Clinicopathological significance of non-small cell lung cancer with high prevalence of Oct-4 tumor cells

Journal of Experimental & Clinical Cancer Research

Andy Peng Xiang⁴  Yiyan Lei¹  Beilong Zhong³  Chunhua Su¹  Lie Cai²  Tao Wang⁴  Zhenguang Chen¹ 

[1] Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Lung Cancer Research Center of Sun Yat-sen University, Guangzhou, Guangdong 510080, China;Department of Rehabilitation, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China;Department of Thoracic Surgery, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong 519000, China;Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Guangzhou, Guangdong 510080, China

关键词: Angiogenesis;    Proliferation;    Prognosis;    Non-small cell lung cancer;    Oct-4;   

Others  :  826860
DOI  :  10.1186/1756-9966-31-10

 received in 2011-11-08, accepted in 2012-02-02,  发布年份 2012

【 摘 要 】

Background

Expression of the stem cell marker octamer 4 (Oct-4) in various neoplasms has been previously reported, but very little is currently known about the potential function of Oct-4 in this setting. The purpose of this study was to assess the prognostic value of Oct-4 expression after surgery in primary non-small cell lung cancer (NSCLC) and investigate its possible molecular mechanism.

Methods

We measured Oct-4 expression in 113 NSCLC tissue samples and three cell lines by immunohistochemical staining and RT-PCR. The association of Oct-4 expression with demographic characteristics, proliferative marker Ki67, microvessel density (MVD), and expression of vascular endothelial growth factor (VEGF) were assessed.

Results

Oct-4 expression was detected in 90.3% of samples and was positively correlated with poor differentiation and adenocarcinoma histology, and Oct-4 mRNA was found in each cell lines detected. Overexpression of Oct-4 had a strong association with cells proliferation in all cases, MVD-negative, and VEGF-negative subsets. A Kaplan-Meier analysis showed that overexpression of Oct-4 was associated with shorter overall survival in all cases, adenocarcinoma, squamous cell carcinoma, MVD-negative, and VEGF-negative subsets. A multivariate analysis demonstrated that Oct-4 level in tumor tissue was an independent prognostic factor for overall survival in all cases, MVD-negative, and VEGF-negative subsets.

Conclusion

Our findings suggest that, even in the context of vulnerable MVD status and VEGF expression, overexpression of Oct-4 in tumor tissue represents a prognostic factor in primary NSCLC patients. Oct-4 may maintain NSCLC cells in a poorly differentiated state through a mechanism that depends on promoting cell proliferation.

【 授权许可】

   
2012 Chen et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Ozols RF, Herbst RS, Colson YL, Gralow J, Bonner J, Curran WJ Jr, Eisenberg BL, Ganz PA, Kramer BS, Kris MG, Markman M, Mayer RJ, Raghavan D, Reaman GH, Sawaya R, Schilsky RL, Schuchter LM, Sweetenham JW, Vahdat LT, Winn RJ: American Society of Clinical Oncology: Clinical cancer advances 2006: major research advances in cancer treatment, prevention, and screening-a report from the American Society of Clinical Oncology. J Clin Oncol 2007, 25:146-162.
• [2]D'Addario G, Felip E: Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009, 20(Suppl 4):68-70.
• [3]Burdon T, Smith A, Savatier P: Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol 2002, 12:432-438.
• [4]Niwa H, Miyazaki J, Smith AG: Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 2000, 24:372-376.
• [5]Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S, Reilly JG, Chandra D, Zhou J, Claypool K, Coghlan L, Tang DG: Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 2006, 25:1696-1708.
• [6]Matoba R, Niwa H, Masui S, Ohtsuka S, Carter MG, Sharov AA, Ko MS: Dissecting Oct3/4-regulated gene networks in embryonic stem cells by expression profiling. PLoS One 2006, 1:e26.
• [7]Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW, Daley GQ: Reprogramming of human somatic cells to pluripotency with defined factors. Nature 2008, 451:141-146.
• [8]Brehm A, Ohbo K, Zwerschke W, Botquin V, Jansen-Dürr P, Schöler HR: Synergism with germ line transcription factor Oct-4: viral oncoproteins share the ability to mimic a stem cell-specific activity. Mol Cell Biol 1999, 19:2635-2643.
• [9]Gu G, Yuan J, Wills M, Kasper S: Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res 2007, 67:4807-4815.
• [10]Ezeh UI, Turek PJ, Reijo RA, Clark AT: Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3are expressed in both seminoma and breast carcinoma. Cancer 2005, 104:2255-2265.
• [11]Atlasi Y, Mowla SJ, Ziaee SA, Bahrami AR: OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer. Int J Cancer 2007, 120:1598-1602.
• [12]Shin S, Mitalipova M, Noggle S, Tibbitts D, Venable A, Rao R, Stice SL: Long-term proliferation of human embryonic stem cell-derived neuroepithelial cells using defined adherent culture conditions. Stem Cells 2006, 24:125-138.
• [13]Hu TS, Liu SR, Breiter DR, Wang F, Tang Y, Sun S: Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis. Cancer Res 2008, 68:6533-6540.
• [14]Hu J, Qin K, Zhang Y, Gong J, Li N, Lv D, Xiang R, Tan X: Downregulation of transcription factor Oct4 induces an epithelial-to-mesenchymal transition via enhancement of Ca2+ influx in breast cancer cells. Biochem Biophys Res Commun 2011, 411(4):786-791.
• [15]Karoubi G, Gugger M, Schmid R, Dutly A: Oct4 expression in human non-small cell lung cancer: implications for therapeutic intervention. Interact Cardiovasc Thorac Surg 2009, 8:393-397.
• [16]Passalidou E, Trivella M, Singh N, Ferguson M, Hu J, Cesario A, Granone P, Nicholson AG, Goldstraw P, Ratcliffe C, Tetlow M, Leigh I, Harris AL, Gatter KC, Pezzella F: Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas. Br J Cancer 2002, 86:244-249.
• [17]Pezzella F, Pastorino U, Tagliabue E, Andreola S, Sozzi G, Gasparini G, Menard S, Gatter KC, Harris AL, Fox S, Buyse M, Pilotti S, Pierotti M, Rilke F: Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis. Am J Pathol 1997, 151:1417-1423.
• [18]Sobin LH, Wittekind CH: International Union Against Cancer (UICC) TNM Classification Of Malignant Tumors. 6th edition. New York: Wiley-Liss; 2002:99-103.
• [19]Travis WD, Brambilla E, Muller-Hermelink HK: WHO classification of tumors. Pathology and Genetics. Tumors of lung, pleura, thymus and heart. Lyon: IARC Press; 2004:9-124.
• [20]Teng Y, Wang X, Wang Y, Ma D: Wnt/beta-catenin signaling regulates cancer stem cells in lung cancer A549 cells. Biochem Biophys Res Commun 2010, 392:373-379.
• [21]Hochedlinger K, Yamada Y, Beard C, Jaenisch R: Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 2005, 121:465-477.
• [22]Gidekel S, Pizov G, Bergman Y, Pikarsky E: Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell 2003, 4:361-370.
• [23]Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M: VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 2005, 201:1089-1099.
• [24]Kadota K, Huang CL, Liu D, Ueno M, Kushida Y, Haba R, Yokomise H: The clinical significance of lymphangiogenesis and angiogenesis in non-small cell lung cancer patients. Eur J Cancer 2008, 44:1057-1067.
• [25]Chen YC, Hsu HS, Chen YW, Tsai TH, How CK, Wang CY, Hung SC, Chang YL, Tsai ML, Lee YY, Ku HH, Chiou SH: Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS One 2008, 3:e2637.
• [26]Sung MT, Jones TD, Beck SD, Foster RS, Cheng L: OCT4 is superior to CD30 in the diagnosis of metastatic embryonal carcinomas after chemotherapy. Hum Pathol 2006, 37:662-667.
• [27]Glinsky GV: "Stemness" genomics law governs clinical behavior of human cancer: implications for decision making in disease management. J Clin Oncol 2008, 26:2846-2853.