Skip to main content
Top
Published in: Cancer Cell International 1/2016

Open Access 01-12-2016 | Primary research

Involvement of human chorionic gonadotropin in regulating vasculogenic mimicry and hypoxia-inducible factor-1α expression in ovarian cancer cells

Authors: Min Su, Xiangxiang Xu, Weiwei Wei, Sainan Gao, Xiaoying Wang, Caoyi Chen, Yuquan Zhang

Published in: Cancer Cell International | Issue 1/2016

Login to get access

Abstract

Background

Human chorionic gonadotropin (hCG) can play a crucial role in angiogenesis. In the present study, we focused on hCG to gain insight into its potential effects on vasculogenic mimicry (VM) in ovarian cancer cells.

Methods

Ovarian cancer OVCAR-3 cells were incubated with different concentrations of recombinant hCG in 3-dimensional cultures. VM was identified by morphological observations and vascular endothelial cell marker detection in OVCAR-3 cells. Expression of hCG, hypoxia-inducible factor-1α (HIF-1α), and the endothelial cell markers CD31, VEGF, and factor VIII were detected by reverse transcription polymerase chain reaction and western blotting. The effect of hCG on endothelial cell-marker expression in ovarian cancer cells was further explored using small interfering RNA (siRNA) and plasmid-based approaches.

Results

Incubation of OVCAR-3 cells with recombinant hCG induced vessel-like network formation, which was accompanied by significant elevation of vascular marker expression. Attenuation of hCG expression by siRNA in OVCAR-3 cells suppressed the expression of endothelial cell markers and HIF-1α by tumour cells. Overexpression of hCG in OVCAR-3 cells resulted in increased expression of endothelial cell markers and HIF-1α.

Conclusions

HCG was crucial for changing the phenotype of OVCAR-3 cells to endothelial-like cells. The effect of hCG induction on VM in ovarian cancer cells is potentially associated with HIF-1α.
Literature
1.
go back to reference Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol. 1999;155:739–52.CrossRefPubMedPubMedCentral Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol. 1999;155:739–52.CrossRefPubMedPubMedCentral
2.
go back to reference Yao LQ, Feng YJ, Ding JX, Jing HM, Xu CJ, Chen SF, et al. Differentiation of vascular endothelial cells-like derived from epithelial ovarian cancer cells induced by hypoxia. Int J Oncol. 2007;30:1069–75.PubMed Yao LQ, Feng YJ, Ding JX, Jing HM, Xu CJ, Chen SF, et al. Differentiation of vascular endothelial cells-like derived from epithelial ovarian cancer cells induced by hypoxia. Int J Oncol. 2007;30:1069–75.PubMed
3.
go back to reference Vartanian AA, Stepanova EV, Gutorov SL, Solomko ES, Grigorieva IN, Sokolova IN, et al. Prognostic significance of periodic acid-Schiff-positive patterns in clear cell renal cell carcinoma. Can J Urol. 2009;16:4726–32.PubMed Vartanian AA, Stepanova EV, Gutorov SL, Solomko ES, Grigorieva IN, Sokolova IN, et al. Prognostic significance of periodic acid-Schiff-positive patterns in clear cell renal cell carcinoma. Can J Urol. 2009;16:4726–32.PubMed
4.
go back to reference Su M, Yao LQ, Feng YJ, Cheng MJ, Xu CJ, Huang Y, et al. Plasticity of ovarian cancer cell and vasculogenic mimicry in vivo. Int J Gynecol Cancer. 2008;18:476–86.CrossRefPubMed Su M, Yao LQ, Feng YJ, Cheng MJ, Xu CJ, Huang Y, et al. Plasticity of ovarian cancer cell and vasculogenic mimicry in vivo. Int J Gynecol Cancer. 2008;18:476–86.CrossRefPubMed
5.
go back to reference Clemente M, Perez M, Illera J, Pena L. Histological, immunohistological, and ultrastructural description of vasculogenic mimicry in canine mammary cancer. Vet Pathol. 2010;47:265–74.CrossRefPubMed Clemente M, Perez M, Illera J, Pena L. Histological, immunohistological, and ultrastructural description of vasculogenic mimicry in canine mammary cancer. Vet Pathol. 2010;47:265–74.CrossRefPubMed
6.
go back to reference Liu C, Huang HN, Doñate F, Dickinson C, Santucci R, El-Sheikh A, et al. Prostate-specific membrane antigen directed selective thrombotic infarction of tumors. Cancer Res. 2002;62:5470–5.PubMed Liu C, Huang HN, Doñate F, Dickinson C, Santucci R, El-Sheikh A, et al. Prostate-specific membrane antigen directed selective thrombotic infarction of tumors. Cancer Res. 2002;62:5470–5.PubMed
7.
go back to reference Scavelli C, Nico B, Cirulli T, Ria R, Pietro GD, Mangieri D, et al. Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma. Oncogene. 2008;27:663–74.CrossRefPubMed Scavelli C, Nico B, Cirulli T, Ria R, Pietro GD, Mangieri D, et al. Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma. Oncogene. 2008;27:663–74.CrossRefPubMed
8.
go back to reference Guzman G, Cotler SJ, Lin AY, Maniotis AJ, Folberg R. A pilot study of vasculogenic mimicry immunohistochemical expression in hepatocellular carcinoma. Arch Pathol Lab Med. 2007;131:1776–81.PubMedPubMedCentral Guzman G, Cotler SJ, Lin AY, Maniotis AJ, Folberg R. A pilot study of vasculogenic mimicry immunohistochemical expression in hepatocellular carcinoma. Arch Pathol Lab Med. 2007;131:1776–81.PubMedPubMedCentral
9.
go back to reference van der Schaft DW, Hillen F, Pauwels P, Kirschmann DA, Castermans K, Egbrink MG, et al. Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia. Cancer Res. 2005;65:11520–8.CrossRefPubMed van der Schaft DW, Hillen F, Pauwels P, Kirschmann DA, Castermans K, Egbrink MG, et al. Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia. Cancer Res. 2005;65:11520–8.CrossRefPubMed
10.
go back to reference Sun BC, Zhang DF, Zhang SW, Zhang WZ, Guo H, Zhao XL. Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett. 2007;249:188–97.CrossRefPubMed Sun BC, Zhang DF, Zhang SW, Zhang WZ, Guo H, Zhao XL. Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett. 2007;249:188–97.CrossRefPubMed
11.
go back to reference Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng PY, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207:2439–53.CrossRefPubMedPubMedCentral Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng PY, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207:2439–53.CrossRefPubMedPubMedCentral
12.
go back to reference Su M, Wei W, Xu X, Wang X, Chen C, Su L, Zhang Y. The role of hCG in vasculogenic mimicry in OVCAR-3 ovarian cancer cell line. Int J Gynecol Cancer. 2011;21:1366–74.CrossRefPubMed Su M, Wei W, Xu X, Wang X, Chen C, Su L, Zhang Y. The role of hCG in vasculogenic mimicry in OVCAR-3 ovarian cancer cell line. Int J Gynecol Cancer. 2011;21:1366–74.CrossRefPubMed
13.
go back to reference Su M, Fan C, Gao SN, Shen AG, Wang XY, Zhang YQ. An HCG-rich microenvironment contributes to ovarian cancer cell differentiation into endothelioid cells in a three-dimensional culture system. Oncol Rep. 2015;34:2395–402.PubMed Su M, Fan C, Gao SN, Shen AG, Wang XY, Zhang YQ. An HCG-rich microenvironment contributes to ovarian cancer cell differentiation into endothelioid cells in a three-dimensional culture system. Oncol Rep. 2015;34:2395–402.PubMed
15.
go back to reference Lempiäinen A, Stenman UH, Blomqvist C, Hotakainen K. Free β-subunit of human chorionic gonadotropin in serum is a diagnostically sensitive marker of seminomatous testicular cancer. Clin Chem. 2008;54:1840–3.CrossRefPubMed Lempiäinen A, Stenman UH, Blomqvist C, Hotakainen K. Free β-subunit of human chorionic gonadotropin in serum is a diagnostically sensitive marker of seminomatous testicular cancer. Clin Chem. 2008;54:1840–3.CrossRefPubMed
16.
go back to reference Iles RK, Delves PJ, Butler SA. Does hCG or hCGβ play a role in cancer cell biology? Mol Cell Endocrinol. 2010;329:62–70.CrossRefPubMed Iles RK, Delves PJ, Butler SA. Does hCG or hCGβ play a role in cancer cell biology? Mol Cell Endocrinol. 2010;329:62–70.CrossRefPubMed
17.
go back to reference Vartiainen J, Lassus H, Lehtovirta P, Finne P, Alfthan H, Butzow R, et al. Combination of serum hCG beta and p53 tissue expression defines distinct subgroups of serous ovarian carcinoma. Int J Cancer. 2008;122:2125–9.CrossRefPubMed Vartiainen J, Lassus H, Lehtovirta P, Finne P, Alfthan H, Butzow R, et al. Combination of serum hCG beta and p53 tissue expression defines distinct subgroups of serous ovarian carcinoma. Int J Cancer. 2008;122:2125–9.CrossRefPubMed
18.
go back to reference Iles RK. Ectopic hCGβ expression by epithelial cancer: malignant behavior metastasis and inhibition of tumor cell apoptosis. Mol Cell Endocrinol. 2007;260:264–70.CrossRefPubMed Iles RK. Ectopic hCGβ expression by epithelial cancer: malignant behavior metastasis and inhibition of tumor cell apoptosis. Mol Cell Endocrinol. 2007;260:264–70.CrossRefPubMed
19.
go back to reference Sun BC, Zhang SW, Zhao X, Zhang W, Hao X. Vasculogenic mimicry is associated with poor survival in patients with mesothelial sarcomas and alveolar rhabdomyosarcomas. Int J Oncol. 2004;25:1609–14.PubMed Sun BC, Zhang SW, Zhao X, Zhang W, Hao X. Vasculogenic mimicry is associated with poor survival in patients with mesothelial sarcomas and alveolar rhabdomyosarcomas. Int J Oncol. 2004;25:1609–14.PubMed
20.
go back to reference Herr F, Baal N, Reisinger K, Lorenz A, McKinnon T, Preissner KT, et al. hCG in the regulation of placental angiogenesis. Results of an in vitro study. Placenta. 2007;28:S85–93.CrossRefPubMed Herr F, Baal N, Reisinger K, Lorenz A, McKinnon T, Preissner KT, et al. hCG in the regulation of placental angiogenesis. Results of an in vitro study. Placenta. 2007;28:S85–93.CrossRefPubMed
21.
go back to reference Li D, Wen X, Ghali L, Al-Shalabi FM, Docherty SM, Purkis P, et al. hCG beta expression by cervical squamous carcinoma-in vivo histological association with tumour invasion and apoptosis. Histopathology. 2008;53:147–55.CrossRefPubMed Li D, Wen X, Ghali L, Al-Shalabi FM, Docherty SM, Purkis P, et al. hCG beta expression by cervical squamous carcinoma-in vivo histological association with tumour invasion and apoptosis. Histopathology. 2008;53:147–55.CrossRefPubMed
22.
go back to reference Arrieta O, Michel Ortega RM, Angeles-Sánchez J, Villarreal-Garza C, Aviles-Salas A, Chanona-Vilchis JG, et al. Serum human chorionic gonadotropin is associated with angiogenesis in germ cell testicular tumors. J Exp Clin Cancer Res. 2009;28:120.CrossRefPubMedPubMedCentral Arrieta O, Michel Ortega RM, Angeles-Sánchez J, Villarreal-Garza C, Aviles-Salas A, Chanona-Vilchis JG, et al. Serum human chorionic gonadotropin is associated with angiogenesis in germ cell testicular tumors. J Exp Clin Cancer Res. 2009;28:120.CrossRefPubMedPubMedCentral
23.
go back to reference Folberg R, Maniotis AJ. Vasculogenic mimicry. Acta Pathol. 2004;112:508. Folberg R, Maniotis AJ. Vasculogenic mimicry. Acta Pathol. 2004;112:508.
24.
go back to reference Dong J, Zhao YD, Huang Q, Fei XF, Diao Y, Shen YT, Xiao H, Zhang TY, Lan Q, Gu XS. Glioma stem/progenitor cells contribute to neovascularization via transdifferentiation. Stem Cell Rev Rep. 2011;7:141–52.CrossRef Dong J, Zhao YD, Huang Q, Fei XF, Diao Y, Shen YT, Xiao H, Zhang TY, Lan Q, Gu XS. Glioma stem/progenitor cells contribute to neovascularization via transdifferentiation. Stem Cell Rev Rep. 2011;7:141–52.CrossRef
25.
go back to reference Petty AP, Garman KL, Winn VD, Spidel CM, Lindsey JS. Overexpression of carcinoma and embryonic cytotrophoblast cell-specific Mig-7 induces invasion and vessel-like structure formation. Am J Pathol. 2007;170:1763–80.CrossRefPubMedPubMedCentral Petty AP, Garman KL, Winn VD, Spidel CM, Lindsey JS. Overexpression of carcinoma and embryonic cytotrophoblast cell-specific Mig-7 induces invasion and vessel-like structure formation. Am J Pathol. 2007;170:1763–80.CrossRefPubMedPubMedCentral
26.
go back to reference Wang JY, Sun T, Zhao XL, Zhang SW, Zhang DF, Gu Q, Wang XH, Zhao N, Qie S, Sun BC. Functional significance of VEGF-a in human ovarian carcinoma: role in vasculogenic mimicry. Cancer Biol Ther. 2008;7:758–66.CrossRefPubMed Wang JY, Sun T, Zhao XL, Zhang SW, Zhang DF, Gu Q, Wang XH, Zhao N, Qie S, Sun BC. Functional significance of VEGF-a in human ovarian carcinoma: role in vasculogenic mimicry. Cancer Biol Ther. 2008;7:758–66.CrossRefPubMed
27.
go back to reference Daniel KD, Kim GY, Vassiliou CC, Jalali-Yazdi F, Langer R, Cima MJ. Multi-reservoir device for detecting a soluble cancer biomarker. Lab Chip. 2007;7:1288–93.CrossRefPubMed Daniel KD, Kim GY, Vassiliou CC, Jalali-Yazdi F, Langer R, Cima MJ. Multi-reservoir device for detecting a soluble cancer biomarker. Lab Chip. 2007;7:1288–93.CrossRefPubMed
28.
go back to reference Jankowska AG, Andrusiewicz M, Fischer N, Warchol PJ. Expression of hCG and GnRHs and their receptors in endometrial carcinoma and hyperplasia. Int J Gynecol Cancer. 2010;20:92–101.CrossRefPubMed Jankowska AG, Andrusiewicz M, Fischer N, Warchol PJ. Expression of hCG and GnRHs and their receptors in endometrial carcinoma and hyperplasia. Int J Gynecol Cancer. 2010;20:92–101.CrossRefPubMed
29.
go back to reference Michel RM, Aguilar JL, Arrieta O. Human chorionic gonadotropin as an angiogenic factor in breast cancer during pregnancy. Med Hypotheses. 2007;68:1035–40.CrossRefPubMed Michel RM, Aguilar JL, Arrieta O. Human chorionic gonadotropin as an angiogenic factor in breast cancer during pregnancy. Med Hypotheses. 2007;68:1035–40.CrossRefPubMed
30.
go back to reference Phan B, Rakenius A, Pietrowski D, Bettendorf H, Keck C, Herr D. hCG-dependent regulation of angiogenic factors in human granulosa lutein cells. Mol Reprod Dev. 2006;73:878–84.CrossRefPubMed Phan B, Rakenius A, Pietrowski D, Bettendorf H, Keck C, Herr D. hCG-dependent regulation of angiogenic factors in human granulosa lutein cells. Mol Reprod Dev. 2006;73:878–84.CrossRefPubMed
31.
go back to reference Pietrowski D, Wiehle P, Sator M, Just A, Keck C. Regulation of the angiopoietin-2 gene by hCG in ovarian cancer cell line OVCAR-3. Horm Metab Res. 2010;42:328–33.CrossRefPubMed Pietrowski D, Wiehle P, Sator M, Just A, Keck C. Regulation of the angiopoietin-2 gene by hCG in ovarian cancer cell line OVCAR-3. Horm Metab Res. 2010;42:328–33.CrossRefPubMed
32.
go back to reference Berndt S, Perrier HS, Blacher S, Péqueux C, Lorquet S, Munaut C, et al. Angiogenic activity of human chorionic gonadotropin through LH receptor activation on endothelial and epithelial cells of the endometrium. FASEB J. 2006;20:2630–2.CrossRefPubMed Berndt S, Perrier HS, Blacher S, Péqueux C, Lorquet S, Munaut C, et al. Angiogenic activity of human chorionic gonadotropin through LH receptor activation on endothelial and epithelial cells of the endometrium. FASEB J. 2006;20:2630–2.CrossRefPubMed
33.
go back to reference Kliman HJ, Nestler JE, Sermasi E, Sanger JM, Strauss JF 3rd. Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology. 1986;118:1567–82.CrossRefPubMed Kliman HJ, Nestler JE, Sermasi E, Sanger JM, Strauss JF 3rd. Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology. 1986;118:1567–82.CrossRefPubMed
34.
go back to reference Licht P, Fluhr H, Neuwinger J, Wallwiener D, Wildt L. Is human chorionic gonadotropin directly involved in the regulation of human implantation? Mol Cell Endocrinol. 2007;269:85–92.CrossRefPubMed Licht P, Fluhr H, Neuwinger J, Wallwiener D, Wildt L. Is human chorionic gonadotropin directly involved in the regulation of human implantation? Mol Cell Endocrinol. 2007;269:85–92.CrossRefPubMed
35.
go back to reference Jiang XS, Russo IH, Russo J. Alternately spliced luteinizing hormone/human chorionic gonadotropin receptor mRNA in human breast epithelial cells. Int J Oncol. 2002;20:735–8.PubMed Jiang XS, Russo IH, Russo J. Alternately spliced luteinizing hormone/human chorionic gonadotropin receptor mRNA in human breast epithelial cells. Int J Oncol. 2002;20:735–8.PubMed
36.
go back to reference Dabizzi S, Noci I, Borri P, Borrani E, Giachi M, Balzi M, et al. Luteinizing hormone increases human endometrial cancer cells invasiveness through activation of protein kinase A. Cancer Res. 2003;63:4281–6.PubMed Dabizzi S, Noci I, Borri P, Borrani E, Giachi M, Balzi M, et al. Luteinizing hormone increases human endometrial cancer cells invasiveness through activation of protein kinase A. Cancer Res. 2003;63:4281–6.PubMed
37.
go back to reference Srisuparp S, Strakova Z, Brudney A, Mukherjee S, Reierstad S, Hunzicker-Dunn M, et al. Signal transduction pathways activated by chorionic gonadotropin in the primate endometrial epithelial cells. Biol Reprod. 2003;68:457–64.CrossRefPubMed Srisuparp S, Strakova Z, Brudney A, Mukherjee S, Reierstad S, Hunzicker-Dunn M, et al. Signal transduction pathways activated by chorionic gonadotropin in the primate endometrial epithelial cells. Biol Reprod. 2003;68:457–64.CrossRefPubMed
38.
go back to reference Savai R, Schermuly RT, Voswinckel R, Renigunta A, Reichmann B, Eul B, et al. HIF-1α attenuates tumor growth in spite of augmented vascularization in an A549 adenocarcinoma mouse model. Int J Oncol. 2005;27:393–400.PubMed Savai R, Schermuly RT, Voswinckel R, Renigunta A, Reichmann B, Eul B, et al. HIF-1α attenuates tumor growth in spite of augmented vascularization in an A549 adenocarcinoma mouse model. Int J Oncol. 2005;27:393–400.PubMed
39.
go back to reference van den Driesche S, Myers M, Gay E, Thong KJ, Duncanet WC. hCG up-regulates hypoxia inducible factor-1 alpha in luteinized granulosa cells: implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteum. Mol Hum Reprod. 2008;14:455–64.CrossRefPubMed van den Driesche S, Myers M, Gay E, Thong KJ, Duncanet WC. hCG up-regulates hypoxia inducible factor-1 alpha in luteinized granulosa cells: implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteum. Mol Hum Reprod. 2008;14:455–64.CrossRefPubMed
40.
go back to reference Dong X, Wang YS, Dou GR, Hou HY, Shi YY, Zhang R, et al. Influence of Dll4 via HIF-1α-VEGF signaling on the angiogenesis of choroidal neovascularization under hypoxic conditions. PLoS One. 2011;6:18481.CrossRef Dong X, Wang YS, Dou GR, Hou HY, Shi YY, Zhang R, et al. Influence of Dll4 via HIF-1α-VEGF signaling on the angiogenesis of choroidal neovascularization under hypoxic conditions. PLoS One. 2011;6:18481.CrossRef
41.
go back to reference Simiantonaki N, Jayasinghe C, Michel-Schmidt R, Peters K, Hermanns MI, Kirkpatrick CJ. Hypoxia-induced epithelial VEGF-C/VEGFR-3 upregulation in carcinoma cell lines. Int J Oncol. 2008;32:585–92.PubMed Simiantonaki N, Jayasinghe C, Michel-Schmidt R, Peters K, Hermanns MI, Kirkpatrick CJ. Hypoxia-induced epithelial VEGF-C/VEGFR-3 upregulation in carcinoma cell lines. Int J Oncol. 2008;32:585–92.PubMed
Metadata
Title
Involvement of human chorionic gonadotropin in regulating vasculogenic mimicry and hypoxia-inducible factor-1α expression in ovarian cancer cells
Authors
Min Su
Xiangxiang Xu
Weiwei Wei
Sainan Gao
Xiaoying Wang
Caoyi Chen
Yuquan Zhang
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2016
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-016-0327-0

Other articles of this Issue 1/2016

Cancer Cell International 1/2016 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine