Yonsei Med J.  2016 May;57(3):549-556. 10.3349/ymj.2016.57.3.549.

Apolipoproteins as Differentiating and Predictive Markers for Assessing Clinical Outcomes in Patients with Small Cell Lung Cancer

Affiliations
  • 1Department of Medical Oncology , Forth Hospital of Hebei Medical University, Tumor Hospital of Hebei Province, Shijiazhuang, Hebei, China. jianshihebei@gmail.com
  • 2Department of Pathology, Forth Hospital of Hebei Medical University, Tumor Hospital of Hebei Province, Shijiazhuang, Hebei, China.

Abstract

PURPOSE
The present study aimed to investigate the value of apolipoproteins, including ApoA-1, ApoC-III, and ApoE, in patients with small cell lung cancer (SCLC) as potential biomarkers for diagnosis, prognosis, and cancer progression.
MATERIALS AND METHODS
Lung samples were collected from 89 patients with SCLC. Nineteen lung samples from non-small cell lung cancer (NSCLC) patients and 12 normal lung tissues were used as controls. Expression profiles of ApoA-1, ApoC-III, and ApoE in different samples were examined using immunohistochemical methods, and the expression levels were correlated with cancer types, treatment, and outcomes using chi-square and Mann-Whitney tests.
RESULTS
Expression of ApoA-1 and ApoC-III in SCLC was significantly different, compared with that in NSCLC and normal lung tissues, and was correlated with recurrence of SCLC. Patients undergoing neoadjuvant chemotherapy before surgery showed significantly reduced expression of ApoA-1 and increased expression of ApoC-III and ApoE. Nevertheless, the expression levels of ApoA-1, ApoC-III, and ApoE were not correlated with SCLC staging.
CONCLUSION
ApoA-1 and ApoC-III may be used as differentiating and predictive markers for SCLC. ApoA-1, ApoC-III, and ApoE may be used to monitor the efficacy of chemotherapy.

Keyword

Small cell lung cancer; apolipoprotein; biomarker; prognosis

MeSH Terms

Adult
Aged
Apolipoprotein A-I/*genetics
Apolipoprotein C-III/*genetics
Apolipoproteins E/*genetics
Biomarkers/analysis
Case-Control Studies
Female
Gene Expression Regulation
Humans
Immunohistochemistry
Male
Middle Aged
Neoplasm Recurrence, Local
Predictive Value of Tests
Prognosis
RNA, Messenger/*genetics
Small Cell Lung Carcinoma/*diagnosis/genetics
Apolipoprotein A-I
Apolipoprotein C-III
Apolipoproteins E
Biomarkers
RNA, Messenger

Figure

  • Fig. 1 Immunohistochemical analysis of apolipoproteins. The expression of ApoA-1 (A-D), ApoC-III (E-H), and ApoE (I-L) in different tissue samples, including SCLC (A, E, and I), adenocarcinoma (B, F, and J), squamous cell carcinoma (C, G, and K), and normal lung tissues (D, H, and L). Brown dots represent stained proteins. SCLC, small cell lung cancer.


Reference

1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011; 61:69–90.
Article
2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010; 127:2893–2917.
Article
3. Jackman DM, Johnson BE. Small-cell lung cancer. Lancet. 2005; 366:1385–1396.
Article
4. Harmsma M, Schutte B, Ramaekers FC. Serum markers in small cell lung cancer: opportunities for improvement. Biochim Biophys Acta. 2013; 1836:255–272.
Article
5. Pillai RN, Owonikoko TK. Small cell lung cancer: therapies and targets. Semin Oncol. 2014; 41:133–142.
Article
6. van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet. 2011; 378:1741–1755.
Article
7. Talmud PJ, Futema M, Humphries SE. The genetic architecture of the familial hyperlipidaemia syndromes: rare mutations and common variants in multiple genes. Curr Opin Lipidol. 2014; 25:274–281.
8. Schilling S, DeStefano AL, Sachdev PS, Choi SH, Mather KA, De-Carli CD, et al. APOE genotype and MRI markers of cerebrovascular disease: systematic review and meta-analysis. Neurology. 2013; 81:292–300.
Article
9. Podzielinski I, Saunders BA, Kimbler KD, Branscum AJ, Fung ET, DePriest PD, et al. Apolipoprotein concentrations are elevated in malignant ovarian cyst fluids suggesting that lipoprotein metabolism is dysregulated in epithelial ovarian cancer. Cancer Invest. 2013; 31:258–272.
Article
10. Honda K, Okusaka T, Felix K, Nakamori S, Sata N, Nagai H, et al. Altered plasma apolipoprotein modifications in patients with pancreatic cancer: protein characterization and multi-institutional validation. PLoS One. 2012; 7:e46908.
Article
11. Shi J, Liu J, Liao L, Guo Y, Wang H, Hu W, et al. Identification of candidate serum biomarkers for small cell lung cancer by proteomics analysis. Minerva Med. 2014; 105:137–147.
12. Bradley JD, Dehdashti F, Mintun MA, Govindan R, Trinkaus K, Siegel BA. Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol. 2004; 22:3248–3254.
Article
13. Shepherd FA, Crowley J, Van Houtte P, Postmus PE, Carney D, Chansky K, et al. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol. 2007; 2:1067–1077.
Article
14. Ploenes T, Osei-Agyemang T, Krohn A, Kayser G, Burger M, Passlick B. Surgical treatment of early stage small cell lung cancer. Asian Cardiovasc Thorac Ann. 2012; 20:694–698.
Article
15. Lee CB, Morris DE, Fried DB, Socinski MA. Current and evolving treatment options for limited stage small cell lung cancer. Curr Opin Oncol. 2006; 18:162–172.
Article
16. Cooper WA, Lam DC, O'Toole SA, Minna JD. Molecular biology of lung cancer. J Thorac Dis. 2013; 5:Suppl 5. S479–S490.
17. Zhang Y, He J. The development of targeted therapy in small cell lung cancer. J Thorac Dis. 2013; 5:538–548.
18. Lund EL, Thorsen C, Pedersen MW, Junker N, Kristjansen PE. Relationship between vessel density and expression of vascular endothelial growth factor and basic fibroblast growth factor in small cell lung cancer in vivo and in vitro. Clin Cancer Res. 2000; 6:4287–4291.
19. Chetty PS, Mayne L, Lund-Katz S, Stranz D, Englander SW, Phillips MC. Helical structure and stability in human apolipoprotein A-I by hydrogen exchange and mass spectrometry. Proc Natl Acad Sci U S A. 2009; 106:19005–19010.
Article
20. TuftStavnes H, Nymoen DA, HetlandFalkenthal TE, Kærn J, Tropé CG, Davidson B. APOA1 mRNA expression in ovarian serous carcinoma effusions is a marker of longer survival. Am J Clin Pathol. 2014; 142:51–57.
Article
21. Ehmann M, Felix K, Hartmann D, Schnölzer M, Nees M, Vorderwülbecke S, et al. Identification of potential markers for the detection of pancreatic cancer through comparative serum protein expression profiling. Pancreas. 2007; 34:205–214.
Article
22. Yang HH, Chen XF, Hu W, Lv DQ, Ding WJ, Tang LJ, et al. Lipoprotein (a) level and its association with tumor stage in male patients with primary lung cancer. Clin Chem Lab Med. 2009; 47:452–457.
23. Li C, Li H, Zhang T, Li J, Liu L, Chang J. Discovery of Apo-A1 as a potential bladder cancer biomarker by urine proteomics and analysis. Biochem Biophys Res Commun. 2014; 446:1047–1052.
Article
24. Gourin CG, Zhi W, Adam BL. Proteomic identification of serum biomarkers for head and neck cancer surveillance. Laryngoscope. 2009; 119:1291–1302.
Article
25. Gao F, Vasquez SX, Su F, Roberts S, Shah N, Grijalva V, et al. L-5F, an apolipoprotein A-I mimetic, inhibits tumor angiogenesis by suppressing VEGF/basic FGF signaling pathways. Integr Biol (Camb). 2011; 3:479–489.
Article
26. Larsson M, Vorrsjö E, Talmud P, Lookene A, Olivecrona G. Apolipoproteins C-I and C-III inhibit lipoprotein lipase activity by displacement of the enzyme from lipid droplets. J Biol Chem. 2013; 288:33997–34008.
Article
27. Yao Z, Wang Y. Apolipoprotein C-III and hepatic triglyceride-rich lipoprotein production. Curr Opin Lipidol. 2012; 23:206–212.
Article
28. Fan Y, Shi L, Liu Q, Dong R, Zhang Q, Yang S, et al. Discovery and identification of potential biomarkers of papillary thyroid carcinoma. Mol Cancer. 2009; 8:79.
Article
29. Kardassis D, Pardali K, Zannis VI. SMAD proteins transactivate the human ApoCIII promoter by interacting physically and functionally with hepatocyte nuclear factor 4. J Biol Chem. 2000; 275:41405–41414.
Article
30. Fraser JD, Martinez V, Straney R, Briggs MR. DNA binding and transcription activation specificity of hepatocyte nuclear factor 4. Nucleic Acids Res. 1998; 26:2702–2707.
Article
31. Reilly M, Rader DJ. Apolipoprotein E and coronary disease: a puzzling paradox. PLoS Med. 2006; 3:e258.
Article
32. Martínez-Clemente M, Ferré N, González-Périz A, López-Parra M, Horrillo R, Titos E, et al. 5-lipoxygenase deficiency reduces hepatic inflammation and tumor necrosis factor alpha-induced hepatocyte damage in hyperlipidemia-prone ApoE-null mice. Hepatology. 2010; 51:817–827.
Article
33. Su WP, Chen YT, Lai WW, Lin CC, Yan JJ, Su WC. Apolipoprotein E expression promotes lung adenocarcinoma proliferation and migration and as a potential survival marker in lung cancer. Lung Cancer. 2011; 71:28–33.
Article
34. Trost Z, Marc J, Sok M, Cerne D. Increased apolipoprotein E gene expression and protein concentration in lung cancer tissue do not contribute to the clinical assessment of non-small cell lung cancer patients. Arch Med Res. 2008; 39:663–667.
Article
35. Zelen M. Keynote address on biostatistics and data retrieval. Cancer Chemother Rep 3. 1973; 4:31–42.
36. Cheng T, Dai X, Zhou DL, Lv Y, Miao LY. Correlation of apolipoprotein A-I kinetics with survival and response to first-line platinum-based chemotherapy in advanced non-small cell lung cancer. Med Oncol. 2015; 32:407.
Article
37. Ko HL, Wang YS, Fong WL, Chi MS, Chi KH, Kao SJ. APOC1 as a novel diagnostic and prognostic biomarker for lung cancer: a marker phase i trial. Thoracic Cancer. 2014; 5:500–508.
Article
38. Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus. Ten-year follow-up. Lancet. 1973; 2:63–65.
39. Shepherd FA, Ginsberg RJ, Evans WK, Feld R, Cooper JD, Ilves R, et al. Reduction in local recurrence and improved survival in surgically treated patients with small cell lung cancer. J Thorac Cardiovasc Surg. 1983; 86:498–506.
Article
40. Koletsis EN, Prokakis C, Karanikolas M, Apostolakis E, Dougenis D. Current role of surgery in small cell lung carcinoma. J Cardiothorac Surg. 2009; 4:30.
Article
41. Turrisi AT 3rd, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999; 340:265–271.
Article
42. Naranjo Gómez JM, Gómez Román JJ. Behaviour and survival of high-grade neuroendocrine carcinomas of the lung. Respir Med. 2010; 104:1929–1936.
Article
43. Yip D, Harper PG. Predictive and prognostic factors in small cell lung cancer: current status. Lung Cancer. 2000; 28:173–185.
Article
44. Foster NR, Mandrekar SJ, Schild SE, Nelson GD, Rowland KM Jr, Deming RL, et al. Prognostic factors differ by tumor stage for small cell lung cancer: a pooled analysis of North Central Cancer Treatment Group trials. Cancer. 2009; 115:2721–2731.
Article
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