Cell-biological mechanisms of amniotic membrane anticancer activity and the possibilities of its use in anticancer therapy

  • Taja Železnik Ramuta Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
  • Tina Cirman Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia
  • Mateja Erdani Kreft Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Keywords: Amniotic membrane, cancer, anticancer activity, immunomodulatory activity, regenerative medicine


Background: The primary role of amniotic membrane is to protect the foetus from drying out and to provide a suitable environment for its development. Understanding of the structure and function of amniotic membrane is important in terms of its use in clinical settings, especially in regenerative medicine. This paper describes favourable mechanical and biological properties of amniotic membrane for regenerative medicine uses and emphasizes its anti-cancer properties.
Conclusion: Studies on in vitro as well as on animal models demonstrate that amniotic membrane inhibits the proliferation of cancer cells and induces their apoptosis. It also acts immunoinhibitory, and it inhibits the metabolic activity of cancer cells and angiogenesis. This work provides an overview of the latest knowledge about the anticancer role of amniotic membrane and evaluates the potential of the amniotic membrane use for anticancer therapy and regenerative medicine.


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Author Biographies

Taja Železnik Ramuta, Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

Tina Cirman, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia

Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia


Hilmy N, Yusof N. Anatomy and Histology of Amnion. Human Amniotic Membrane. WORLD SCIENTIFIC; 2017. pp. 87–101. https://doi.org/10.1142/9789813226357_0005.

Cirman T, Beltram M, Schollmayer P, Rožman P, Kreft ME. Amniotic membrane properties and current practice of amniotic membrane use in ophthalmology in Slovenia. Cell Tissue Bank. 2014 Jun;15(2):177–92. https://doi.org/10.1007/s10561-013-9417-6 PMID:24352631

Jerman UD, Veranič P, Kreft ME. Amniotic membrane scaffolds enable the development of tissue-engineered urothelium with molecular and ultrastructural properties comparable to that of native urothelium. Tissue Eng Part C Methods. 2014 Apr;20(4):317–27. https://doi.org/10.1089/ten.tec.2013.0298 PMID:23947657

Parolini O, Soncini M, Evangelista M, Schmidt D. Amniotic membrane and amniotic fluid-derived cells: potential tools for regenerative medicine? Regen Med. 2009 Mar;4(2):275–91. https://doi.org/10.2217/17460751.4.2.275 PMID:19317646

Caruso M, Evangelista M, Parolini O. Human term placental cells: phenotype, properties and new avenues in regenerative medicine. Int J Mol Cell Med. 2012;1(2):64–74. PMID:24551761

Cornwell KG, Landsman A, James KS. Extracellular matrix biomaterials for soft tissue repair. Clin Podiatr Med Surg. 2009 Oct;26(4):507–23. https://doi.org/10.1016/j.cpm.2009.08.001 PMID:19778685

Koizumi NJ, Inatomi TJ, Sotozono CJ, Fullwood NJ, Quantock AJ, Kinoshita S. Growth factor mRNA and protein in preserved human amniotic membrane. Curr Eye Res. 2000 Mar;20(3):173–7. https://doi.org/10.1076/0271-3683(200003)2031-9FT173 PMID:10694891

Fukuda K, Chikama T, Nakamura M, Nishida T. Differential distribution of subchains of the basement membrane components type IV collagen and laminin among the amniotic membrane, cornea, and conjunctiva. Cornea. 1999 Jan;18(1):73–9. https://doi.org/10.1097/00003226-199901000-00013 PMID:9894941

Kim JS, Kim JC, Na BK, Jeong JM, Song CY. Amniotic membrane patching promotes healing and inhibits proteinase activity on wound healing following acute corneal alkali burn. Exp Eye Res. 2000 Mar;70(3):329–37. https://doi.org/10.1006/exer.1999.0794 PMID:10712819

Jerman UD, Kreft ME, Veranič P. Epithelial-Mesenchymal Interactions in Urinary Bladder and Small Intestine and How to Apply Them in Tissue Engineering. Tissue Eng Part B Rev. 2015 Dec;21(6):521–30. https://doi.org/10.1089/ten.teb.2014.0678 PMID:26066408

Insausti CL, Blanquer M, García-Hernández AM, Castellanos G, Moraleda JM. Amniotic membrane-derived stem cells: immunomodulatory properties and potential clinical application. Stem Cells Cloning. 2014 Mar;7:53–63. https://doi.org/10.2147/SCCAA.S58696 PMID:24744610

Szekeres-Bartho J. Immunological relationship between the mother and the fetus. Int Rev Immunol. 2002 Nov-Dec;21(6):471–95. https://doi.org/10.1080/08830180215017 PMID:12650238

Koob TJ, Lim JJ, Massee M, Zabek N, Denozière G. Properties of dehydrated human amnion/chorion composite grafts: implications for wound repair and soft tissue regeneration. J Biomed Mater Res B Appl Biomater. 2014 Aug;102(6):1353–62. https://doi.org/10.1002/jbm.b.33141 PMID:24664953

Niknejad H, Khayat-Khoei M, Peirovi H, Abolghasemi H. Human amniotic epithelial cells induce apoptosis of cancer cells: a new anti-tumor therapeutic strategy. Cytotherapy. 2014 Jan;16(1):33–40. https://doi.org/10.1016/j.jcyt.2013.07.005 PMID:24113429

Niknejad H, Paeini-Vayghan G, Tehrani FA, Khayat-Khoei M, Peirovi H. Side dependent effects of the human amnion on angiogenesis. Placenta. 2013 Apr;34(4):340–5. https://doi.org/10.1016/j.placenta.2013.02.001 PMID:23465536

King AE, Paltoo A, Kelly RW, Sallenave JM, Bocking AD, Challis JR. Expression of natural antimicrobials by human placenta and fetal membranes. Placenta. 2007 Feb-Mar;28(2-3):161–9. https://doi.org/10.1016/j.placenta.2006.01.006 PMID:16513165

Kjaergaard N, Hein M, Hyttel L, Helmig RB, Schønheyder HC, Uldbjerg N, et al. Antibacterial properties of human amnion and chorion in vitro. Eur J Obstet Gynecol Reprod Biol. 2001 Feb;94(2):224–9. https://doi.org/10.1016/S0301-2115(00)00345-6 PMID:11165729

Hao Y, Ma DH, Hwang DG, Kim WS, Zhang F. Identification of antiangiogenic and antiinflammatory proteins in human amniotic membrane. Cornea. 2000 May;19(3):348–52. https://doi.org/10.1097/00003226-200005000-00018 PMID:10832697

Rocha SC, Baptista CJ. Biochemical Properties of Amniotic Membrane. V: Mamede AC, Botelho MF, ur. Amniotic Membrane. Netherlands: Springer; 2015. pp. 19–40. https://doi.org/10.1007/978-94-017-9975-1_2.

Niknejad H, Yazdanpanah G, Mirmasoumi M, Abolghasemi H, Peirovi H, Ahmadiani A. Inhibition of HSP90 could be possible mechanism for anti-cancer property of amniotic membrane. Med Hypotheses. 2013 Nov;81(5):862–5. https://doi.org/10.1016/j.mehy.2013.08.018 PMID:24054818

Davis JW. Skin transplantation with a review of 550 cases at the Johns Hopkins Hospital. Johns Hopkins Med J. 1910;15:87.

Costa E, Murta JN. Amniotic Membrane in Ophthalmology. In: Mamede AC, Botelho MF, editors. Amniotic Membrane: Origin, Characterization and Medical Applications. Dordrecht: Springer Netherlands; 2015. pp. 105–22. https://doi.org/10.1007/978-94-017-9975-1_6.

Lo V, Pope E. Amniotic membrane use in dermatology. Int J Dermatol. 2009 Sep;48(9):935–40. https://doi.org/10.1111/j.1365-4632.2009.04173.x PMID:19702975

Kubanyi A. Prevention of peritoneal adhesions by transplantation of amnion. BMJ. 1947 Jul;2(4514):55–6. https://doi.org/10.1136/bmj.2.4514.55-a PMID:20344011

Gharib M, Ure BM, Klose M. Use of amniotic grafts in the repair of gastroschisis. Pediatr Surg Int. 1996 Mar;11(2-3):96–9. https://doi.org/10.1007/BF00183734 PMID:24057525

Silini AR, Cargnoni A, Magatti M, Pianta S, Parolini O. The Long Path of Human Placenta, and Its Derivatives, in Regenerative Medicine. Front Bioeng Biotechnol. 2015 Oct;3:162. https://doi.org/10.3389/fbioe.2015.00162 PMID:26539433

Koziak A, Salagierski M, Marcheluk A, Szcześniewski R, Sosnowski M. Early experience in reconstruction of long ureteral strictures with allogenic amniotic membrane. Int J Urol. 2007 Jul;14(7):607–10. https://doi.org/10.1111/j.1442-2042.2007.01781.x PMID:17645603

Iijima K, Igawa Y, Imamura T, Moriizumi T, Nikaido T, Konishi I, et al. Transplantation of preserved human amniotic membrane for bladder augmentation in rats. Tissue Eng. 2007 Mar;13(3):513–24. https://doi.org/10.1089/ten.2006.0170 PMID:17518600

Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, MacIntyre MF, et al.; Global Burden of Disease Cancer Collaboration. The Global Burden of Cancer 2013. JAMA Oncol. 2015 Jul;1(4):505–27. https://doi.org/10.1001/jamaoncol.2015.0735 PMID:26181261

Shiga K, Hara M, Nagasaki T, Sato T, Takahashi H, Takeyama H. Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth. Cancers (Basel). 2015 Dec;7(4):2443–58. https://doi.org/10.3390/cancers7040902 PMID:26690480

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan;100(1):57–70. https://doi.org/10.1016/S0092-8674(00)81683-9 PMID:10647931

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646:74. https://doi.org/10.1016/j.cell.2011.02.013.

Magatti M, De Munari S, Vertua E, Parolini O. Amniotic membrane-derived cells inhibit proliferation of cancer cell lines by inducing cell cycle arrest. J Cell Mol Med. 2012 Sep;16(9):2208–18. https://doi.org/10.1111/j.1582-4934.2012.01531.x PMID:22260183

Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009 Mar;9(3):153–66. https://doi.org/10.1038/nrc2602 PMID:19238148

Magatti M, De Munari S, Vertua E, Nassauto C, Albertini A, Wengler GS, et al. Amniotic mesenchymal tissue cells inhibit dendritic cell differentiation of peripheral blood and amnion resident monocytes. Cell Transplant. 2009;18(8):899–914. https://doi.org/10.3727/096368909X471314 PMID:19523334

Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011 Sep;30(1):87. https://doi.org/10.1186/1756-9966-30-87 PMID:21943236

McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 2013 Apr;5(4):a008656. https://doi.org/10.1101/cshperspect.a008656 PMID:23545416

Jiao H, Guan F, Yang B, Li J, Song L, Hu X, et al. Human amniotic membrane derived-mesenchymal stem cells induce C6 glioma apoptosis in vivo through the Bcl-2/caspase pathways. Mol Biol Rep. 2012 Jan;39(1):467–73. https://doi.org/10.1007/s11033-011-0760-z PMID:21556762

Chan KT, Lung ML. Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line. Cancer Chemother Pharmacol. 2004 Jun;53(6):519–26. https://doi.org/10.1007/s00280-004-0767-4 PMID:15004724

Mamede AC, Guerra S, Laranjo M, Carvalho MJ, Oliveira RC, Gonçalves AC, et al. Selective cytotoxicity and cell death induced by human amniotic membrane in hepatocellular carcinoma. Med Oncol. 2015 Dec;32(12):257. https://doi.org/10.1007/s12032-015-0702-z PMID:26507652

Kang NH, Hwang KA, Kim SU, Kim YB, Hyun SH, Jeung EB, et al. Potential antitumor therapeutic strategies of human amniotic membrane and amniotic fluid-derived stem cells. Cancer Gene Ther. 2012 Aug;19(8):517–22. https://doi.org/10.1038/cgt.2012.30 PMID:22653384

Paeini-Vayghan G, Peirovi H, Niknejad H. Inducing of angiogenesis is the net effect of the amniotic membrane without epithelial cells. Irn J Med Hypotheses Ideas. 2011;5:16–21.

Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009 May;324(5930):1029–33. https://doi.org/10.1126/science.1160809 PMID:19460998

Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011 Feb;11(2):85–95. https://doi.org/10.1038/nrc2981 PMID:21258394

Mamede AC, Laranjo M, Carvalho MJ, Abrantes AM, Pires AS, Brito AF, et al. Effect of amniotic membrane proteins in human cancer cell lines: an exploratory study. J Membr Biol. 2014 Apr;247(4):357–60. https://doi.org/10.1007/s00232-014-9642-3 PMID:24577414

Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape. Curr Opin Immunol. 2014 Apr;27:16–25. https://doi.org/10.1016/j.coi.2014.01.004 PMID:24531241

Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010 Mar;140(6):883–99. https://doi.org/10.1016/j.cell.2010.01.025 PMID:20303878

Roelen DL, van der Mast BJ, in’t Anker PS, Kleijburg C, Eikmans M, van Beelen E, et al. Differential immunomodulatory effects of fetal versus maternal multipotent stromal cells. Hum Immunol. 2009 Jan;70(1):16–23. https://doi.org/10.1016/j.humimm.2008.10.016 PMID:19010366

Chang CJ, Yen ML, Chen YC, Chien CC, Huang HI, Bai CH, et al. Placenta-derived multipotent cells exhibit immunosuppressive properties that are enhanced in the presence of interferon-gamma. Stem Cells. 2006 Nov;24(11):2466–77. https://doi.org/10.1634/stemcells.2006-0071 PMID:17071860

Banas RA, Trumpower C, Bentlejewski C, Marshall V, Sing G, Zeevi A. Immunogenicity and immunomodulatory effects of amnion-derived multipotent progenitor cells. Hum Immunol. 2008;69(6)-321–8.

Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008 Nov;14(21):6735–41. https://doi.org/10.1158/1078-0432.CCR-07-4843 PMID:18980965

De Larco JE, Wuertz BR, Furcht LT. The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clin Cancer Res. 2004 Aug;10(15):4895–900. https://doi.org/10.1158/1078-0432.CCR-03-0760 PMID:15297389

Takamori H, Oades ZG, Hoch OC, Burger M, Schraufstatter IU. Autocrine growth effect of IL-8 and GROalpha on a human pancreatic cancer cell line, Capan-1. Pancreas. 2000 Jul;21(1):52–6. https://doi.org/10.1097/00006676-200007000-00051 PMID:10881932

Lang K, Niggemann B, Zanker KS, Entschladen F. Signal processing in migrating T24 human bladder carcinoma cells: role of the autocrine interleukin-8 loop. Int J Cancer. 2002 Jun;99(5):673–80. https://doi.org/10.1002/ijc.10424 PMID:12115500

Yao C, Lin Y, Chua MS, Ye CS, Bi J, Li W, et al. Interleukin-8 modulates growth and invasiveness of estrogen receptor-negative breast cancer cells. Int J Cancer. 2007 Nov;121(9):1949–57. https://doi.org/10.1002/ijc.22930 PMID:17621625

Maxwell PJ, Gallagher R, Seaton A, Wilson C, Scullin P, Pettigrew J, et al. HIF-1 and NF-kappaB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells. Oncogene. 2007 Nov;26(52):7333–45. https://doi.org/10.1038/sj.onc.1210536 PMID:17533374

Magatti M, Caruso M, De Munari S, Vertua E, De D, Manuelpillai U, et al. Human Amniotic Membrane-Derived Mesenchymal and Epithelial Cells Exert Different Effects on Monocyte-Derived Dendritic Cell Differentiation and Function. Cell Transplant. 2015;24(9):1733–52. https://doi.org/10.3727/096368914X684033 PMID:25259480

Li H, Niederkorn JY, Neelam S, Mayhew E, Word RA, McCulley JP, et al. Immunosuppressive factors secreted by human amniotic epithelial cells. Invest Ophthalmol Vis Sci. 2005 Mar;46(3):900–7. https://doi.org/10.1167/iovs.04-0495 PMID:15728546

U.S. National Institutes of Health. Clinical Trials. U.S. Bethesda: National Library of Medicine; 2017 [cited 2018 Feb 26]. Dostopno: https://clinicaltrials.gov

How to Cite
Železnik Ramuta T, Cirman T, Kreft ME. Cell-biological mechanisms of amniotic membrane anticancer activity and the possibilities of its use in anticancer therapy. ZdravVestn [Internet]. 28Oct.2018 [cited 20Jul.2019];87(9-10):483-92. Available from: https://vestnik.szd.si/index.php/ZdravVest/article/view/2674
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