GnRH and VEGF have been investigated as prostate carcinoma enhancers that support tumor spread and progression. Although both have documented roles in prostate carcinoma and many cancer types, the weak immunogenicity of these peptides has remained a major challenge for use in immunotherapy. Here, we describe a novel strategy to inhibit GnRH and VEGF production and assess the effect on the immune responses against these hormones using the RM-1 prostate cancer model. We designed a novel recombinant fusion protein which combined GnRH and VEGF as a vaccine against this tumor. The newly constructed fusion protein hVEGF121-M2-GnRH3-hinge-MVP contains the human vascular endothelial growth factor (hVEGF121) and three copies of GnRH in sequential linear alignment and T helper epitope MVP as an immunogenic vaccine. The effectiveness of the vaccine in eliciting an immune response and attenuating the prostate tumor growth was evaluated. Results showed that administration of a new vaccine effectively elicited humoral and cellular immune responses. We found that, a novel fusion protein, hVEGF121-M2-GnRH3-hinge-MVP, effectively inhibited growth of RM-1 prostate model and effectively promoted immune response. In conclusion, hVEGF121-M2-GnRH3-hinge-MVP is an effective dual mechanism tumor vaccine that limits RM-1 prostate growth. This vaccine may be a promising strategy for the treatment of hormone refractory prostate malignancies.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $36.38 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.
Hennis AJM, Hambleton IR, Wu S-Y, Skeete DH-A, Nemesure B, Leske MC. Prostate cancer incidence and mortality in Barbados, West Indies. Prostate Cancer. 2011;2011:565230. http://dx.doi.org/10.1155/2011/947870 .
Chu LW, Ritchey J, Devesa SS, Quraishi SM, Zhang H, Hsing AW. Prostate cancer incidence rates in Africa. Prostate Cancer 2011;2011:947870. http://dx.doi.org/10.1155/2011/565230.
Baade PD, Youlden DR, Krnjacki LJ. International epidemiology of prostate cancer: geographical distribution and secular trends. Mol Nutr Food Res. 2009;53:171–84.
Ye D, Zhu Y. Epidemiology of prostate cancer in China: an overview and clinical implication. Chin J Surg. 2015;53:249–52.
Furtado P, Lima MVA, Nogueira C, Franco M, Tavora F. Review of small cell carcinomas of the prostate. Prostate Cancer 2011;2011:543272. http://dx.doi.org/dx.doi.org/10.1155/2011/543272
Tosoian JJ, Trock BJ, Landis P, Feng Z, Epstein JI, Partin AW, et al. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol. 2011;29:2185–90.
Seruga B, Ocana A, Tannock IF. Drug resistance in metastatic castration-resistant prostate cancer. Nat Rev Clin Oncol. 2011;8:12–23.
Ehlers K, Halvorson L. Gonadotropin-releasing Hormone (GnRH) and the GnRH receptor (GnRHR). Glob. Libr. Women’s med., (ISSN: 1756-2228) 2013. https://doi.org/10.3843/GLOWM.10285
Massie CE, Lynch A, Ramos-Montoya A, Boren J, Stark R, Fazli L, et al. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. EMBO J. 2011;30:2719–33.
Rove KO, Crawford ED. Androgen annihilation as a new therapeutic paradigm in advanced prostate cancer. Curr Opin Urol. 2013;23:208–13.
Paul S, Piontkivska H. Frequent associations between CTL and T-helper epitopes in HIV-1 genomes and implications for multi-epitope vaccine designs. BMC Microbiol. 2010;10:212–212.
Hsu C-T, Ting C-Y, Ting C-J, Chen T-Y, Lin C-P, Whang Peng J, et al. Vaccination against gonadotropin-releasing hormone (GnRH) using toxin. Cancer Res. 2000;60:3701–5.
Wang XJ, Gu K, Xu JS, Li MH, Cao RY, Wu J, et al. Preparation of a peptide vaccine against GnRH by a bioprocess system based on asparaginase. Vaccine. 2010;28:4984–8.
Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219:983–5.
Smerdel MP, Steffensen KD, Waldstrom M, Andersen RF, Olsen DA, Brandslund I, et al. VEGF in the development of ovarian malignancy. Clin Ovarian Cancer. 2011;4:19–25.
Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, et al. VEGF-trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99:11393–8.
Rosenwaks Z, Benadiva C. Ovarian hyperstimulation syndrome: a preventable syndrome? Semin Reprod Med. 2010;28:437–9.
Gründker C, Emons G. Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer. Reprod Biol Endocrinol. 2003;1:65–71.
Huang F, Wang H, Zou Y, Liu Q, Cao J, Yin T. Effect of GnRH-II on the ESC proliferation, apoptosis and VEGF secretion in patients with endometriosis in vitro. Int J Clin Exp Pathol. 2013;6:2487–96.
Satcher RL, Bamidele O, Lin P, Lin SH, Moon B, Hernandez M, et al. Racial disparities in survival outcomes of prostate cancer patients after surgery for bone metastases. J Cancer Ther. 2013;4:27–36.
Salvage AV, Quinn B. Cancer and chemotherapy. Br Med J. 2009;339:b2875.
Choi S, Lee AK. Efficacy and safety of gonadotropin-releasing hormoneagonists used in the treatment of prostate cancer. Drug Health Patient Saf. 2011;3:107–19. https://doi.org/10.2147/DHPS.S24106
Yin L, Hu Q, Hartmann RW. Recent progress in pharmaceutical therapies for castration-resistant prostate cancer. Int J Mol Sci. 2013;14:13958–78.
Shojaei F. Anti-angiogenesis therapy in cancer: current challenges and future perspectives. Cancer Lett. 2012;320:130–7.
Chang JH, Garg NK, Lunde E, Han KY, Jain S, Azar DT. Corneal neovascularization: an anti-VEGF therapy review. Surv Ophthalmol. 2012;57:415–29.
Cenksoy C, Cenksoy PO, Erdem O, Sancak B, Gursoy R. A potential novel strategy, inhibition of vasopressin-induced VEGF secretion by relcovaptan, for decreasing the incidence of ovarian hyperstimulation syndrome in the hyperstimulated rat model. Eur J Obstet Gynecol Reprod Biol. 2014;174:86–90.
Park S, Han JM, Cheon J, Hwang JI, Seong JY. Apoptotic death of prostate cancer cells by a gonadotropin-releasing hormone-II antagonist. PloS ONE. 2014;9:1–12.
Wang XJ, Gu K, Xiong QY, Shen L, Cao RY, Li MH, et al. A novel virus-like particle based on hepatitis core antigen and substrate-binding domain of bacterial molecular chaperone DnaK. Vaccine. 2009;27:7377–84.
McCabe NP, Madajka M, Vasanji A, Byzova TV. Intraosseous injection of RM1 murine prostate cancer cells promotes rapid osteolysis and periosteal bone deposition. Clin Exp Metastas. 2008;25:581–90.
Messina A, Giacobini P. Semaphorin signaling in the development and function of the gonadotropin hormone-releasing hormone system. Front Endocrinol. 2013;4:133–133.
Baek S, Kim CS, Kim SB, Ym Kim, Kwon SW, Kim Y, et al. Combination therapy of renal cell carcinoma or breast cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial. J Transl Med. 2011;9:178–178.
Iversen P, Melezinek I, Schmidt A. Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function. BJU Int. 2001;87: 47–56.
Aslam MS, Naveed S, Ahmed A, Abbas Z, Gull I, Athar MA. Side effects of chemotherapy in cancer patients and evaluation of patients opinion about starvation based differential chemotherapy. J Cancer Ther. 2014;5:817–22.
This project was supported by the National Training Programs of Innovation and Entrepreneurship for Undergraduates (No. J1030830); Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); Excellent Youth Foundation of Jiangsu Scientific Committee (BK20140029); the National Natural Science Foundation of China (Nos. 81373232 and 81172973).
Conflict of interest
The authors declare that they have no competing interests.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
International Journal of Molecular Sciences (2019)