Top

Published in:

Open Access 01-12-2015 | Research

Effect of targeted ovarian cancer immunotherapy using ovarian cancer stem cell vaccine

Authors: Di Wu, Jing Wang, Yunlang Cai, Mulan Ren, Yuxia Zhang, Fangfang Shi, Fengshu Zhao, Xiangfeng He, Meng Pan, Chunguang Yan, Jun Dou

Published in: Journal of Ovarian Research | Issue 1/2015

Abstract

Background

Accumulating evidence has shown that different immunotherapies for ovarian cancer might overcome barriers to resistance to standard chemotherapy. The vaccine immunotherapy may be a useful one addition to conditional chemotherapy regimens. The present study investigated the use of vaccine of ovarian cancer stem cells (CSCs) to inhibit ovarian cancer growth.

Methods

CD117⁺CD44⁺CSCs were isolated from human epithelial ovarian cancer (EOC) SKOV3 cell line by using a magnetic-activated cell sorting system. Pre-inactivated CD117⁺CD44⁺CSC vaccine was vacccinated into athymic nude mice three times, and then the mice were challenged subcutaneously with SKOV3 cells. The anti-tumor efficacy of CSC vaccine was envaluated by in vivo tumorigenicity, immune efficient analysis by flow cytometer, and enzyme-linked immunosorbent assays, respectively.

Results

The CD117⁺ CD44⁺CSC vaccine increased anti-ovarian cancer efficacy in that it depressed ovarian cancer growth in the athymic nude mice. Vaccination resulted in enhanced serum IFN-γ, decreased TGF-β levels, and increased cytotoxic activity of natural killer cells in the CD117⁺ CD44⁺CSC vaccine immunized mice. Moreover, the CSC-based vaccine significantly reduced the CD117⁺CD44⁺CSC as well as the aldehyde dehydrogenase 1 positive cell populations in the ovarian cancer tissues in the xenograft mice.

Conclusion

The present study provided the first evidence that human SKOV3 CD117⁺ CD44⁺CSC-based vaccine may induce the anti-ovarian cancer immunity against tumor growth by reducing the CD117⁺CD44⁺CSC population.

Ayub TH, Keyver-Paik MD, Debald M, Rostamzadeh B, Thiesler T, Schröder L, et al. Accumulation of ALDH1-positive cells after neoadjuvant chemotherapy predicts treatment resistance and prognosticates poor outcome in ovarian cancer. Oncotarget. 2015;6:16437–48.CrossRefPubMed

Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, et al. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 2008;68:4311–20.PubMedCentralCrossRefPubMed

Chen D, Zhang Y, Wang J, Chen J, Yang C, Cai K, et al. MicroRNA-200c overexpression inhibits tumorigenicity and metastasis of CD117⁺CD44⁺ovarian cancer stem cells by regulating epithelial-mesenchymal transition. J Ovarian Res. 2013;6:50.PubMedCentralCrossRefPubMed

Schwab CL, English DP, Roque DM, Pasternak M, Santin AD. Past, present and future targets for immunotherapy in ovarian cancer. Immunotherapy. 2014;6:1279–93.PubMedCentralCrossRefPubMed

Calderwood SK, Gong J, Stevenson MA, Murshid A. Cellular and molecular chaperone fusion vaccines: targeting resistant cancer cellpopulations. Int J Hyperthermia. 2013;29:376–9.PubMedCentralCrossRefPubMed

Wefers C, Lambert LJ, Torensma R, Hato SV. Cellular immunotherapy in ovarian cancer: Targeting the stem of recurrence. Gynecol Oncol. 2015;137:335–42.CrossRefPubMed

Ning N, Pan Q, Zheng F, Teitz-Tennenbaum S, Egenti M, Yet J, et al. Cancer stem cell vaccination confers significant antitumor immunity. Cancer Res. 2012;72:1853–64.PubMedCentralCrossRefPubMed

Duarte S, Momier D, Baque P, Casanova V, Loubat A, Samson M, et al. Preventive cancer stem cell-based vaccination reduces liver metastasis development in a rat colon carcinoma syngeneic model. Stem Cells. 2013;31:423–32.CrossRefPubMed

Shen YA, Li WH, Chen PH, He CL, Chang YH, Chuang CM. Intraperitoneal delivery of a novel liposome-encapsulated paclitaxel redirects metabolic reprogramming and effectively inhibits cancer stem cells in Taxol(®)-resistant ovarian cancer. Am J Transl Res. 2015;7:841–55.PubMedCentralPubMed

10.

Chen J, Wang J, Chen Yang J, Yang C, Zhang Y, Zhang H, et al. Evaluation of characteristics of CD44⁺CD117⁺ovarian cancer stem cells in three dimensional basement membrane extract scaffold versus two dimensional monocultures. BMC Cell Biol. 2013;14:7.PubMedCentralCrossRefPubMed

11.

Wang J, Chen D, He X, Zhang Y, Shi F, Wu D, et al. Downregulated lincRNA HOTAIR expression in ovarian cancer stem cells decreases its tumorgeniesis and metastasis by inhibiting epithelial-mesenchymal transition. Cancer Cell Int. 2015;15:24.PubMedCentralCrossRefPubMed

12.

Chen J, Wang J, Zhang Y, Chen D, Yang C, Kai C, et al. Observation of ovarian cancer stem cell behavior and investigation of potential mechanisms of drug resistance in three-dimensional cell culture. J Biosci Bioeng. 2014;118:214–22.CrossRefPubMed

13.

Arnhold S, Glüer S, Hartmann K, Raabe O, Addicks K, Wenisch S, et al. Amniotic-Fluid Stem Cells: Growth Dynamics and Differentiation Potential after a CD-117-Based Selection Procedure. Stem Cells Int. 2011;23:715341.

14.

Luo L, Zeng J, Liang B, Zhao Z, Sun L, Cao D, et al. Ovarian cancer cells with the CD117 phenotype are highly tumorigenic and are related to chemotherapy outcome. Exp Mol Pathol. 2011;91:596–602.CrossRefPubMed

15.

Chen D, Wang, J, Zhang Y, Chen J, Yang C, Cao W, et al. Effect of down-regulated transcriptional repressor ZEB1 on the epithelial-mesenchymal transition of ovarian cancer cells. Int J Gynecol Cancer. 2013; 23:1357–66.CrossRefPubMed

16.

Zhang Y, Wang J, Ren M, Li M, Chen D, Chen J, et al. Gene therapy of ovarian cancer using IL-21-secreting human umbilical cord mesenchymal stem cells in nude mice. J Ovarian Res. 2014;7:8.PubMedCentralCrossRefPubMed

17.

Banerjee S, Nandyala A, Podili R. Mycobacterium tuberculosis (Mtb) isocitrate dehydrogenases show strong B cell response and distinguish vaccinated with controls from TB patients. PNAS. 2004;101:12652–7.PubMedCentralCrossRefPubMed

18.

Dou J, Wang Y, Wang J, Zhao F, Li Y, Cao M, et al. Antitumor efficacy induced by human ovarian cancer cells secreting IL-21 alone or combination with GM-CSF cytokines in nude mice model. Immunobiology. 2009;214:83–92.CrossRef

19.

Hervé L, Michèle F, Sylvie G, Rivière Y, Gougeon ML. A novel flow cytometric assay for quantitation and multiparametric characterization of cell-mediated cytotoxicity. J Immunol Methods. 2001;253:177–87.CrossRef

20.

Zhao FS, Dou J, He X, Wang J, Chu L, Hu W, et al. Enhancing therapy of B16F10 melanoma efficacy through tumor vaccine expressing GPI-anchored IL-21 and secreting GM-CSF in mouse model. Vaccine. 2010;28:2846–52.CrossRefPubMed

21.

Choi YP, Shim HS, Gao MQ, Kang S, Cho NH. Molecular portraits of intratumoral heterogeneity in human ovarian cancer. Cancer Lett. 2011;307:62–71.CrossRefPubMed

22.

Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical Outcome. Cell Stem Cell. 2007;1:555–67.PubMedCentralCrossRefPubMed

23.

Huang R, Li X, Holm R, Trope CG, Nesland JM, Suo Z. The expression of aldehyde dehydrogenase 1 (ALDH1) in ovarian carcinomas and its clinicopathological associations: a retrospective study. BMC Cancer. 2015;15:502.PubMedCentralCrossRefPubMed

24.

Young MJ, Wu YH, Chiu WT, Weng TY, Huang YF, Chou CY. All-trans retinoic acid downregulates ALDH1-mediated stemness and inhibits tumour formation in ovarian cancer cells. Carcinogenesis. 2015;36:498–507.CrossRefPubMed

25.

Zhang M, Graor H, Visioni A, Strohl M, Yan L, Caja K, Kim JA. T Cells Derived From Human Melanoma Draining Lymph Nodes Mediate Melanoma-specific Antitumor Responses In Vitro and In Vivo in uman Melanoma Xenograft Model. J Immunother. 2015,38:229–38.CrossRefPubMed

26.

Wakahashi S, Sudo T, Oka N, Ueno S, Yamaguchi S, Fujiwara K, et al. VAV1 represses E-cadherin expression through the transactivation of Snail and Slug: a potential mechanism for aberrant epithelial to mesenchymal transition in human epithelial ovarian cancer. Transl Res. 2013;162:181–90.CrossRefPubMed

27.

Fiorillo M, Verre AF, Iliut M, Peiris-Pagés M, Ozsvari B, Gandara R, et al. Graphene oxide selectively targets cancer stem cells, across multiple tumor types: implications for non- toxic cancer treatment, via “differentiation-based nano-therapy”. Oncotarget. 2015;6:3553–62.PubMedCentralCrossRefPubMed

28.

Roda JM, Parihar R, Lehman A, Mani A, Tridandapani S, Carson WE. Interleukin-21 enhances NK cell activation in response to antibody-coated targets. J Immunol. 2006;177:120–9.CrossRefPubMed

29.

Dou J, Chu LL, Zhao FS, Tang Q, Zhang A, Zhang L, et al. Study of immunotherapy of murine myeloma by an IL-21-based tumor vaccine in Balb/c mice. Cancer Biol Therapy. 2007;6:1871–9.CrossRef

30.

Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001;29:117–29.CrossRefPubMed

31.

Krasagakis K, Tholke D, Farthmann B, Eberle J, Mansmann U, Orfanos CE. Elevated plasma levels of transforming growth factor (TGF)-beta1 and TGF-beta2 in patients with disseminated malignant melanoma. Br J Cance. 1998;77:1492–4.CrossRef

32.

Wang X, Zhao F, He X, Wang J, Zhang Y, Zhang H, et al. Combining TGF-β1 knockdown and miR200c administration to Optimize Antitumor Efficacy of B16F10/GPI-IL-21 Vaccine. Oncotarget. 2015;6:12493–504.PubMedCentralCrossRefPubMed

33.

Chou JL, Huang RL, Shay J, Chen LY, Lin SJ, Yan PS, et al. Hypermethylation of the TGF-β target, ABCA1 is associated with poor prognosis inovarian cancer patients. Clin Epigenetics. 2015;7:1.PubMedCentralCrossRefPubMed

34.

DA Cruz Paula A, Marques O, Rosa AM, DE Fátima Faria M, Rêma A, Lopes C. Co-expression of stem cell markers ALDH1 and CD44 in non-malignant and neoplastic lesions of the breast. Anticancer Res. 2014;34:1427–34.PubMed

35.

Heldin P, Basu K, Kozlova I, Porsch H. HAS2 and CD44 in breast tumorigenesis. Adv Cancer Res. 2014;123:211–29.CrossRefPubMed

36.

Mackiewicz J, Kazimierczak U, Kotlarski M, Dondajewska E, Kozłowska A, Kwiatkowska E, et al. Cellular Vaccines Modified with Hyper IL6 or Hyper IL11 Combined with Docetaxel in an Orthotopic Prostate Cancer Model. Anticancer Res. 2015; 35:3275–88.PubMed

37.

Weng D, Song B, Durfee J, Sugiyama V, Wu Z, Koido S, et al. Induction of cytotoxic T lymphocytes against ovarian cancer-initiating cells. Int J Cancer. 2011;129:1990–2001.CrossRefPubMed

38.

Zhang Z, Chen X, Chang X, Ye X, Li Y, Cui H. Vaccination with embryonic stem cells generates effective antitumor immunity against ovarian cancer. Int J Mol Med. 2013;31:147–53.PubMed

Title: Effect of targeted ovarian cancer immunotherapy using ovarian cancer stem cell vaccine
Authors: Di Wu
Jing Wang
Yunlang Cai
Mulan Ren
Yuxia Zhang
Fangfang Shi
Fengshu Zhao
Xiangfeng He
Meng Pan
Chunguang Yan
Jun Dou
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Journal of Ovarian Research / Issue 1/2015
Electronic ISSN: 1757-2215
DOI: https://doi.org/10.1186/s13048-015-0196-5

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Effect of targeted ovarian cancer immunotherapy using ovarian cancer stem cell vaccine

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2015

An association study between USP34 and polycystic ovary syndrome

Gene expression profiling of ovarian carcinomas and prognostic analysis of outcome

Comparative analysis of Rb1, P16 and ER as diagnostic, prognostic and potential targets for therapeutic agents in ovarian epithelial tumors: an immunohistochemical study of 130 ovarian carcinomas

M-CSF in a new biomarker panel with HE4 and CA 125 in the diagnostics of epithelial ovarian cancer patients

Progesterone administration for luteal phase deficiency in human reproduction: an old or new issue?

Erratum to: microRNA 490-3P enhances the drug-resistance of human ovarian cancer cells