Skip to main content

Advertisement

SpringerLink
Log in

Induction of apoptosis, stimulation of cell-cycle arrest and inhibition of angiogenesis make human amnion-derived cells promising sources for cell therapy of cancer

  • Mini Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Amniotic membrane (AM), the nearest layer of fetal membranes to the fetus, contains two types of cells with unique characteristics that make them excellent candidates for clinical applications. Amniotic epithelial and mesenchymal cells have low immunogenicity, anti-inflammation, anti-fibrosis and anti-bacterial properties and no ethical issues. Although amniotic cells have stem cell properties and express transcription factors specific for pluripotent stem cells, they are not tumorigenic after transplantation. In the last decade, a new line of research has been initiated with a focus on the anti-proliferative effects of amniotic epithelial and mesenchymal cells on tumor growth. Amnion-derived epithelial and mesenchymal cells inhibit tumor growth and invasion through three pathways: the induction of apoptosis, the stimulation of cell-cycle arrest and the inhibition of angiogenesis. In this review, the various aspects of the anti-cancer properties of amnion-derived cells and the underlying mechanisms are discussed with emphasis on the translation of the cell therapy of cancer from experimental into clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Alviano F, Fossati V, Marchionni C, Arpinati M, Bonsi L, Franchina M, Lanzoni G, Cantoni S, Cavallini C, Bianchi F, Tazzari PL, Pasquinelli G, Foroni L, Ventura C, Grossi A, Bagnara GP (2007) Term amniotic membrane is a high throughput source for multipotent mesenchymal stem cells with the ability to differentiate into endothelial cells in vitro. BMC Dev Biol 7:11

    Article  PubMed Central  PubMed  Google Scholar 

  • Banerjee A, Weidinger A, Hofer M, Steinborn R, Lindenmair A, Hennerbichler-Lugscheider S, Eibl J, Redl H, Kozlov AV, Wolbank S (2015) Different metabolic activity in placental and reflected regions of the human amniotic membrane. Placenta 36:1329–1332

    Article  PubMed  Google Scholar 

  • Barboni B, Russo V, Curini V, Martelli A, Berardinelli P, Mauro A, Mattioli M, Marchisio M, Bonassi Signoroni P, Parolini O, Colosimo A (2014) Gestational stage affects amniotic epithelial cells phenotype, methylation status, immunomodulatory and stemness properties. Stem Cell Rev 10:725–741

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bauer D, Wasmuth S, Hennig M, Baehler H, Steuhl KP, Heiligenhaus A (2009) Amniotic membrane transplantation induces apoptosis in T lymphocytes in murine corneas with experimental herpetic stromal keratitis. Invest Ophthalmol Vis Sci 50:3188–3198

    Article  PubMed  Google Scholar 

  • Bauer D, Hennig M, Wasmuth S, Baehler H, Busch M, Steuhl KP, Thanos S, Heiligenhaus A (2012) Amniotic membrane induces peroxisome proliferator-activated receptor-gamma positive alternatively activated macrophages. Invest Ophthalmol Vis Sci 53:799–810

    Article  CAS  PubMed  Google Scholar 

  • Bourcier T, Becmeur PH, Mutter D (2015) Robotically assisted amniotic membrane transplant surgery. JAMA Ophthalmol 133:213–214

    Article  PubMed  Google Scholar 

  • de Weerd L, Weum S, Sjavik K, Acharya G, Hennig RO (2013) A new approach in the repair of a myelomeningocele using amnion and a sensate perforator flap. J Plast Reconstr Aesthet Surg 66:860–863

    Article  PubMed  Google Scholar 

  • Diaz-Prado S, Muinos-Lopez E, Hermida-Gomez T, Rendal-Vazquez ME, Fuentes-Boquete I, de Toro FJ, Blanco FJ (2010) Multilineage differentiation potential of cells isolated from the human amniotic membrane. J Cell Biochem 111:846–857

    Article  CAS  PubMed  Google Scholar 

  • Garfias Y, Zaga-Clavellina V, Vadillo-Ortega F, Osorio M, Jimenez-Martinez MC (2011) Amniotic membrane is an immunosuppressor of peripheral blood mononuclear cells. Immunol Invest 40:183–196

    Article  CAS  PubMed  Google Scholar 

  • Hao Y, Ma DH, Hwang DG, Kim WS, Zhang F (2000) Identification of antiangiogenic and antiinflammatory proteins in human amniotic membrane. Cornea 19:348–352

    Article  CAS  PubMed  Google Scholar 

  • Hemphill C, Stavoe K, Khalpey Z (2014) First in man: amniotic stem cell injection promotes scar remodeling and healing processes in late-stage fibrosis. Int J Cardiol 174:442–443

    Article  PubMed  Google Scholar 

  • Henley SA, Dick FA (2012) The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle. Cell Div 7:10

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hupfeld J, Gorr IH, Schwald C, Beaucamp N, Wiechmann K, Kuentzer K, Huss R, Rieger B, Neubauer M, Wegmeyer H (2014) Modulation of mesenchymal stromal cell characteristics by microcarrier culture in bioreactors. Biotechnol Bioeng 111:2290–2302

    Article  CAS  PubMed  Google Scholar 

  • Hwang JH, Shim SS, Seok OS, Lee HY, Woo SK, Kim BH, Song HR, Lee JK, Park YK (2009) Comparison of cytokine expression in mesenchymal stem cells from human placenta, cord blood, and bone marrow. J Korean Med Sci 24:547–554

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ilancheran S, Michalska A, Peh G, Wallace EM, Pera M, Manuelpillai U (2007) Stem cells derived from human fetal membranes display multilineage differentiation potential. Biol Reprod 77:577–588

    Article  CAS  PubMed  Google Scholar 

  • Jablonski EM, Mattocks MA, Sokolov E, Koniaris LG, Hughes FM Jr, Fausto N, Pierce RH, McKillop IH (2007) Decreased aquaporin expression leads to increased resistance to apoptosis in hepatocellular carcinoma. Cancer Lett 250:36–46

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jiang YJ, Kim P, Lu YF, Feingold KR (2011) PPARgamma activators stimulate aquaporin 3 expression in keratinocytes/epidermis. Exp Dermatol 20:595–599

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jiang H, He D, Xu H, Liu J, Qu L, Tong S (2015) Cullin-1 promotes cell proliferation via cell cycle regulation and is a novel in prostate cancer. Int J Clin Exp Pathol 8:1575–1583

    PubMed Central  PubMed  Google Scholar 

  • Jiao H, Guan F, Yang B, Li J, Song L, Hu X, Du Y (2012) Human amniotic membrane derived-mesenchymal stem cells induce C6 glioma apoptosis in vivo through the Bcl-2/caspase pathways. Mol Biol Rep 39:467–473

    Article  CAS  PubMed  Google Scholar 

  • Kakavand M, Yazdanpanah G, Ahmadiani A, Niknejad H (2015) Blood compatibility of human amniotic membrane compared with heparin-coated ePTFE for vascular tissue engineering. J Tissue Eng Regen Med. doi:10.1002/term.2064

    PubMed  Google Scholar 

  • Kang JW, Koo HC, Hwang SY, Kang SK, Ra JC, Lee MH, Park YH (2012a) Immunomodulatory effects of human amniotic membrane-derived mesenchymal stem cells. J Vet Sci 13:23–31

    Article  PubMed Central  PubMed  Google Scholar 

  • Kang NH, Yi BR, Lim SY, Hwang KA, Baek YS, Kang KS, Choi KC (2012b) Human amniotic membrane-derived epithelial stem cells display anticancer activity in BALB/c female nude mice bearing disseminated breast cancer xenografts. Int J Oncol 40:2022–2028

    CAS  PubMed  Google Scholar 

  • Khalpey Z, Marsh KM, Ferng A, Riaz IB, Friedman M, Indik J, Avery R, Jokerst C, Oliva I (2015) First in man: amniotic patch reduces postoperative inflammation. Am J Med 128:e5–e6

    Article  PubMed  Google Scholar 

  • Klein JD, Fauza DO (2011) Amniotic and placental mesenchymal stem cell isolation and culture. Methods Mol Biol 698:75–88

    Article  CAS  PubMed  Google Scholar 

  • Koike C, Zhou K, Takeda Y, Fathy M, Okabe M, Yoshida T, Nakamura Y, Kato Y, Nikaido T (2014) Characterization of amniotic stem cells. Cell Reprogram 16:298–305

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kubo M, Sonoda Y, Muramatsu R, Usui M (2001) Immunogenicity of human amniotic membrane in experimental xenotransplantation. Invest Ophthalmol Vis Sci 42:1539–1546

    CAS  PubMed  Google Scholar 

  • Lalier L, Pedelaborde F, Braud C, Menanteau J, Vallette FM, Olivier C (2011) Increase in intracellular PGE2 induces apoptosis in Bax-expressing colon cancer cell. BMC Cancer 11:153

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Li H, Niederkorn JY, Neelam S, Mayhew E, Word RA, McCulley JP, Alizadeh H (2005) Immunosuppressive factors secreted by human amniotic epithelial cells. Invest Ophthalmol Vis Sci 46:900–907

    Article  PubMed  Google Scholar 

  • Magatti M, De Munari S, Vertua E, Parolini O (2012) Amniotic membrane-derived cells inhibit proliferation of cancer cell lines by inducing cell cycle arrest. J Cell Mol Med 16:2208–2218

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Magatti M, Caruso M, De Munari S, Vertua E, De D, Manuelpillai U, Parolini O (2015) Human amniotic membrane-derived mesenchymal and epithelial cells exert different effects on monocyte-derived dendritic cell differentiation and function. Cell Transplant 24:1733–1752

    Article  PubMed  Google Scholar 

  • Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9:153–166

    Article  CAS  PubMed  Google Scholar 

  • Mamede AC, Laranjo M, Carvalho MJ, Abrantes AM, Pires AS, Brito AF, Moura P, Maia CJ, Botelho MF (2014) Effect of amniotic membrane proteins in human cancer cell lines: an exploratory study. J Membr Biol 247:357–360

    Article  CAS  PubMed  Google Scholar 

  • Mamede AC, Guerra S, Laranjo M, Carvalho MJ, Oliveira RC, Goncalves AC, Alves R, Prado Castro L, Sarmento-Ribeiro AB, Moura P, Abrantes AM, Maia CJ, Botelho MF (2015) Selective cytotoxicity and cell death induced by human amniotic membrane in hepatocellular carcinoma. Med Oncol 32:257

    Article  CAS  PubMed  Google Scholar 

  • Masiero M, Simoes FC, Han HD, Snell C, Peterkin T, Bridges E, Mangala LS, Wu SY, Pradeep S, Li D, Han C, Dalton H, Lopez-Berestein G, Tuynman JB, Mortensen N, Li JL, Patient R, Sood AK, Banham AH, Harris AL, Buffa FM (2013) A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis. Cancer Cell 24:229–241

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Miki T, Lehmann T, Cai H, Stolz DB, Strom SC (2005) Stem cell characteristics of amniotic epithelial cells. Stem Cells 23:1549–1559

    Article  CAS  PubMed  Google Scholar 

  • Mogami H, Keller PW, Shi H, Word RA (2014) Effect of thrombin on human amnion mesenchymal cells, mouse fetal membranes, and preterm birth. J Biol Chem 289:13295–13307

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Moore RM, Mansour JM, Redline RW, Mercer BM, Moore JJ (2006) The physiology of fetal membrane rupture: insight gained from the determination of physical properties. Placenta 27:1037–1051

    Article  CAS  PubMed  Google Scholar 

  • Niknejad H, Yazdanpanah G (2014a) Anticancer effects of human amniotic membrane and its epithelial cells. Med Hypotheses 82:488–489

    Article  CAS  PubMed  Google Scholar 

  • Niknejad H, Yazdanpanah G (2014b) Opposing effect of amniotic membrane on angiogenesis originating from amniotic epithelial cells. J Med Hypotheses Ideas 8:39–41

    Article  CAS  Google Scholar 

  • Niknejad H, Peirovi H, Jorjani M, Ahmadiani A, Ghanavi J, Seifalian AM (2008) Properties of the amniotic membrane for potential use in tissue engineering. Eur Cell Mater 15:88–99

    CAS  PubMed  Google Scholar 

  • Niknejad H, Deihim T, Solati-Hashjin M, Peirovi H (2011) The effects of preservation procedures on amniotic membrane’s ability to serve as a substrate for cultivation of endothelial cells. Cryobiology 63:145–151

    Article  CAS  PubMed  Google Scholar 

  • Niknejad H, Khayat-Khoei M, Peirovi H (2012) Inhibition of MMPs might increase anticancer properties of amniotic epithelial cells. Med Hypotheses 78:690–691

    Article  CAS  PubMed  Google Scholar 

  • Niknejad H, Deihim T, Peirovi H, Abolghasemi H (2013a) Serum-free cryopreservation of human amniotic epithelial cells before and after isolation from their natural scaffold. Cryobiology 67:56–63

    Article  CAS  PubMed  Google Scholar 

  • Niknejad H, Paeini-Vayghan G, Tehrani FA, Khayat-Khoei M, Peirovi H (2013b) Side dependent effects of the human amnion on angiogenesis. Placenta 34:340–345

    Article  CAS  PubMed  Google Scholar 

  • Niknejad H, Yazdanpanah G, Mirmasoumi M, Abolghasemi H, Peirovi H, Ahmadiani A (2013c) Inhibition of HSP90 could be possible mechanism for anti-cancer property of amniotic membrane. Med Hypotheses 81:862–865

    Article  CAS  PubMed  Google Scholar 

  • Niknejad H, Khayat-Khoei M, Peirovi H, Abolghasemi H (2014) Human amniotic epithelial cells induce apoptosis of cancer cells: a new anti-tumor therapeutic strategy. Cytotherapy 16:33–40

    Article  CAS  PubMed  Google Scholar 

  • Niknejad H, Yazdanpanah G, Kakavand M (2015) Extract of fetal membrane would inhibit thrombosis and hemolysis. Med Hypotheses 85:197–202

    Article  CAS  PubMed  Google Scholar 

  • Pavan B, Paganetto G, Dalpiaz A, Biondi C, Lunghi L (2011) Estrogen metabolites in the release of inflammatory mediators from human amnion-derived cells. Life Sci 88:551–558

    Article  CAS  PubMed  Google Scholar 

  • Peirovi H, Rezvani N, Hajinasrollah M, Mohammadi SS, Niknejad H (2012) Implantation of amniotic membrane as a vascular substitute in the external jugular vein of juvenile sheep. J Vasc Surg 56:1098–1104

    Article  PubMed  Google Scholar 

  • Penny H, Rifkah M, Weaver A, Zaki P, Young A, Meloy G, Flores R (2015) Dehydrated human amnion/chorion tissue in difficult-to-heal DFUs: a case series. J Wound Care 24:104–111

    Article  CAS  PubMed  Google Scholar 

  • Pianta S, Bonassi Signoroni P, Muradore I, Rodrigues MF, Rossi D, Silini A, Parolini O (2015) Amniotic membrane mesenchymal cells-derived factors skew T cell polarization toward Treg and downregulate Th1 and Th17 cells subsets. Stem Cell Rev 11:394–407

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Qi X, Wang J, Sun D, Zhou Q, Xie L (2014) Postoperative changes in amniotic membrane as a carrier for allogeneic cultured limbal epithelial transplantation. Am J Ophthalmol 158:e1191

    Article  Google Scholar 

  • Secchiero P, Zorzet S, Tripodo C, Corallini F, Melloni E, Caruso L, Bosco R, Ingrao S, Zavan B, Zauli G (2010) Human bone marrow mesenchymal stem cells display anti-cancer activity in SCID mice bearing disseminated non-Hodgkin’s lymphoma xenografts. PLoS One 5:e11140

    Article  PubMed Central  PubMed  Google Scholar 

  • Seo JH, Kim YH, Kim JS (2008) Properties of the amniotic membrane may be applicable in cancer therapy. Med Hypotheses 70:812–814

    Article  CAS  PubMed  Google Scholar 

  • Singh R, Chacharkar MP (2011) Dried gamma-irradiated amniotic membrane as dressing in burn wound care. J Tissue Viability 20:49–54

    Article  PubMed  Google Scholar 

  • Stenqvist AC, Nagaeva O, Baranov V, Mincheva-Nilsson L (2013) Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus. J Immunol 191:5515–5523

    Article  CAS  PubMed  Google Scholar 

  • Tan SL, Sulaiman S, Pingguan-Murphy B, Selvaratnam L, Tai CC, Kamarul T (2011) Human amnion as a novel cell delivery vehicle for chondrogenic mesenchymal stem cells. Cell Tissue Bank 12:59–70

    Article  PubMed  Google Scholar 

  • Tehrani FA, Ahmadiani A, Niknejad H (2013) The effects of preservation procedures on antibacterial property of amniotic membrane. Cryobiology 67:293–298

    Article  CAS  PubMed  Google Scholar 

  • Wirt SE, Sage J (2010) p107 in the public eye: an Rb understudy and more. Cell Div 5:9

    Article  PubMed Central  PubMed  Google Scholar 

  • Yazdanpanah G, Paeini-Vayghan G, Asadi S, Niknejad H (2015) The effects of cryopreservation on angiogenesis modulation activity of human amniotic membrane. Cryobiology 71:413–418

    Article  CAS  PubMed  Google Scholar 

  • Yu X, Su B, Ge P, Wang Z, Li S, Huang B, Gong Y, Lin J (2015) Human adipose derived stem cells induced cell apoptosis and S phase arrest in bladder tumor. Stem Cells Int 2015:1–12

    Article  Google Scholar 

Download references

Acknowledgments

The authors thank Prof. H. Peirovi for his critical comments.

Author information

Authors and Affiliations

  1. Department of Tissue Engineering and Regenerative Medicine, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Aerabi St, Velenjak, P.O. Box 1985711151, Tehran, Iran

    Hassan Niknejad & Ghasem Yazdanpanah

  2. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Abolhassan Ahmadiani

Authors
  1. Hassan Niknejad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ghasem Yazdanpanah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abolhassan Ahmadiani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hassan Niknejad.

Additional information

This work was supported in part by the School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Niknejad, H., Yazdanpanah, G. & Ahmadiani, A. Induction of apoptosis, stimulation of cell-cycle arrest and inhibition of angiogenesis make human amnion-derived cells promising sources for cell therapy of cancer. Cell Tissue Res 363, 599–608 (2016). https://doi.org/10.1007/s00441-016-2364-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-016-2364-3

Keywords

Search

Navigation