Abstract
Gene therapeutic approaches currently favor adenoviral vectors over alternatively available vector systems. Ovarian cancer represents an attractive model for an intraperitoneal adenovirus-based gene therapy, which is now under intensive clinical investigation. Adenovirus-mediated gene transfer depends on adequate virus uptake and thus on the presence of sufficient amounts of high-affinity coxsackie-adenovirus receptor (CAR) and αvβ3- and αvβ5 integrins on target cells. This fact has been ignored in most ongoing clinical trials. This investigation, therefore, determined expression of CAR by immunohistochemistry in 37 ovarian carcinomas and compared it with that of αvβ3 and αvβ5 integrins. In all samples, except one undifferentiated carcinoma, CAR was immunohistochemically demonstrable. Grade 1 tumors exhibited stronger CAR immunostaining as compared with higher-grade cancers (P < 0.03). Integrins αvβ3 and αvβ5 were detectable in 62% and 65% of carcinomas, respectively, and staining for both classes correlated positively (P < 0.005). Cancers classified as undifferentiated completely lacked αvβ3 expression. Furthermore, in undifferentiated and grade 3 carcinomas the three molecules studied exhibited marked distributional heterogeneity with regard to focal positivity and negativity within the same tumor. Either the absence of CAR, αvβ3 and αvβ5 or the pronounced heterogeneity in their expression might seriously compromise the efficiency of adenovirus-based gene therapy in ovarian cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Clayman GL et al. In vivo molecular therapy with p53 adenovirus for microscopic residual head and neck squamous carcinoma Cancer Res 1995 54: 1–6
Yang C, Cirielli C, Capogrossi MC, Passaniti A . Adenovirus-mediated wild-type p53 expression induces apoptosis and suppresses tumorigenesis of prostatic tumor cells Cancer Res 1995 55: 4210–4213
Hamada K et al. Growth inhibition of human cervical cancer cells by the recombinant adenovirus-mediated transfer of wild-type p53 gene Gynecol Oncol 1995 56: 130–132
Kim J et al. Intraperitoneal gene therapy with adenoviral-mediated p53 tumor suppressor gene for ovarian cancer model in nude mouse Cancer Gene Ther 1999 6: 172–178
Bischoff JR et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells Science 1996 274: 373–376
Bischoff JR et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells Vasey PA et al. Phase I trial of intraperitoneal Onyx-015 adenovirus in patients with recurrent ovarian cancer. Proc Am Soc Clin Oncol 2000; 19: 382a (Abstr. 1512).
Ries SJ et al. Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015) Nat Med 2000 6: 1128–1133
Heise C et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy Nat Med 2000 6: 1134–1139
Stevenson SC et al. Human adenovirus serotypes 3 and 5 bind to two different cellular receptors via the fiber head domain J Virol 1995 69: 2850–2857
Wickham TJ, Mathias P, Cheresh DA, Nemerow GR . Integrins (v(3 and (v(5 promote adenovirus internalization but not virus attachment Cell 1993 73: 309–319
Sewell DA et al. Optimizing suicide gene therapy for head and neck cancer Laryngoscope 1997 107: 1490–1495
Bergelson JM et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5 Science 1997 275: 1320–1323
Li Y 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
Okegawa T et al. The dual impact of coxsackie and adenovirus receptor expression on human prostate cancer gene therapy Cancer Res 2000 60: 5031–5036
Carreiras F et al. Expression and localization of alpha v integrins and their ligand vitronectin in normal ovarian epithelium and in ovarian carcinoma Gynecol Oncol 1996 62: 260–267
Jones JL, Walker RA . Integrins: a role as cell signalling molecules Mol Path 1999 52: 208–213
Khuu H et al. Detection of coxsackie-adenovirus receptor (CAR) immunoreactivity in ovarian tumors of epithelial derivation Appl Immunohistochem Mol Morphol 1999 7: 266–270
Hsu KHL, Lonberg-Holm K, Alstein B, Crowell RL . A monoclonal antibody specific for the cellular receptor for the group B coxsackieviruses J Virol 1988 62: 1647–1652
Dechecchi MC, Tamanini A, Bonizzato A, Cabrini G . Heparan sulfate glycosaminoglycans are involved in adenovirus type 5 and 2 host cell interactions Virology 2000 268: 382–390
Hong SS et al. Adenovirus type 5 fiber knob binds to MHC class I alpha 2 domain at the surface of human epithelial and B lymphoblastoid cells EMBO J 1997 16: 2294–2306
Worgall S et al. Free cholesterol enhances adenoviral vector gene transfer and expression in CAR-deficient cells Mol Ther 2000 1: 39–48
Zeimet AG et al. New insights into p53 regulation and gene therapy for cancer Biochem Pharmacol 2000 60: 1153–1163
Miller CR et al. Differential susceptibility of primary and established human glioma cells to adenovirus infection: targeting via epidermal growth factor receptor achieves fiber receptor-independent gene transfer Cancer Res 1998 58: 5738–5748
Hemmi S et al. The presence of human coxsackievirus and adenovirus receptor is associated with efficient adenovirus-mediated transgene expression in human melanoma cell cultures Gene Therapy 1998 9: 2363–2373
Asaoka K et al. Dependence of efficient adenoviral gene delivery in malignant glioma cells on the expression level of the coxsackievirus and adenovirus receptor J Neurosurg 2000 92: 1002–1008
Bruning A et al. Adenoviral transduction efficiency of ovarian cancer cells can be limited by loss of integrin beta3 subunit expression and increased by reconstitution of integrin alphavbeta3 Hum Gene Ther 2001 12: 391–399
Li E . Integrin (v(1 is an adenovirus coreceptor J Virol 2001 75: 5405–5409
Simon KO et al. The (v(3 integrin regulates (5(1-mediated cell migration toward fibronectin J Biol Chem 1997 272: 29380–29389
Hu DD et al. A biochemical characterization of the binding of osteospontin to integrins (v(1 and (v(5 J Biol Chem 1995 270: 26232–26238
Dmitriev I et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism J Virol 1998 72: 9706–9713
Pujade-Lauraine E et al. Intraperitoneal recombinant interferon gamma in ovarian cancer patients with residual disease at second look laparotomy J Clin Oncol 1996 14: 343–350
Alberts DS et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer N Engl J Med 1996 335: 1950–1955
Runnebaum IB . Intraperitoneale p53-Gentherapie des Ovarialkarzinoms in der klinischen Prüfung: Interimsanalyse eines vielversprechenden Ansatzes zur kausalen Therapie Arch Gynecol Obstet 1999 263: 166–168
Wen WH et al. p53 mutations and expression in ovarian cancer: correlation with overall survival Int J Gynecol Pathol 1999 18: 29–41
Liapis H, Adler LM, Wick MR, Rader JS . Expression of alpha(v)beta3 integrin is less frequent in ovarian epithelial tumors of low malignant potential in contrast to ovarian carcinomas Hum Pathol 1997 28: 443–449
Hidaka C et al. CAR-dependent and CAR-independent pathways of adenovirus vector-mediated gene transfer and expression in human fibroblasts J Clin Invest 1999 103: 579–587
Dye JF et al. Phenotype of the endothelium in human term placenta Placenta 2001 22: 32–43
Kim S, Harris M, Varner JA . Regulation of integrin alpha-v-beta-3-mediated endothelial cell migration and angiogenesis by integrin alpha5-beta1 and protein kinase A J Biol Chem 2000 275: 3920–3928
Kumar CC et al. Targeting integrins alpha v beta 3 and alpha v beta 5 for blocking tumor-induced angiogenesis Adv Exp Med Biol 2000 476: 169–180
Nielsen LL et al. Efficacy of p53 adenovirus-mediated gene therapy against human breast cancer xenografts Cancer Gene Ther 1997 4: 129–138
Acknowledgements
This work was supported in part by a grant from the Fondation Lions Vaincre le Cancer, Luxembourg. The authors thank Mrs Martina Kaindl and Mrs Vera Stivic for their excellent technical assistance.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Zeimet, A., Müller-Holzner, E., Schuler, A. et al. Determination of molecules regulating gene delivery using adenoviral vectors in ovarian carcinomas. Gene Ther 9, 1093–1100 (2002). https://doi.org/10.1038/sj.gt.3301775
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3301775
Keywords
This article is cited by
-
Understanding and addressing barriers to successful adenovirus-based virotherapy for ovarian cancer
Cancer Gene Therapy (2021)
-
A simple detection system for adenovirus receptor expression using a telomerase-specific replication-competent adenovirus
Gene Therapy (2013)
-
Combination of a MDR1-targeted replicative adenovirus and chemotherapy for the therapy of pretreated ovarian cancer
Journal of Cancer Research and Clinical Oncology (2012)
-
Role of cell surface molecules and autologous ascitic fluid in determining efficiency of adenoviral transduction of ovarian cancer cells
Cancer Gene Therapy (2010)
-
Dilated cardiomyopathy alters the expression patterns of CAR and other adenoviral receptors in human heart
Histochemistry and Cell Biology (2010)