Evaluation of coxsackievirus and adenovirus receptor expression in human benign and malignant thyroid lesions
CONSTANTINOS GIAGINIS
Department of Forensic Medicine and Toxicology, Medical School, University of Athens, Athens
Search for more papers by this authorAPOSTOLOS ZARROS
Department of Forensic Medicine and Toxicology, Medical School, University of Athens, Athens
Search for more papers by this authorPARASKEVI ALEXANDROU
First Department of Pathology, Medical School, University of Athens, Athens, Greece
Search for more papers by this authorJERZY KLIJANIENKO
Department of Pathology, Institut Curie, Paris, France
Search for more papers by this authorIOANNA DELLADETSIMA
First Department of Pathology, Medical School, University of Athens, Athens, Greece
Search for more papers by this authorSTAMATIOS THEOCHARIS
Department of Forensic Medicine and Toxicology, Medical School, University of Athens, Athens
Search for more papers by this authorCONSTANTINOS GIAGINIS
Department of Forensic Medicine and Toxicology, Medical School, University of Athens, Athens
Search for more papers by this authorAPOSTOLOS ZARROS
Department of Forensic Medicine and Toxicology, Medical School, University of Athens, Athens
Search for more papers by this authorPARASKEVI ALEXANDROU
First Department of Pathology, Medical School, University of Athens, Athens, Greece
Search for more papers by this authorJERZY KLIJANIENKO
Department of Pathology, Institut Curie, Paris, France
Search for more papers by this authorIOANNA DELLADETSIMA
First Department of Pathology, Medical School, University of Athens, Athens, Greece
Search for more papers by this authorSTAMATIOS THEOCHARIS
Department of Forensic Medicine and Toxicology, Medical School, University of Athens, Athens
Search for more papers by this authorAbstract
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: 210–21.
Coxsackievirus and adenovirus receptor (CAR) expression on tumor cells is associated with sensitivity to adenoviral infection, being considered as a surrogate marker for monitoring and/or predicting adenovirus-mediated gene therapy. The aim of this study was to evaluate the clinical significance of CAR expression in human benign and malignant thyroid lesions. CAR protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues from 107 patients with benign and malignant lesions and was statistically analyzed in relation to histopathologic type; tumor size; lymph node metastasis; capsular, lymphatic and vessel invasion; as well as follicular cells’ proliferative capacity. CAR immunoreactivity was characterized as negative/weak in 53 (49.53%), moderate in 31 (28.97%) and strong in 23 (21.50%) of 107 thyroid cases. CAR immunoreactivity was significantly increased in malignant compared with that in benign thyroid lesions (p = 0.00002). Both malignant and benign thyroid lesions with enhanced follicular cells’ proliferative capacity showed significantly increased CAR immunoreactivity (p = 0.00027). In malignant thyroid lesions, enhanced CAR immunoreactivity was significantly associated with larger tumor size (p = 0.0067). The current data revealed that CAR immunoreactivity could be considered of diagnostic utility in thyroid neoplasia. Further research effort is warranted to delineate whether CAR could be considered clinically important for both diagnosis and future (gene) therapeutic applications in thyroid neoplasia.
Supporting Information
Figure S1. Representative immunostaining for coxsackievirus and adenovirus receptor in a positive control, colon cancer tissue section (original magnification ×400).
Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.
Filename | Description |
---|---|
APM_2582_sm_FigureS1.doc656 KB | Supporting info item |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1 Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 1997; 275: 1320–3.
- 2 Bowles KR, Gibson J, Wu J, Shaffer LG, Towbin JA, Bowles NE. Genomic organization and chromosomal localization of the human coxsackievirus B-adenovirus receptor gene. Hum Genet 1999; 105: 354–9.
- 3 Carson SD. Receptor for the group B coxsackieviruses and adenoviruses: CAR. Rev Med Virol 2001; 11: 219–26.
- 4 Thoelen I, Magnusson C, Tagerud S, Polacek C, Lindberg M, Van Ranst M. Identification of alternative splice products encoded by the human coxsackie-adenovirus receptor gene. Biochem Biophys Res Commun 2001; 287: 216–22.
- 5 Coyne CB, Bergelson JM. CAR: a virus receptor within the tight junction. Adv Drug Deliv Rev 2005; 57: 869–82.
- 6 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: 2363–73.
- 7 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: 325–30.
- 8 Kim JS, Lee SH, Cho YS, Choi JJ, Kim YH, Lee JH. Enhancement of the adenoviral sensitivity on human ovarian cancer cells by transient expression of coxsackievirus and adenovirus receptor (CAR). Gynecol Oncol 2002; 85: 260–5.
- 9 Leon RP, Hedlund T, Meech SJ, Li S, Schaack J, Hunger SP, et al. Adenoviral-mediated gene transfer in lymphocytes. Proc Natl Acad Sci USA 1998; 95: 13159–64.
- 10 Wang X, Bergelson JM. Coxsackievirus and adenovirus receptor cytoplasmic and transmembrane domains are not essential for coxsackievirus and adenovirus infection. J Virol 1999; 73: 2559–62.
- 11 Bai M, Campisi L, Freimuth P. Vitronectin receptor antibodies inhibit infection of HeLa and A549 cells by adenovirus type 12 but not by adenovirus type 2. J Virol 1994; 68: 5925–32.
- 12 Huang C, Li M, Chen C, Yao Q. Small interfering RNA therapy in cancer: mechanism, potential targets, and clinical applications. Expert Opin Ther Target 2008; 12: 637–45.
- 13 Zhang WW. Development and application of adenoviral vectors for gene therapy of cancer. Cancer Gene Ther 1999; 6: 113–8.
- 14 Barnett BG, Crews CJ, Douglas JT. Targeted adenoviral vectors. Biochim Biophys Acta 2002; 1575: 1–14.
- 15 Green NK, Hale SJ. Viral approaches to cancer gene therapy. Expert Opin Ther Patent 2002; 12: 369–78.
- 16 Hedley SJ, Chen J, Mountz JD, Li J, Curiel DT, Korokhov N, et al. Targeted and shielded adenovectors for cancer therapy. Cancer Immunol Immunother 2006; 55: 1412–9.
- 17 Kim JS, Lee SH, Cho YS, Choi JJ, Kim YH, Lee JH. Enhancement of the adenoviral sensitivity on human ovarian cancer cells by transient expression of coxsackievirus and adenovirus receptor (CAR). Ectopic expression of the coxsackievirus and adenovirus receptor increases susceptibility to adenoviral infection in the human cervical cancer cell line, SiHa. Biochem Biophys Res Commun 2001; 288: 240–4.
- 18 Okegawa T, Li Y, Pong RC, Hsieh JT. Cell adhesion proteins as tumor suppressors. J Urol 2002; 167: 1836–43.
- 19 Persson A, Fan X, Widegren B, Englund E. Cell type- and region- dependent coxsackie adenovirus receptor expression in the central nervous system. J Neurooncol 2006; 78: 1–6.
- 20 Persson A, Fan X, Salford LG, Widegren B, Englund E. Neuroblastomas and medulloblastomas exhibit more coxsackie adenovirus receptor expression than gliomas and other brain tumors. Neuropathology 2007; 27: 233–6.
- 21 Martin TA, Watkins G, Jiang WG. The coxsackievirus adenovirus receptor has elevated expression in human breast cancer. Clin Exp Med 2005; 5: 122–8.
- 22 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.
- 23 Okegawa T, Pong RC, Li Y, Bergelson JM, Sagalowsky AI, Hsieh JT. The mechanism of the growth-inhibitory effect of coxsackie and adenovirus receptor (CAR) on human bladder cancer: a functional analysis of car protein structure. Cancer Res 2001; 61: 6592–600.
- 24 Huang KC, Altinoz M, Wosik K, Larochelle N, Koty Z, Zhu L, et al. Impact of the coxsackie and adenovirus receptor (CAR) on glioma cell growth and invasion: requirement for the C-terminal domain. Int J Cancer 2005; 113: 38–745.
- 25 Kim M, Sumerel LA, Belousova N, Lyons GR, Carey DE, Krasnykh V, et al. The coxsackievirus and adenovirus receptor acts as a tumor suppressor in malignant glioma cells. Br J Cancer 2003; 88: 1411–6.
- 26 Gharib H, Papini E. Thyroid nodules: clinical importance, assessment, and treatment. Endocrinol Metab Clin North Am 2007; 36: 707–35.
- 27 Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA 2006; 295: 2164–7.
- 28
Noguchi S,
Noguchi A,
Murakami N.
Papillary carcinoma of the thyroid. I. Developing pattern of metastasis.
Cancer
1970; 26: 1053–60.
10.1002/1097-0142(197011)26:5<1053::AID-CNCR2820260513>3.0.CO;2-X CAS PubMed Web of Science® Google Scholar
- 29 Fisher S, Asa L. Application of immunohistochemistry to thyroid neoplasms. Arch Pathol Lab Med 2008; 132: 359–72.
- 30 Messina M, Robinson BG. Technology insight: gene therapy and its potential role in the treatment of medullary thyroid carcinoma. Nat Clin Pract Endocrinol Metab 2007; 3: 290–301.
- 31 Barzon L, Pacenti M, Boscaro M, Palù G. Gene therapy for thyroid cancer. Expert Opin Biol Ther 2004; 4: 1225–39.
- 32 Kim M, Zinn KR, Barnett BG, Sumerel LA, Krasnykh V, Curiel DT, et al. The therapeutic efficacy of adenoviral vectors for cancer gene therapy is limited by a low level of primary adenovirus receptors on tumor cells. Eur J Cancer 2002; 38: 1917–26.
- 33 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: 4992–9.
- 34 Douglas JT, Kim M, Sumerel LA, Carey DE, Curiel DT. Efficient oncolysis by a replicating adenovirus (ad) in vivo is critically dependent on tumor expression of primary ad receptors. Cancer Res 2001; 61: 813–7.
- 35 Rosai J, Appendix C. Staging of cancer. In: M Houston, editor. Rosai and Ackerman’s Surgical Pathology, 9th edn. London: Mosby, 2004: 2809–10.
- 36 Theocharis S, Papaefthymiou M, Giaginis C, Papadopouli E, Sfiniadakis I. CAR expression in gastrointestinal and pancreatic adenocarcinoma. Virchows Arch 2007; 451: 316.
- 37 Giaginis C, Davides D, Zarros A, Noussia O, Zizi-Serbetzoglou A, Kouraklis G, et al. Clinical significance of tumor-associated antigen RCAS1 expression in human pancreatic ductal adenocarcinoma. Dig Dis Sci 2008; 53: 1728–34.
- 38 Giaginis CT, Vgenopoulou S, Tsourouflis GS, Politi EN, Kouraklis GP, Theocharis SE. Expression and clinical significance of focal adhesion kinase in the two distinct histological types, intestinal and diffuse, of human gastric adenocarcinoma. Pathol Oncol Res 2009; 15: 173–81.
- 39 Mar KC, Eimoto T, Tateyama H, Arai Y, Fujiyoshi Y, Hamaguchi M. Expression of matrix metalloproteinases in benign and malignant follicular thyroid lesions. Histopathology 2006; 48: 286–94.
- 40 Melck A, Masoudi H, Griffith OL, Rajput A, Wilkins G, Bugis S, et al. Cell cycle regulators show diagnostic and prognostic utility for differentiated thyroid cancer. Ann Surg Oncol 2007; 14: 3403–11.
- 41 Wiseman SM, Griffith OL, Melck A, Masoudi H, Gown A, Nabi IR, et al. Evaluation of type 1 growth factor receptor family expression in benign and malignant thyroid lesions. Am J Surg 2008; 195: 667–73.
- 42 Li D, Duan L, Freimuth P, O’Malley BW Jr. Variability of adenovirus receptor density influences gene transfer efficiency and therapeutic response in head and neck cancer. Clin Cancer Res 1999; 5: 4175–81.
- 43 Haviv YS, Blackwell JL, Kanerva A, Nagi P, Krasnykh V, Dmitriev I, et al. Adenoviral gene therapy for renal cancer requires retargeting to alternative cellular receptors. Cancer Res 2002; 62: 4273–81.
- 44 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: 531–6.
- 45 Reimer D, Steppan I, Wiedemair A, Concin N, Hofstetter G, Marth C, et al. Soluble isoforms but not the transmembrane form of coxsackie-adenovirus receptor are of clinical relevance in epithelial ovarian cancer. Int J Cancer 2007; 120: 2568–75.
- 46 Auer D, Reimer D, Porto V, Fleischer M, Roessler J, Wiedemair A, et al. Expression of coxsackie-adenovirus receptor is related to estrogen sensitivity in breast cancer. Breast Cancer Res Treat 2009; 116: 103–11.
- 47 Abdolazimi Y, Mojarrad M, Pedram M, Modarressi MH. Analysis of the expression of coxsackievirus and adenovirus receptor in five colon cancer cell lines. World J Gastroenterol 2007; 13: 6365–9.
- 48 Pearson AS, Koch PE, Atkinson N, Xiong M, Finberg RW, Roth JA, et al. Factors limiting adenovirus-mediated gene transfer into human lung and pancreatic cancer cell lines. Clin Cancer Res 1999; 5: 4208–13.
- 49 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 cancers. J Mol Hist 2006; 37: 153–60.
- 50 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: 5031–6.
- 51 Korn WM, Macal M, Christian MM, Lacher MD, McMillan A, Rauen KA, et al. Expression of the coxsackievirus- and adenovirus receptor in gastrointestinal cancer correlates with tumor differentiation. Cancer Gene Ther 2006; 13: 792–7.
- 52 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: 3831–8.
- 53 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: 2953–60.
- 54 Marsee DK, Vadysirisack DD, Morrison CD, Prasad ML, Eng C, Duh QY, et al. Variable expression of coxsackie-adenovirus receptor in thyroid tumors: implications for adenoviral gene therapy. Thyroid 2005; 15: 977–87.
- 55 Libertini S, Iacuzzo I, Ferraro A, Vitale M, Bifulco M, Fusco A, et al. Lovastatin enhances the replication of the oncolytic adenovirus dl1520 and its antineoplastic activity against anaplastic thyroid carcinoma cells. Endocrinology 2007; 148: 5186–94.
- 56 Marsee DK, Shen DH, MacDonald LR, Vadysirisack DD, Lin X, Hinkle G, et al. Imaging of metastatic pulmonary tumors following NIS gene transfer using single photon emission computed tomography. Cancer Gene Ther 2004; 11: 121–7.