Advertisement

Ovarian Cancer pp 335-351 | Cite as

Organotypic Models of Metastasis: A Three-dimensional Culture Mimicking the Human Peritoneum and Omentum for the Study of the Early Steps of Ovarian Cancer Metastasis

  • Hilary A. Kenny
  • Songuel Dogan
  • Marion Zillhardt
  • Anirban K. Mitra
  • S. Diane Yamada
  • Thomas Krausz
  • Ernst Lengyel
Chapter
Part of the Cancer Treatment and Research book series (CTAR, volume 149)

Introduction

Because most ovarian cancer (OvCa) patients present at a late stage, when metastasis has already occurred, the study of early events in peritoneal dissemination is difficult. One problem has been the lack of adequate model systems for the study of ovarian tumor transformation and metastasis.1,2 Current models in use include co-cultures, whole tissue cultures, and immunocompromised and genetic mouse models. All of these have unique advantages; however, none of them replicates the human in vivo situation. The development and use of a three-dimensional (3D) organotypic model of OvCa has the potential to bridge the gap between the current models of OvCa and the human disease.

Ovarian Cancer Metastasis

Most patients with OvCa present with advanced disease metastatic to the peritoneum. Despite aggressive surgery and chemotherapy, patients with intra-abdominal, widely disseminated OvCa rarely achieve long-term cures.3The key to improved treatment of OvCa is a better...

Keywords

Mesothelial Cell OvCa Cell OvCa Cell Line Human Mesothelial Cell Omental Metastasis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The development of the 3D ovarian cancer culture was supported over the years through grants to Ernst Lengyel from the Gynecologic Cancer Foundation (2005/2006 GCF/Molly Cade Ovarian Cancer Research Grant), the Ovarian Cancer Research Fund (OCRF, Liz Tilberis Scholars Program), and the NCI (R01 CA111882). Ernst Lengyel holds a Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund. Hilary A. Kenny was supported by a Penny Severns Breast, Cervical, and Ovarian Cancer Research postdoctoral fellowship from the Illinois Department of Public Health and a Graduate Training Program in Cancer Biology postdoctoral fellowship through the University of Chicago (NIH/NCI 5T32 CA09594). Songuel Dogan was supported by the Deutsche Forschungsgemeinschaft (German Research Council) DOI309/1–1. Marion Zillhardt was supported by the Graduate Training Program in Cancer Biology through the University of Chicago (NIH/NCI T32 CA09594). The authors would like to thank Gail Isenberg (University of Chicago) for her graphic designs and editorial expertise.

References

  1. 1.
    Tan D, Agarwal R, Kaye SB. Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet. 2006;7:925–934.CrossRefGoogle Scholar
  2. 2.
    Landen C, Birrer MJ, Sood AK. Early events in the pathogenesis of epithelial ovarian cancer. J Clin Oncol. 2008;26(6):995–1005.CrossRefPubMedGoogle Scholar
  3. 3.
    Agarwal R, Kaye S. Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer. 2003;3(7):502–516.CrossRefPubMedGoogle Scholar
  4. 4.
    Doig T, Monaghan H. Sampling the omentum in ovarian neoplasia: when one block is enough. Int J Gynecol Cancer. 2006;16:36–40.CrossRefPubMedGoogle Scholar
  5. 5.
    Fidler IJ. The pathogenesis of cancer metastasis: the “seed and soil” hypothesis revisited. Nat Rev Cancer. 2003;5:355–366.Google Scholar
  6. 6.
    Kenny HA, Krausz T, Yamada SD, Lengyel E. Development of an organotypic peritoneal three-dimensional culture to study peritoneal attachment of ovarian cancer cells. Int J Cancer. 2007;121(7):1463–1472.CrossRefPubMedGoogle Scholar
  7. 7.
    Wilkosz S, Ireland G, Khwaja N, et al. A comparative study of the structure of human and murine greater omentum. Anat Embryol. 2005;209:251–261.CrossRefPubMedGoogle Scholar
  8. 8.
    Liebermann-Meffert D. The greater omentum, anatomy, embryology, and surgical applications. Surg Clin North Am. 2000;80(1):275–293.CrossRefPubMedGoogle Scholar
  9. 9.
    Lieberman-Meffert D. The greater omentum, anatomy, physiology, pathology and surgery with a historical survey. New York, Berlin Heidelberg: Springer; 1985:3–30.Google Scholar
  10. 10.
    Daya D, McCaughy WT. Pathology of the peritoneum: a review of selected topics. Semin Diagn Pathol. 1991;8(4):277–289.PubMedGoogle Scholar
  11. 11.
    Leung JC, Chan LY, Li FF, et al. Glucose degradation products downregulate ZO-1 expression in human peritoneal mesothelial cells: the role of VEGF. Nephrol Dial Transplant. 2005;20(7):1336–1349.CrossRefPubMedGoogle Scholar
  12. 12.
    Liaw YS, Yu CJ, Shun CT, et al. Expression of integrins in human cultured mesothelial cells: the roles in cell-to-extracellular matrix adhesion and inhibition by RGD-containing peptide. Respir Med. 2001;95(3):221–226.CrossRefPubMedGoogle Scholar
  13. 13.
    Strobel T, Swanson L, Cannistra SA. In vivo inhibition of CD44 limits intra-abdominal spread of a human ovarian cancer xenograft in nude mice: a novel role for CD 44 in the process of peritoneal implantation. Cancer Res. 1997;57:1228–1232.PubMedGoogle Scholar
  14. 14.
    Strobel T, Cannistra SA. β1-integrins partly mediate binding of ovarian cancer cells to peritoneal mesothelium in vitro. Gynecol Oncol. 1999;73:362–367.CrossRefPubMedGoogle Scholar
  15. 15.
    Lessan K, Aguiar D, Oegema TR, Siebenson L, Skubitz AP. CD44 and β1 integrin mediate ovarian carcinoma cell adhesion to peritoneal mesothelial cells. Am J Pathol. 1999;154(5):1525–1537.PubMedGoogle Scholar
  16. 16.
    Ahmed N, Riley C, Rice G, Quinn M. Role of integrin receptors for fibronectin, collagen and laminin in the regulation of ovarian carcinoma functions in response to a matrix microenvironment. Clin Exp Metastasis. 2005;22:391–402.CrossRefPubMedGoogle Scholar
  17. 17.
    Rieppi M, Vergani V, Gatto C, et al. Mesothelial cells induce the motility of human ovarian carcinoma cells. Int J Cancer. 1999;80:303–307.CrossRefPubMedGoogle Scholar
  18. 18.
    Sawada K, Radjabi AR, Bhaskar V, et al. Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target. Cancer Res. 2008;68(7):2329–2339.CrossRefPubMedGoogle Scholar
  19. 19.
    Kalluri R, Zeisberg M. Fibroblasts in cancer. Nature. 2006;6:392–401.Google Scholar
  20. 20.
    Mueller M, Fusenig N. Friends or foes – bipolar effects of the tumour stroma in cancer. Nat Rev. 2004;4:839–849.CrossRefGoogle Scholar
  21. 21.
    Witz C, Montoya-Rodriguez I, Cho S, Centonze V, Bonewald L, Schenken R. Composition of the extracellular matrix of the peritoneum. J Soc Gynecol Investig. 2001;8(5):299–304.CrossRefPubMedGoogle Scholar
  22. 22.
    Kenny HA, Kaur S, Coussens L, Lengyel E. The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin. J Clin Invest. 2008;118(4):1367–1379.CrossRefPubMedGoogle Scholar
  23. 23.
    Moser TL, Pizzo SV, Bafetti L, Fishman DA, Stack MS. Evidence for preferential adhesion of ovarian epithelial carcinoma cells to type I collagen mediated by the α2β1 integrin. Int J Cancer. 1996;67:695–701.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhu G, Risteli J, Puistola U, Kauppila A, Risteli L. Progressive ovarian carcinoma induces synthesis of type 1 and type III procollagens in the tumor tissue and peritoneal cavity. Cancer Res. 1993;53:5028–5032.PubMedGoogle Scholar
  25. 25.
    Cannistra SA, Ottensmeier C, Niloff J, Orta B, DiCarlo J. Expression and function of β1 and αvβ3 integrins in ovarian cancer. Gynecol Oncol. 1995;58:216–225.CrossRefPubMedGoogle Scholar
  26. 26.
    Symowicz J, Adley BP, Gleason KJ, et al. Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells. Cancer Res. 2007;67(5):2030–2039.CrossRefPubMedGoogle Scholar
  27. 27.
    Barbolina MV, Adley BP, Ariztia EV, Liu Y, Stack MS. Microenvironmental regulation of membrane type 1 matrix metalloproteinase activity in ovarian carcinoma cells via collagen-induced EGR1 expression. J Biol Chem. 2007;282(7):4924–4931.CrossRefPubMedGoogle Scholar
  28. 28.
    Ellerbroek SM, Wu YI, Overall CM, Stack MS. Functional interplay between type I collagen and cell surface matrix metalloproteinase activity. J Biol Chem. 2001;276:24833–24842.CrossRefPubMedGoogle Scholar
  29. 29.
    Fishman DA, Liu Y, Ellerbroek SM, Stack MS. Lysophosphatidic acid promotes matrix metalloproteinase (MMP) activation and MMP-dependent invasion in ovarian cancer cells. Cancer Res. 2001;61(7):3194–3199.PubMedGoogle Scholar
  30. 30.
    Fishman DA, Kearns AS, Chilukuri K, et al. Metastatic dissemination of human ovarian epithelial carcinoma is promoted by a α2β1-integrin-mediated interaction with type I collagen. Invasion Metastasis. 1998;18:15–26.CrossRefPubMedGoogle Scholar
  31. 31.
    Ellerbroek SM, Fishman DA, Kearns AS, Bafetti L, Stack MS. Ovarian carcinoma regulation of matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase through β1 integrin. Cancer Res. 1999;59:1635–1641.PubMedGoogle Scholar
  32. 32.
    Moser TL, Young TN, Rodriguez GC, Pizzo SV, Bast RC, Stack MS. Secretion of extracellular matrix-degrading proteinases is increased in epithelial ovarian carcinoma. Int J Cancer. 1994;56:552–559.CrossRefPubMedGoogle Scholar
  33. 33.
    Cheng K, Lahad J, Kuo W, et al. The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat Med. 2004;10(11):1251–1256.CrossRefPubMedGoogle Scholar
  34. 34.
    Shayesteh L, Lu Y, Kuo W, et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet. 1999;21:99–102.CrossRefPubMedGoogle Scholar
  35. 35.
    Debnath J, Mills KR, Collins NL, Reginato MJ, Muthuswamy SK, Brugge JS. The role of apoptosis in creating and maintaining luminal space within normal and oncogene-expressing mammary acini. Cell. 2002;111:29–40.CrossRefPubMedGoogle Scholar
  36. 36.
    Beningo K, Dembo M, Wanf Yu. Responses of fibroblasts to anchorage of dorsal extracellular matrix receptors. Proc Natl Acad Sci USA. 2004;101(52):18024–18029.CrossRefPubMedGoogle Scholar
  37. 37.
    Sawada M, Shii J, Akedo H, Tanizawa O. An experimental model for ovarian tumor invasion of cultured mesothelial cell monolayer. Lab Invest. 1994;70(3):333–338.PubMedGoogle Scholar
  38. 38.
    Westerlund A, Hujanen E, Puistola U, Turpeenniemi-Hujanen T. Fibroblasts stimulate human ovarian cancer cell invasion and expression of 72-kDa gelatinase A (MMP-2). Gynecol Oncol. 1997;67:76–82.CrossRefPubMedGoogle Scholar
  39. 39.
    Boyd R, Balkwill F. MMP-2 release and activation in ovarian carcinoma: the role of fibroblasts. Br J Cancer. 1999;80:315–321.CrossRefPubMedGoogle Scholar
  40. 40.
    Rygaard J, Povlsen CO. Heterotransplantation of a human malignant tumor to “Nude” mice. Acta Pathol Microbiol Scand. 1969;77(4):758–760.CrossRefPubMedGoogle Scholar
  41. 41.
    Voskoglou-Nomikos T, Pater JL, Seymour L. Clinical predicitive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models. Clin Cancer Res. 2003;9:4227–4239.PubMedGoogle Scholar
  42. 42.
    Bissell MJ, Hall HG, Parry G. How does the extracellular matrix direct gene expression. J Theor Biol. 1982;99:31–68.CrossRefPubMedGoogle Scholar
  43. 43.
    Niedbala MJ, Crickard K, Bernacki R. In vitro degradation of extracellular matrix by human ovarian carcinoma cells. Clin Exp Metastasis. 1987;5(2):181–197.CrossRefPubMedGoogle Scholar
  44. 44.
    Kanemoto T, Martin GR, Hamilton TC, Fridman R. Effects of synthetic peptides and protease inhibitors on the interaction of a human ovarian cancer cell line (NIH:OVCAR-3) with a reconstituted basement membrane (matrigel). Invasion Metastasis. 1991;11:84–92.PubMedGoogle Scholar
  45. 45.
    Burleson KM, Boente MP, Pambuccian SE, Skubitz AP. Disaggregation and invasion of ovarian carcinoma ascites spheroids. J Transl Med. 2006;24:4–6.Google Scholar
  46. 46.
    Burleson KM, Casey RC, Skubitz KM, Pambuccian SE, Oegema TR, Skubitz AP. Ovarian carcinoma ascites spheroids adhere to extracellular matrix components and mesothelial cell monolayers. Gynecol Oncol. 2004;93:170–181.CrossRefPubMedGoogle Scholar
  47. 47.
    Burleson KM, Hansen LK, Skubitz AP. Ovarian carcinoma spheroids disaggregate on type I collagen and invade live human mesothelial cell monolayers. Clin Exp Metastasis. 2004;21(8):685–697.CrossRefPubMedGoogle Scholar
  48. 48.
    Casey RC, Skubitz AP. CD44 and β1 integrins mediate ovarian carcinoma cell migration toward extracellular matrix proteins. Clin Exp Metastasis. 2000;18:67–75.CrossRefPubMedGoogle Scholar
  49. 49.
    Casey RC, Oegema TR, Skubitz KM, Pambuccian SE, Grindle SM, Skubitz AP. Cell membrane glycosylation mediates the adhesion, migration, and invasion of ovarian carcinoma cells. Clin Exp Metastasis. 2003;20(2):143–152.CrossRefPubMedGoogle Scholar
  50. 50.
    Casey RC, Koch KA, Oegema TR, et al. Establishment of an in vitro assay to measure the invasion of ovarian carcinoma cells through mesothelial cell monolayers. Clin Exp Metastasis. 2003;20:343–356.CrossRefPubMedGoogle Scholar
  51. 51.
    Casey RC, Burleson KM, Skubitz KM, et al. β1-integrins regulate the formation and adhesion of ovarian carcinoma multicellular spheroids. Am J Pathol. 2001;159:2071–2080.PubMedGoogle Scholar
  52. 52.
    Skubitz AP, Bast RC, Wayner EA, Letourneau PC, Wilke MS. Expression of α6 and β4 integrins in serous ovarian carcinoma correlates with expression of the basement membrane protein laminin. Am J Pathol. 1996;148(5):1445–1461.PubMedGoogle Scholar
  53. 53.
    Barbolina MV, Adley BP, Shea LD, Stack MS. Wilms tumor gene protein 1 is associated with ovarian cancer metastasis and modulates cell invasion. Cancer. 2007;112(7):1632–1641.CrossRefGoogle Scholar
  54. 54.
    Suzuki N, Aoki D, Tamada Y, et al. HMOCC-1, a human monoclonal antibody that inhibits adhesion of ovarian cancer cells to human mesothelial cells. Gynecol Oncol. 2004;95:290–298.CrossRefPubMedGoogle Scholar
  55. 55.
    Kishikawa T, Sakamoto M, Ino Y, Kubushiro K, Nozawa S, Hirohashi S. Two distinct pattern of peritoneal involvement shown by in vitro and in vivo ovarian cancer dissemination models. Invasion Metastasis. 1995;15:11–21.PubMedGoogle Scholar
  56. 56.
    Niedbala MJ, Crickard K, Bernacki R. Interactions of human ovarian tumor cells with human mesothelial cells grown on extracellular matrix. An in vitro model system for studying tumor cell adhesion and invasion. Exp Cell Res. 1985;160(2):499–513.CrossRefPubMedGoogle Scholar
  57. 57.
    Weaver VM, Fischer A, Peterson O, Bissell MJ. The importance of the microenvironment in breast cancer progression: recapitulation of mammary tumorigenesis using a unique human mammary epithelial cell model and a three-dimensional culture assay. Biochem Cell Biol. 1996;74(6):833–851.CrossRefPubMedGoogle Scholar
  58. 58.
    Weaver VM, Petersen OW, Wang F, et al. Revision of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol. 1997;137(1):231–245.CrossRefPubMedGoogle Scholar
  59. 59.
    Park CC, Zhang H, Pallavicini M, et al. β1 Integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growths, and distinguishes malignant from normal phenotype in three dimensional cultures and in vivo. Cancer Res. 2006;66(3):1526–1535.CrossRefPubMedGoogle Scholar
  60. 60.
    Weaver VM, Howlett AR, Langton-Webster B, Petersen O, Bissell M. The development of a functionally relevant cell culture model of progressive human breast cancer. Semin Cancer Biol. 1995;6(3):175–184.CrossRefPubMedGoogle Scholar
  61. 61.
    Wang F, Weaver VM, Petersen OW, et al. Reciprocal interactions between β1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology. Proc Natl Acad Sci USA. 1998;95:14821–14826.CrossRefPubMedGoogle Scholar
  62. 62.
    Rizki A, Weaver VM, Lee SY, et al. A human breast cell model of preinvasive to invasive transition. Cancer Res. 2008;68(5):1378–1387.CrossRefPubMedGoogle Scholar
  63. 63.
    Lee GY, Kenny PA, Lee EH, Bissel MJ. Three-dimensional culture models of normal and malignant breast epithelial cells. Nat Methods. 2007;4(4):359–365.CrossRefPubMedGoogle Scholar
  64. 64.
    Peterson OW, Ronnov-Jessen L, Bissell MJ. Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant breast epithelial cells. Proc Natl Acad Sci USA. 1992;89(19):9064–9068.CrossRefGoogle Scholar
  65. 65.
    Roskelley CD, Desprez PY, Bissell MJ. Extracellular matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both physical and biochemiacal signal transduction. Proc Natl Acad Sci USA. 1994;91:12378–12382.CrossRefPubMedGoogle Scholar
  66. 66.
    Zutter MM, Santoro SA, Staatz WD, Tsung YL. Re-expression of the α2β1-integrin abrogates the malignant phenotype of breast carcinoma cells. Proc Natl Acad Sci USA. 1995;92:7411–7415.CrossRefPubMedGoogle Scholar
  67. 67.
    Berking C, Herlyn M. Human skin reconstruct models: a new application for studies of melanocyte and melanoma biology. Histo Histopathol. 2001;16:669–674.Google Scholar
  68. 68.
    Meier FE, Nesland M, Hsu M, et al. Human melanoma progression in skin reconstructs. Am J Pathol. 2000;156(1):193–200.PubMedGoogle Scholar
  69. 69.
    Haass NK, Smalley KS, Li L, Hermes M. Adhesion, migration and communication in melanocytes and melanoma. Pigment Cell Res. 2005;18(3):150–159.CrossRefPubMedGoogle Scholar
  70. 70.
    Auersperg N, Ota T, Mitchell GW. Early events in ovarian epithelial carcinogenesis progress and problems in experimental approaches. Int J Gynecol Cancer. 2002;12:691–703.CrossRefPubMedGoogle Scholar
  71. 71.
    Puiffe ML, Le Page C, Filali-Mouhim A et al. Characterization of ovarian cancer ascites on cell invasion, proliferation, spheroid formation, and gene expression in an in vitro model of epithelial ovarian cancer. Neoplasia. 2007;9(10):820–829.CrossRefPubMedGoogle Scholar
  72. 72.
    Hotary KB, Li X, Allen E, Stevens SL, Weiss SJ. A cancer cell metalloprotease triad regulates the basement membrane transmigration program. Genes Dev. 2006;20:2673–2686.CrossRefPubMedGoogle Scholar
  73. 73.
    Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66(2):605–612.CrossRefPubMedGoogle Scholar
  74. 74.
    Lu M, Gao R, Xiao L, Wang Z. Construction of three-dimensional in vitro culture model of ovarian carcinoma and the study of its multicellular drug resistance. J Huazhong Univ Sci Technol Med Sci. 2006;26(6):741–743.CrossRefPubMedGoogle Scholar
  75. 75.
    Zietarska M, Maugard C, Filali-Mouhim A, et al. Molecular description of a 3D in vitro model for the study of epithelial ovarian cancer (EOC). Mol Carcinog. 2007;46:872–885.CrossRefPubMedGoogle Scholar
  76. 76.
    Kurman R, Visvanathan K, Roden R, Wu TC, Shih I-M. Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis. J Obstet Gynecol. 2008;351–356.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Hilary A. Kenny
    • 1
  • Songuel Dogan
    • 1
  • Marion Zillhardt
    • 1
  • Anirban K. Mitra
    • 1
  • S. Diane Yamada
    • 1
  • Thomas Krausz
    • 2
  • Ernst Lengyel
    • 1
  1. 1.Department of Obstetrics and GynecologyUniversity of ChicagoChicagoUSA
  2. 2.Department of Surgical PathologyUniversity of ChicagoChicagoUSA

Personalised recommendations