Background. Fibulin-3 is a new potential biomarker for malignant mesothelioma (MM). This study evaluated the potential applicability of fibulin-3 plasma levels as a biomarker of response to treatment and its prognostic value for progressive disease within 18 months. The potential applicability of fibulin-3 in comparison with or in addition to soluble mesothelin-related peptides (SMRP) was also assessed.
Patients and methods. The study included 78 MM patients treated at the Institute of Oncology Ljubljana between 2007 and 2011. Fibulin-3 levels in plasma samples obtained before treatment and in various responses to treatment were measured with the enzyme-linked immunosorbent assay.
Results. In patients evaluated before the treatment, fibulin-3 levels were not influenced by histopathological sub-types, tumour stages or the presence of metastatic disease. Significantly higher fibulin-3 levels were found in progressive disease as compared to the levels before treatment (Mann-Whitney [U] test = 472.50, p = 0.003), in complete response to treatment (U = 42.00, p = 0.010), and in stable disease (U = 542.00, p = 0.001). Patients with fibulin-3 levels exceeding 34.25 ng/ml before treatment had more than four times higher probability for developing progressive disease within 18 months (odds ratio [OR] = 4.35, 95% confidence interval [CI] 1.56–12.13). Additionally, patients with fibulin-3 levels above 34.25 ng/ml after treatment with complete response or stable disease had increased odds for progressive disease within 18 months (OR = 6.94, 95% CI 0.99–48.55 and OR = 4.39, 95% CI 1.63–11.81, respectively).
Conclusions. Our findings suggest that in addition to SMRP fibulin-3 could also be helpful in detecting the progression of MM.
1. Berry M. Mesothelioma incidence and community asbestos exposure. Environ Res 1997; 75: 34-40.
2. Iwatsubo Y, Pairon JC, Boutin C, Menard O, Massin N, Caillaud D, et al. Pleural mesothelioma: dose-response relation at low levels of asbestos exposure in a French population-based case-control study. Am J Epidemiol 1998; 148: 133-42.
3. Howel D, Gibbs A, Arblaster L, Swinburne L, Schweiger M, Renvoize E, et al. Mineral fibre analysis and routes of exposure to asbestos in the development of mesothelioma in an English region. Occup Environ Med 1999; 56: 51-8.
4. Agudo A, González CA, Bleda MJ, Ramirez J, Hernandez S, Lopez F, et al. Occupation and risk of malignant pleural mesothelioma: a case-control study in Spain. Am J Ind Med 2000; 37: 159-68.
5. Magnani C, Dalmasso P, Biggeri A, Ivaldi C, Mirabelli D, Terracini B. Increased risk of malignant mesothelioma of the pleura after residential or domestic exposure to asbestos: a case-control study in Casale Monferrato, Italy. Environ Health Perspect 2001; 109: 915-9.
6. Zellos L, Christiani DC. Epidemiology, biologic behaviour, and natural history of mesothelioma. Thorac Surg Clin 2004; 14: 469-77.
7. Pan XL, Day HW, Wang W, Beckett LA, Schenker MB. Residential proximity to naturally occurring asbestos and mesothelioma risk in California. Am J Respir Crit Care Med 2005; 172: 1019-25.
8. Maule MM, Magnani C, Dalmasso P. Modeling mesothelioma risk associated with environmental asbestos exposure. Environ Health Perspect 2007; 115: 1066-71.
9. Robinson BW, Lake RA. Advances in malignant mesothelioma. N Engl J Med 2005; 353: 1591-603.
10. Kovac V, Zwitter M, Zagar T. Improved survival after introduction of chemotherapy for malignant pleural mesothelioma in Slovenia: population-based survey of 444 patients. Radiol Oncol 2012; 46: 136-44.
11. Hollevoet K, Reitsma JB, Creaney J, Grigoriu BD, Robinson BW, Scherpereel A, et al. Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data meta-analysis. J Clin Oncol 2012; 30: 1541-9.
12. Franko A, Dolzan V, Kovac V, Arneric N, Dodic-Fikfak M. Soluble mesothelin-related peptides levels in patients with malignant mesothelioma. Dis Markers 2012; 32: 123-31.
13. Pass HI, Levin SM, Harbut MR, Melamed J, Chiriboga L, Donington J, et al. Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma. N Engl J Med 2012; 367: 1417-27.
14. Timpl R, Sasaki T, Kostka G, Chu ML. Fibulins: a versatile family of extracellular matrix proteins. Nat Rev Mol Cell Biol 2003; 4: 479-89.
16. Zhang Y, Marmorstein LY. Focus on molecules: fibulin-3 (EFEMP1). Exp Eye Res 2010; 90: 374-5.
17. Kim IG, Kim SY, Choi SI, Lee JH, Kim KC, Cho EW. Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling. Oncogene 2014; 33: 3908-17.
18. Kobayashi N, Kostka G, Garbe JH, Keene DR, Bachinger HP, Hanisch FG, et al. A comparative analysis of the fibulin protein family. Biochemical characterization, binding interactions, and tissue localization. J Biol Chem 2007; 282: 11805-16.
19. Yue W, Dacic S, Sun Q, Landreneau R, Guo M, Zhou W, et al. Frequent inactivation of RAMP2, EFEMP1 and Dutt1 in lung cancer by promoter hypermethylation. Clin Cancer Res 2007; 13: 4336-44.
20. Xu S, Yang Y, Sun YB, Wang HY, Sun CB, Zhang X. Role of fibulin-3 in lung cancer: in vivo and in vitro analyses. Oncol Rep 2014; 31: 79-86.
21. Sadr-Nabavi A, Ramser J, Volkmann J, Naehrig J, Wiesmann F, Betz B, et al. Decreased expression of angiogenesis antagonist EFEMP1 in sporadic breast cancer is caused by aberrant promoter methylation and points to an impact of EFEMP1 as molecular biomarker. Int J Cancer 2009; 124: 1727-35.
22. Nomoto S, Kanda M, Okamura Y, Nishikawa Y, Qiyong L, Fujii T, et al. Epidermal growth factor-containing fibulin-like extracellular matrix protein 1, EFEMP1, a novel tumor-suppressor gene detected in hepatocellular carcinoma using double combination array analysis. Ann Surg Oncol 2010; 17: 923-32.
23. Hu B, Thirtamara-Rajamani KK, Sim H, Viapiano MS. Fibulin-3 is uniquely upregulated in malignant gliomas and promotes tumor cell motility and invasion. Mol Cancer Res 2009; 7: 1756-70.
24. En-lin S, Sheng-guo C, Hua-qiao W. The expression of EFEMP1 in cervical carcinoma and its relationship with prognosis. Gynecol Oncol 2010; 117: 417-22.
25. Seeliger H, Camaj P, Ischenko I, Kleespies A, De Toni EN, Thieme SE, et al. EFEMP1 expression promotes in vivo tumor growth in human pancreatic adenocarcinoma. Mol Cancer Res 2009; 7: 189-98.
26. Creaney J, Dick IM, Meniawy TM, Leong SL, Leon JS, Demelker Y, et al. Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma. Thorax 2014; 69: 895-902.
27. UICC International Union Against Cancer. Pleurak mesothelioma. In: Sobin LH, Gospodarowicz MK, Wittekind C, editors. TNM classification of malignant tumours, 7th edition. Chichester: Wiley-Blackwell; 2009. p. 147-50.
28. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 2004; 15: 257-60.
29. Podobnik J, Kocijancic I, Kovac V, Sersa I. 3T MRI in evaluation of asbestos-related thoracic diseases - preliminary results. Radiol Oncol 2010; 44: 92-6.
30. Zwitter M, Stanic K, Rajer M, Kern I, Vrankar M, Edelbaher N, et al. Intercalated chemotherapy and erlotinib for advanced NSCLC: high proportion of complete remissions and prolonged progression-free survival among patients with EGFR activating mutations. Radiol Oncol 2014; 48: 361-8.
31. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003; 21: 2636-44.
32. Goricar K, Kovac V, Dolzan V. Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesothelioma. Radiol Oncol 2014; 48: 163-72.
33. Lee CW, Murray N, Anderson H, Rao SC, Bishop W. Outcomes with first-line platinum-based combination chemotherapy for malignant pleural mesothelioma: A review of practice in British Columbia. Lung Cancer 2009; 64: 308-13.
34. Kovac V, Zwitter M, Rajer M, Marin A, Debeljak A, Smrdel U, et al. A phase II trial of low-dose gemcitabine in prolonged infusion and cisplatin for malignant pleural mesothelioma. Anticancer Drugs 2012; 23: 230-8.
36. Dodic Fikfak M, Kriebel D, Quinn MM, Eisen EA, Wegman DH. A case control study of lung cancer and exposure to chrysotile and amphibole at a Slovenian asbestos-cement plant. Ann Occup Hyg 2007; 51: 261-8.