Mesothelioma and Effects of Epigenetic and Genetic Alterations

Another interesting study is called, "Thrombospondin-1 expression and clinical implications in malignant pleural Mesothelioma" by Yasuhiko Ohta M.D., Viji Shridhar Ph.D., Gregory P. Kalemkerian M.D., Robert K. Bright Ph.D., Yoh Watanabe M.D., Harvey I. Pass M.D. – Cancer Volume 85, Issue 12, pages 2570–2576, 15 June 1999.  Here is an excerpt: "RESULTS - TSP-1 was highly expressed in 74 of the 78 MPM tumors (95%) with a mean value of 2.27 ± 0.42 compared with normal pleura (0.50 ± 0.06) and surrounding normal lung (0.96 ± 0.20) (P = 0.05 vs. normal pleura and P = 0.0006 vs. surrounding normal lung). The mean TSP-1 expression was significantly greater in high VEGF-expressing tumors (2.63 ± 0.51) compared with low VEGF-expressing tumors (1.17 ± 0.39; P < 0.0001) and TSP-1 expression was lower in patients with TNM Stage III/IV disease (n = 60) (1.85 ± 0.37) than in patients with Stage I/II disease (n = 13) (4.46 ± 1.74) (P = 0.025). The TSP-1 expression levels in tumors with lymph node metastases were significantly lower than in those without lymph node metastases (P = 0.0305). Although high TSP-1 expression was associated with good prognosis in patients with low VEGF-expressing tumors, TSP-1 itself appeared to have no overall impact on survival. The methylation status of a CpG island associated with the TSP-1 promoter was evident in MPM tumor samples despite high levels of TSP-1 mRNA expression."

CONCLUSIONS - TSP-1 is overexpressed in MPM tumors but its expression is of little value as a prognostic indicator in MPM. However, the relations between TSP-1 and VEGF in MPM merit further investigation for possible innovative therapeutic interventions. Cancer 1999;85:2570–6.

Angiogenesis is regulated by a wide variety of angiogenesis stimulators and inhibitors. Thrombospondin-1 (TSP-1) is a matricellular glycoprotein that is secreted by a variety of cells, including tumor cells.1, 2 Although TSP-1 originally was reported to be an angiogenesis inhibitor, recent data suggest that TSP-1 also may function as an angiogenesis stimulator.3, 4 Domain analysis has revealed that TSP-1 possesses binding sites for CD36, which is antiangiogenic, as well as for alpha v beta 3 integrin and transforming growth factor (TGF)-β, which are proangiogenic.4–6 In addition, TSP-1 appears to be involved in the adhesion, chemotaxis, and proliferation of endothelial cells.4 Therefore, the true role of TSP-1 in tumor angiogenesis remains unclear. The utility of TSP-1 expression as a prognostic factor in patients with cancer also remains controversial. For example, TSP-1 expression appears to portend a good prognosis in bladder carcinoma,7 whereas it is associated with a poor prognosis in breast carcinoma.8 These conflicting findings suggest that other angiogenesis mediators may be involved in tumor progression. Among such mediators, vascular endothelial growth factor (VEGF) is the most potent known endothelial cell specific mitogen and its overexpression is associated with poor prognosis in several tumors.9–11 Although the association between TSP-1 and VEGF has not been well defined, the effect of VEGF should be considered when attempting to determine the impact of TSP-1 on prognosis. We already confirmed that VEGF plays an important stimulatory role in tumor neovascularization in malignant pleural mesothelioma (MPM), and that the simultaneous expression of VEGF and its receptors has potential prognostic value in this disease (unpublished data). In this study, we assessed TSP-1 expression and its impact on prognosis in MPM while accounting for variable VEGF expression. We also examined the effects of epigenetic and genetic alterations in the TSP-1 gene on TSP-1 expression in MPM.

We all owe a debt of gratitude to these fine researchers.  If you found any of these excerpts interesting, please read the studies in their entirety.