Skip to main content
SpringerLink
Log in

Orthotopic Model of Ovarian Cancer

  • Protocol
  • First Online:
Tumor Angiogenesis Assays

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1464))

Abstract

Epithelial ovarian cancer (EOC) is the fifth commonest cancer-related cause of female death in the developed world. In spite of current surgical and chemotherapeutic options the vast majority of patients have widely metastatic disease and the survival rate has not much changed over the last years. The anti-angiogenic drugs are driving the field of agents targeting the tumor microenvironment in ovarian cancer. Preclinical models that accurately reproduce the molecular and biological features of ovarian cancer patients are a valuable means of producing reliable data on personalized medicine and predicting the therapeutic response in clinical trials.

In this methodological chapter we describe the orthotopic model of ovarian cancer implanted under the ovarian bursa of mice. In spite of anatomical differences between the rodent and human bursa-fallopian tube, the appropriate primary tumor microenvironment at the site of the implant allows investigation of tumor–stroma interactions (e.g., angiogenesis), and is well suited for studying the tumor dissemination and metastasis typical of this disease.

This model—although fairly labor intensive—may be useful for assessing novel, more selective therapeutic interventions and for biomarker discovery, reflecting the behavior of this disease.

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

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29

    Article  PubMed  Google Scholar 

  2. Stuart GC, Kitchener H, Bacon M, duBois A, Friedlander M, Ledermann J et al (2011) 2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference. Int J Gynecol Cancer 21(4):750–755

    Article  PubMed  Google Scholar 

  3. Jayson GC, Kohn EC, Kitchener HC, Ledermann JA (2014) Ovarian cancer. Lancet 384(9951):1376–1388

    Article  PubMed  Google Scholar 

  4. Eskander RN, Tewari KS (2014) Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—mechanistics, review of phase III randomized clinical trials, and regulatory implications. Gynecol Oncol 132(2):496–505

    Article  CAS  PubMed  Google Scholar 

  5. House CD, Hernandez L, Annunziata CM (2014) Recent technological advances in using mouse models to study ovarian cancer. Front Oncol 4:26. doi:10.3389/fonc.2014.00026

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kuhn E, Tisato V, Rimondi E, Secchiero P (2015) Current preclinical models of ovarian cancer. J Carcinog Mutagen 6(2). doi:10.4172/2157-2518.1000220

    Google Scholar 

  7. Lengyel E, Burdette JE, Kenny HA, Matei D, Pilrose J, Haluska P et al (2014) Epithelial ovarian cancer experimental models. Oncogene 33(28):3619–3633

    Article  CAS  PubMed  Google Scholar 

  8. Ricci F, Bizzaro F, Cesca M, Guffanti F, Ganzinelli M, Decio A et al (2014) Patient-derived ovarian tumor xenografts recapitulate human clinicopathology and genetic alterations. Cancer Res 74(23):6980–6990

    Article  CAS  PubMed  Google Scholar 

  9. Weroha SJ, Becker MA, Enderica-Gonzalez S, Harrington SC, Oberg AL, Maurer MJ et al (2014) Tumorgrafts as in vivo surrogates for women with ovarian cancer. Clin Cancer Res 20(5):1288–1297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Alkema NG, Tomar T, Duiker EW, Jan Meersma G, Klip H, van der Zee AG et al (2015) Biobanking of patient and patient-derived xenograft ovarian tumour tissue: efficient preservation with low and high fetal calf serum based methods. Sci Rep 5:14495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Colombo PE, du Manoir S, Orsett B, Bras-Goncalves R, Lambros MB, MacKay A et al (2015) Ovarian carcinoma patient derived xenografts reproduce their tumor of origin and preserve an oligoclonal structure. Oncotarget 6(29):28327–28340

    Article  PubMed  PubMed Central  Google Scholar 

  12. Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM et al (2012) Patient-derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol 9(6):338–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Langdon SP (2012) Animal modeling of cancer pathology and studying tumor response to therapy. Curr Drug Targets 13(12):1535–1547

    Article  CAS  PubMed  Google Scholar 

  14. Peterson JK, Houghton PJ (2004) Integrating pharmacology and in vivo cancer models in preclinical and clinical drug development. Eur J Cancer 40(6):837–844

    Article  CAS  PubMed  Google Scholar 

  15. Daniel VC, Marchionni L, Hierman JS, Rhodes JT, Devereux WL, Rudin CM et al (2009) A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro. Cancer Res 69(8):3364–3373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ricci F, Broggini M, Damia G (2013) Revisiting ovarian cancer preclinical models: implications for a better management of the disease. Cancer Treat Rev 39(6):561–568

    Article  CAS  PubMed  Google Scholar 

  17. Hasan N, Ohman AW, Dinulescu DM (2015) The promise and challenge of ovarian cancer models. Transl Cancer Res 4(1):14–28

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Oliva P, Decio A, Castiglioni V, Bassi A, Pesenti E, Cesca M et al (2012) Cisplatin plus paclitaxel and maintenance of bevacizumab on tumour progression, dissemination, and survival of ovarian carcinoma xenograft models. Br J Cancer 107(2):360–369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kurman RJ, Shih Ie M (2010) The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 34(3):433–443

    Article  PubMed  PubMed Central  Google Scholar 

  20. Nunez-Cruz S, Connolly DC, Scholler N (2010) An orthotopic model of serous ovarian cancer in immunocompetent mice for in vivo tumor imaging and monitoring of tumor immune responses. J Vis Exp (45). doi:2146 [pii] 10.3791/2146

    Google Scholar 

  21. Fu X, Hoffman RM (1993) Human ovarian carcinoma metastatic models constructed in nude mice by orthotopic transplantation of histologically-intact patient specimens. Anticancer Res 13(2):283–286

    CAS  PubMed  Google Scholar 

  22. Shaw TJ, Senterman MK, Dawson K, Crane CA, Vanderhyden BC (2004) Characterization of intraperitoneal, orthotopic, and metastatic xenograft models of human ovarian cancer. Mol Ther 10(6):1032–1042

    Article  CAS  PubMed  Google Scholar 

  23. Tamada Y, Aoki D, Nozawa S, Irimura T (2004) Model for paraaortic lymph node metastasis produced by orthotopic implantation of ovarian carcinoma cells in athymic nude mice. Eur J Cancer 40(1):158–163

    Article  CAS  PubMed  Google Scholar 

  24. Decio A, Taraboletti G, Patton V, Alzani R, Perego P, Fruscio R et al (2014) Vascular endothelial growth factor c promotes ovarian carcinoma progression through paracrine and autocrine mechanisms. Am J Pathol 184(4):1050–1061

    Article  CAS  PubMed  Google Scholar 

  25. Greenaway J, Moorehead R, Shaw P, Petrik J (2008) Epithelial–stromal interaction increases cell proliferation, survival and tumorigenicity in a mouse model of human epithelial ovarian cancer. Gynecol Oncol 108(2):385–394

    Article  CAS  PubMed  Google Scholar 

  26. Decio A, Cesca M, Bizzaro F, Porcu L, Bettolini R, Ubezio P et al (2015) Cediranib combined with chemotherapy reduces tumor dissemination and prolongs the survival of mice bearing patient-derived ovarian cancer xenografts with different responsiveness to cisplatin. Clin Exp Metastasis 32(7):647–658

    Article  CAS  PubMed  Google Scholar 

  27. Cesca M, Morosi L, Berndt A, Fuso Nerini I, Frapolli R, Richter P et al (2016) Bevacizumab-induced inhibition of angiogenesis promotes a more homogeneous intratumoral distribution of paclitaxel, improving the antitumor response. Mol Cancer Ther. 15(1):125–35

    Google Scholar 

  28. Bankert RB, Balu-Iyer SV, Odunsi K, Shultz LD, Kelleher RJ Jr, Barnas JL et al (2011) Humanized mouse model of ovarian cancer recapitulates patient solid tumor progression, ascites formation, and metastasis. PLoS One 6(9):e24420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ et al (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102(11):1555–1577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yang M, Jiang P, An Z, Baranov E, Li L, Hasegawa S et al (1999) Genetically fluorescent melanoma bone and organ metastasis models. Clin Cancer Res 5(11):3549–3559

    CAS  PubMed  Google Scholar 

  31. Amoh Y, Bouvet M, Li L, Tsuji K, Moossa AR, Katsuoka K et al (2006) Visualization of nascent tumor angiogenesis in lung and liver metastasis by differential dual-color fluorescence imaging in nestin-linked-GFP mice. Clin Exp Metastasis 23(7–8):315–322

    PubMed  Google Scholar 

  32. Shaner NC, Campbell RE, Steinbach PA, Giepmans BN, Palmer AE, Tsien RY (2004) Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nat Biotechnol 22(12):1567–1572

    Article  CAS  PubMed  Google Scholar 

  33. Shcherbo D, Merzlyak EM, Chepurnykh TV, Fradkov AF, Ermakova GV, Solovieva EA et al (2007) Bright far-red fluorescent protein for whole-body imaging. Nat Methods 4(9):741–746

    Article  CAS  PubMed  Google Scholar 

  34. Shu X, Royant A, Lin MZ, Aguilera TA, Lev-Ram V, Steinbach PA et al (2009) Mammalian expression of infrared fluorescent proteins engineered from a bacterial phytochrome. Science 324(5928):804–807

    Article  PubMed  PubMed Central  Google Scholar 

  35. Landy A (1989) Dynamic, structural, and regulatory aspects of lambda site-specific recombination. Annu Rev Biochem 58:913–949

    Article  CAS  PubMed  Google Scholar 

  36. Snyder CS, Kaushal S, Kono Y, Tran Cao HS, Hoffman RM, Bouvet M (2009) Complementarity of ultrasound and fluorescence imaging in an orthotopic mouse model of pancreatic cancer. BMC Cancer 9:106

    Article  PubMed  PubMed Central  Google Scholar 

  37. Sastra SA, Olive KP (2013) Quantification of murine pancreatic tumors by high-resolution ultrasound. Methods Mol Biol 980:249–266

    Article  CAS  PubMed  Google Scholar 

  38. Hensley H, Quinn BA, Wolf RL, Litwin SL, Mabuchi S, Williams SJ et al (2007) Magnetic resonance imaging for detection and determination of tumor volume in a genetically engineered mouse model of ovarian cancer. Cancer Biol Ther 6(11):1717–1725

    Article  PubMed  Google Scholar 

  39. Gerling M, Zhao Y, Nania S, Norberg KJ, Verbeke CS, Englert B et al (2014) Real-time assessment of tissue hypoxia in vivo with combined photoacoustics and high-frequency ultrasound. Theranostics 4(6):604–613

    Article  PubMed  PubMed Central  Google Scholar 

  40. Paproski RJ, Heinmiller A, Wachowicz K, Zemp RJ (2014) Multi-wavelength photoacoustic imaging of inducible tyrosinase reporter gene expression in xenograft tumors. Sci Rep 4:5329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant from the Italian Association for Cancer Research (AIRC) no. IG14532 to R.G. A.D. is the recipient of a fellowship from the Umberto Veronesi Foundation, Milan, Italy. We thank J.D. Baggott for editing.

Author information

Authors and Affiliations

  1. Department of Oncology, Laboratory of Biology and Treatment of Metastasis, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via Giuseppe La Masa 19, 20156, Milan, Italy

    Alessandra Decio & Raffaella Giavazzi

Authors
  1. Alessandra Decio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raffaella Giavazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raffaella Giavazzi .

Editor information

Editors and Affiliations

  1. Neurosciences and Sensory Organs, University of Bari,School of Med Dept of Basic Med Sci, Bari, Italy

    Domenico Ribatti

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this protocol

Cite this protocol

Decio, A., Giavazzi, R. (2016). Orthotopic Model of Ovarian Cancer. In: Ribatti, D. (eds) Tumor Angiogenesis Assays. Methods in Molecular Biology, vol 1464. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3999-2_13

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-3999-2_13

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3997-8

  • Online ISBN: 978-1-4939-3999-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation