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Expression of the coxsackie adenovirus receptor in neuroendocrine lung cancers and its implications for oncolytic adenoviral infection

Cancer Gene Therapy volume 20, pages 25–32 (2013)Cite this article

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Abstract

Coxsackie adenovirus receptor (CAR) is the primary receptor to which oncolytic adenoviruses have to bind for internalization and viral replication. A total of 171 neuroendocrine lung tumors in form of multitissue arrays have been analyzed resulting in a positivity of 112 cases (65.5%). Immunostaining correlated statistically significant with histopathology and development of recurrence. The subtype small cell lung cancer (SCLC) showed the highest CAR expression (77.6%), moreover the CAR level was correlated to the disease-free survival. Further, high CAR expression level in SCLC cell lines was found in vitro and in vivo when cell lines had been transplanted into immunodeficient mice. A correlation between CAR expression in the primary tumors and metastases development in the tumor model underlined the clinical relevance. Cell lines with high CAR level showed a high infectivity when infected with a replication-deficient adenovirus. Low levels of CAR expression in SCLC could be upregulated with Trichostatin A, a histone deacetylase inhibitor. As a result of the unaltered poor prognosis of SCLC and its high CAR expression it seems to be the perfect candidate for oncolytic therapy. With our clinically relevant tumor model, we show that xenograft experiments are warrant to test the efficiency of oncolytic adenoviral therapy.

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References

  1. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, in collaboration with Sobin LH and pathologists from 14 countries Histological Typing of Lung an Pleural Tumours., 3rd edn. Springer-Verlag: Berlin, Heidelberg, Germany, 1999.

    Book  Google Scholar 

  2. Hoffman P, Mauer A, Vokes E . Lung cancer. Lancet 2000; 355: 479–485.

    Article  CAS  PubMed  Google Scholar 

  3. Pandit N, Gonen M, Krug L, Larson S . Prognostic value of [18F] FDG-PET imaging in small lung cancer. Eur J Nucl Med Mol Imaging 2003; 30: 78–84.

    Article  PubMed  Google Scholar 

  4. Murray N, Turrisi AT . A review of first-line treatment for small-cell lung cancer. J Thorac. Oncol 2006; 1: 270–278.

    Google Scholar 

  5. Gaspar LE, McNamara EJ, Gay EG, Putnam JB, Crawford J, Herbst RS et al. Small-cell lung cancer: prognostic factors and changing treatment over 15 years. Clin Lung Cancer 2012; 13: 115–122.

    Article  PubMed  Google Scholar 

  6. Nemunaitis J, Khuri F, Ganly I, Arseneau J, Posner M, Vokes E et al. Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer. J Clin Oncol 2001; 19: 289–298.

    Article  CAS  PubMed  Google Scholar 

  7. Hecht JR, Bedford R, Abbruzzese JL, Lahoti S, Reid TR, Soetikno RM et al. A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res 2003; 9: 555–561.

    CAS  PubMed  Google Scholar 

  8. Habib N, Salama H, Abd El Latif Abu Median A, Isac Anis I, Abd Al Aziz RA, Sarraf C et al. Clinical trial of E1B-deleted adenovirus (dl1520) gene therapy for hepatocellular carcinoma. Cancer Gene Ther 2002; 9: 254–259.

    Article  CAS  PubMed  Google Scholar 

  9. Vasey PA, Shulman LN, Campos S, Davis J, Gore M, Johnston S et al. Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol 2002; 20: 1562–1569.

    CAS  PubMed  Google Scholar 

  10. Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS et al. Isolation of common receptor for coxsackie B virus and adenoviruses 2 and 5. Science 1997; 275: 1320–1323.

    Article  CAS  PubMed  Google Scholar 

  11. Fechner H, Wang X, Wang H, Jansen A, Pauschinger M, Scherübl H et al. Trans-complementation of vector replication versus coxsackie-adenovirus-receptor overexpression to improve transgene expression in poorly permissive cancer cells. Gene Ther 2000; 7: 1954–1968.

    Article  CAS  PubMed  Google Scholar 

  12. Graat HC, Wuisman PI, van Beusechem VW, Carette JE, Gerritsen WR, Bras J et al. Coxsackievirus and adenovirus receptor expression on primary osteosarcoma specimens and implications for gene therapy with recombinant adenoviruses. Clin Cancer Res 2005; 11: 2445–2447 author reply 2447–2448.

    Article  CAS  PubMed  Google Scholar 

  13. Li D, Duan L, Freimuth P, O’Malley BW . Variability of adenovirus receptor densitiy influences gene transfer efficiency and therapeutic response in head and neck cancer. Clin Cancer Res 1999; 5: 4175–4181.

    CAS  PubMed  Google Scholar 

  14. Matsumoto K, Shariat SF, Ayala GE, Rauen KA, Lerner SP . Loss of coxsackie and adenovirus receptor expression is associated with features of aggressive bladder cancer. Urology 2005; 66: 441–446.

    Article  PubMed  Google Scholar 

  15. Li Y, Pong RC, Bergelson JM, Hall MC, Sagalowski AI, Tseng CP et al. Loss of adenoviral receptor expression in human bladder cancer cells: a potential impact on the efficacy of gene therapy. Cancer Res 1999; 59: 325–330.

    CAS  PubMed  Google Scholar 

  16. Cripe TP, Dunphy EJ, Holub AD, Saini A, Vasi NH, Mahller YY et al. Fiber knob modifications overcome low, heterogeneous expression of the coxsackievirus-adenovirus receptor that limits adenovirus gene transfer and oncolysis for human rhabdomyosarcoma cells. Cancer Res 2001; 61: 2953–2960.

    CAS  PubMed  Google Scholar 

  17. Cohen C, Shieh J, Pickles R, Okegawa T, Hsieh J, Bergelson J . The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction. Proc Natl Acad Sci USA 2001; 98: 15191–15196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nilsson O . Carbohydrate antigens in human lung carcinomas. APMIS Suppl 1992; 27: 149–161.

    CAS  PubMed  Google Scholar 

  19. Mabry M, Nakagawa T, Nelkin BD, McDowell E, Gesell M, Eggleston JC et al. v-Ha-ras oncogene insertion: a model for tumor progression of human small cell lung cancer. Proc Natl Acad Sci USA 1988; 85: 6523–6527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gazdar AF, Carney DN, Russell EK, Sims HL, Baylin SB, Bunn PA et al. Establishment of continuous, clonable cultures of small-cell carcinoma of lung which have amine precursor uptake and decarboxylation cell properties. Cancer Res 1980; 40: 3502–3507.

    CAS  PubMed  Google Scholar 

  21. Griffin CA, Baylin SB . Expression of the c-myb oncogene in human small cell lung carcinoma. Cancer Res 1985; 45: 272–275.

    CAS  PubMed  Google Scholar 

  22. Derbyshire EJ, Stahel RA, Wawrzynczak EJ . Cytotoxic properties of a ricin A chain immunotoxin recognising the cluster-5A antigen associated with human small-cell lung cancer. Cancer Immunol Immunother 1992; 35: 417–420.

    Article  CAS  PubMed  Google Scholar 

  23. Carney DN, Gazdar AF, Bepler G, Guccion JG, Marangos PJ, Moody TW et al. Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res 1985; 45: 2913–2923.

    CAS  PubMed  Google Scholar 

  24. Zimmermann S, Wels W, Froesch BA, Gerstmayer B, Stahel RA, Zangemeister-Wittke U . A novel immunotoxin recognising the epithelial glycoprotein-2 has potent antitumoural activity on chemotherapy-resistant lung cancer. Cancer Immunol Immunother 1997; 44: 1–9.

    Article  CAS  PubMed  Google Scholar 

  25. He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B . A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 1998; 95: 2509–2514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sodeur S, Ullrich S, Gustke H, Zangemeister-Wittke U, Schumacher U . Increades numers of spontaneous SCLC metastasis in abscence of NK cells after subcutaneous inoculation of different SCLC cell Lines into pfp/rag2 double knock out mice. Cancer Lett 2009; 282: 146–151.

    Article  CAS  PubMed  Google Scholar 

  27. Sachs MD, Rauen KA, Ramamurthy M, Dodson JL, De Marzo AM, Putzi MJ et al. Integrin alpha(v) and coxsackie adenovirus receptor expression in clinical bladder cancer. Urology 2002; 60: 531–536.

    Article  PubMed  Google Scholar 

  28. Okegawa T, Li Y, Pong RC, Bergelson JM, Zhou J, Hsieh JT . The dual impact of coxsackie and adenovirus receptor expression on human prostate cancer gene therapy. Cancer Res 2000; 60: 5031–5036.

    CAS  PubMed  Google Scholar 

  29. Anders M, Vieth M, Röcken C, Ebert M, Pross M, Gretschel S et al. Loss of the coxsackie and adenovirus receptor contributes to gastric cancer progression. Br J Cancer 2009; 100: 352–359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Giaginis C, Zarros A, Alexandrou P, Klijanienko J, Delladetsima I, Theocharis S . Evaluation of coxsackievirus and adenovirus receptor expression in human benign and malignant thyroid lesions. APMIS 2010; 118: 210–221.

    Article  CAS  PubMed  Google Scholar 

  31. Giaginis CT, Zarros AC, Papaefthymiou MA, Papadopouli AE, Sfiniadakis IK, Theocharis SE . Coxsackievirus and adenovirus receptor expression in human endometrial adenocarcinoma: possible clinical implications. World J Surg Oncol 2008; 6: 59.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Gu W, Ogose A, Kawashima H, Ito M, Ito T, Matsuba A et al. High-level expression of the coxsackievirus and adenovirus receptor messenger RNA in osteosarcoma, Ewing's sarcoma, and benign neurogenic tumors among musculoskeletal tumors. Clin Cancer Res 2004; 10: 3831–3838.

    Article  CAS  PubMed  Google Scholar 

  33. García-Morales MP, Castro-Galache MD, Menéndez-Gutiérrez MP, García-Poveda E, Ferragut JA, Saceda M . Trichostatin A effects in different drug-resistant tumor cell lines. Av Diabetol 2002; 18: 175–179.

    Google Scholar 

  34. Gu AK, Sun LN, Chen ZL, Zhan ZL, Li JW . [Expression of coxsackievirus and adenovirus receptor in non-small cell lung cancer and its significance]. Zhonghua Zhong Liu Za Zhi 2009; 31: 278–281.

    CAS  PubMed  Google Scholar 

  35. Wang Y, Wang S, Bao Y, Ni C, Guan N, Zhao J et al. Coxsackievirus and adenovirus receptor expression in non-malignant lung tissues and clinical lung cancers. J Mol Histol 2006; 37: 153–160.

    Article  CAS  PubMed  Google Scholar 

  36. Bao Y, Wang Y, Ma L, Guan N, Cheng Y, Wang S et al. Expression of coxsackie and adenovirus receptor in small cell lung cancer. Chinese-German J Clin Oncol 2009; 9: 504–505.

    Article  Google Scholar 

  37. Sun L, Gu A, Chen Z, Wang Q, Li J, Sun B . Expression of coxsackievirus and adenovirus receptor in human lung cancer: Possible clinical significance. Clin Oncol Cancer Res 2010; 7: 48–54.

    Article  CAS  Google Scholar 

  38. Qin M, Chen S, Yu T, Escuadro B, Sharma S, Batra RK . Coxsackievirus adenovirus receptor expression predicts the efficiency of adenoviral gene transfer into non-small cell lung cancer xenografts. Clin Cancer Res 2003; 9: 4992–4999.

    CAS  PubMed  Google Scholar 

  39. Li Y, Pong RC, Bergelson JM, Hall MC, Sagalowsky AI, Tseng CP et al. Loss of adenoviral receptor expression in human bladder cancer cells: a potential impact on the efficacy of gene therapy. Cancer Res 1999; 59: 325–330.

    CAS  PubMed  Google Scholar 

  40. Hemmi S, Geertsen R, Mezzacasa A, Peter I, Dummer R . The presence of human coxsackievirus and adenovirus receptor is associated with efficient adenovirus-mediated transgene expression in human melanoma cell cultures. Hum Gene Ther 1998; 9: 2363–2373.

    Article  CAS  PubMed  Google Scholar 

  41. Cripe TP, Dunphy EJ, Holub AD, Saini A, Vasi NH, Mahller YY et al. Fiber knob modifications overcome low, heterogeneous expression of the coxsackievirus-adenovirus receptor that limits adenovirus gene transfer and oncolysis for human rhabdomyosarcoma cells. Cancer Res 2001; 61: 2953–2960.

    CAS  PubMed  Google Scholar 

  42. Rauen KA, Sudilovsky D, Le JL, Chew KL, Hann B, Weinberg V et al. Expression of the coxsackie adenovirus receptor in normal prostate and in primary and metastatic prostate carcinoma: potential relevance to gene therapy. Cancer Res 2002; 62: 3812–3818.

    CAS  PubMed  Google Scholar 

  43. Stecker K, Vieth M, Koschel A, Wiedenmann B, Röcken C, Anders M . Impact of the coxsackievirus and adenovirus receptor on the adenoma-carcinoma sequence of colon cancer. Br J Cancer 2011; 104: 1426–1433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chu RL, Post DE, Khuri FR, Van Meier EG . Use of replicating oncolytic adenoviruses in combination therapy for cancer. Clin Cancer Res 2004; 10: 5299–5312.

    Article  CAS  PubMed  Google Scholar 

  45. Wistuba II, Gazdar AF, Minna JD . Molecular genetics of small cell lung carcinoma. Semin Oncol 2001; 28: 3–13.

    Article  CAS  PubMed  Google Scholar 

  46. Winter SF, Minna JD, Johnson BE, Takahashi T, Gazdar AF, Carbone DP . Development of antibodies against p53 in lung cancer patients appears to be dependent on the type of p53 mutation. Cancer Res 1992; 52: 4168–4174.

    CAS  PubMed  Google Scholar 

  47. D'Amico D, Carbone D, Mitsudomi T, Nau M, Fedorko J, Russell E et al. High frequency of somatically acquired p53 mutations in small-cell lung cancer cell lines and tumors. Oncogene 1992; 7: 339–346.

    CAS  PubMed  Google Scholar 

  48. Fujita T, Kiyama M, Tomizawa Y, Kohno T, Yokota J . Comprehensive analysis of p53 gene mutation characteristics in lung carcinoma with special reference to histological subtypes. Int J Oncol 1999; 15: 927–934.

    CAS  PubMed  Google Scholar 

  49. Chen G, Wang BB, Li FJ, Liu DY, Zhou JF, Lu YP et al. [Enhancive effect of histone deacetylase inhibitor trichostatin a on transfection efficiency of adenovirus in ovarian carcinoma cell line A2780]. Ai Zheng 2005; 24: 1196–1200.

    CAS  PubMed  Google Scholar 

  50. VanOosten RL, Earel JK, Griffith TS . Enhancement of Ad5-TRAIL cytotoxicity against renal cell carcinoma with histone deacetylase inhibitors. Cancer Gene Ther 2006; 13: 628–632.

    Article  CAS  PubMed  Google Scholar 

  51. Watanabe T, Hioki M, Fujiwara T, Nishizaki M, Kagawa S, Taki M et al. Histone deacetylase inhibitor FR901228 enhances the antitumor effect of telomerase-specific replication-selective adenoviral agent OBP-301 in human lung cancer cells. Exp Cell Res 2006; 312: 256–265.

    CAS  PubMed  Google Scholar 

  52. Papeleu P, Vanhaecke T, Elaut G, Vinken M, Henkens T, Snykers S et al. Differential effects of histone deacetylase inhibitors in tumor and normal cells-what is the toxicological relevance? Crit Rev Toxicol 2005; 35: 363–378.

    Article  CAS  PubMed  Google Scholar 

  53. Suzuki T, Yokozaki H, Kuniyasu H, Hayashi K, Naka K, Ono S et al. Effect of trichostatin A on cell growth and expression of cell cycle- and apoptosis-related molecules in human gastric and oral carcinoma cell lines. Int J Cancer 2000; 88: 992–997.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Anatomy and Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    T Wunder, K Schmid, D Wicklein, T Lange & U Schumacher

  2. Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Molecular Virology, Hamburg, Germany

    P Groitl & T Dobner

  3. Department of Interdisciplinary Endoscopy, University Hospital Hamburg Eppendorf, Hamburg, Germany

    M Anders

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Wunder, T., Schmid, K., Wicklein, D. et al. Expression of the coxsackie adenovirus receptor in neuroendocrine lung cancers and its implications for oncolytic adenoviral infection. Cancer Gene Ther 20, 25–32 (2013). https://doi.org/10.1038/cgt.2012.80

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