with malignant mesothelioma (MM), but not lung cancer (LC).To verify the clinical role of this marker for both these tumors, we tested serum SMRP in the largest population of thoracic cancers ever assembled. Experimental Design: SMRP blood concentrations were measured in 107 patients with MM, 215 patients with LC, 130 patients with benign respiratory diseases (BRD), and 262 controls. Statistical comparison between mean serum SMRP levels in all groups was done and receiver operating characteristic curves were constructed to evaluate the performance of this marker. Results: SMRP levels were significantly higher in patients with MM and LC than in patients with benign respiratory diseases and controls (P < 0.001). The area under the receiver operating characteristic curve for serum SMRP discriminating MM and controls was 0.77 (95% confidence interval, 0.71-0.83), with a best cutoff of 1.00 nmol/L (sensitivity, 68.2%; specificity, 80.5%). In both MM and LC, serum SMRP levels did not differ significantly between early and late stages. High SMRP levels proved to be an independent negative prognostic factor in patients with MM. Conclusions: Our data confirm that serum SMRP is a promising marker for the diagnosis, prognosis, and clinical monitoring of MM.We found that serum SMRP dosage may prove helpful in LC diagnosis as well.These data may also have positive repercussions on secondary preventive medical strategies for workers previously exposed to asbestos.

A case-control study involving interviews with 1,016 gastric cancer (GC) patients and 1,159 population-based controls in high- and low-risk areas was conducted to evaluate dietary factors and their contribution to the marked geographic variation in mortality from this cancer within Italy. Risks of GC were found to vary significantly with estimated nutrient intake. Risk rose with increasing consumption of nitrites and protein, and decreased in proportion to intake of ascorbic acid, beta-carotene, alpha-tocopherol, and vegetable fat. The associations with nitrite and beta-carotene tended to fade, however, in multivariate analyses adjusting for intake of other nutrients. Ascorbic acid showed the strongest geographic gradient, with highest consumption in low-risk areas. The findings suggest that the protective effects we previously reported for consumption of fresh fruit, fresh vegetables and olive oil may be linked to the vitamins C and E contained in these foods. The findings are consistent with the hypothesis that N-nitroso compounds are involved in GC risks, since elevated risks were apparent for agents (nitrites, protein) that promote nitrosation, while decreased risks were found for nutrients (ascorbic acid and alpha-tocopherol) which inhibit the process.

Malignant pleural mesothelioma is an asbestos-related neoplasm with poor prognosis, refractory to current therapies, the incidence of which is expected to increase in the next decades. Female gender was identified as a positive prognostic factor among other clinical and biological prognostic markers for malignant mesothelioma, yet a role of estrogen receptors (ERs) has not been studied. Our goal was to investigate ERs expression in malignant mesothelioma and to assess whether their expression correlates with prognosis. Immunohistochemical analysis revealed intense nuclear ERB staining in normal pleura that was reduced in tumor tissues. Conversely, neither tumors nor normal pleura stained positive for ERA. Multivariate analysis of 78 malignant mesothelioma patients with pathologic stage, histologic type, therapy, sex, and age at diagnosis indicated that ERB expression is an independent prognostic factor of better survival. Moreover, studies in vitro confirmed that treatment with 17B-estradiol led to an ERB-mediated inhibition of malignant mesothelioma cell proliferation as well as p21 CIP1 and p27 KIP1 up-regulation. Consistently cell growth was suppressed by ERB overexpression, causing a G 2 -M-phase cell cycle arrest, paralleled by cyclin B1 and survivin down-regulation. Our data support the notion that ERB acting as a tumor suppressor is of high potential relevance to prediction of disease progression and to therapeutic response of malignant mesothelioma patients.

We conducted a case-control study on asbestos exposure and presence of SV40 in tumor samples of malignant mesotheliomas (MMs) and bladder urotheliomas (BUs). PCR analysis revealed the presence of SV40 DNA (SV40+) in eight (42.1%) MMs and 6 (33.3%) BUs. The odds ratio for MM Asb- and SV40+ was 0.4 [95% confidence interval (95% CI), 0.03-4.0], for Asb+ and SV40- was 3.6 (95% CI, 0.6-21.0), and for Asb+ and SV40+ was 12.6 (95% CI, 1.2-133.9). Our results suggest that SV40 increases the risk of MM among individuals exposed to asbestos.