Animal Model: Xenograft Mouse Models in Esophageal Adenocarcinoma

Part of the Methods in Molecular Biology book series (MIMB, volume 1756)


Researchers often use murine models of esophageal cancer to evaluate novel therapies prior to clinical protocol treatment. Subcutaneous xenograft models are often used for testing the efficacy of anticancer agents in many cancers including esophageal adenocarcinoma. However, mice subcutaneous esophageal adenocarcinoma models only represent local tumor growth and do not provide any information about a survival benefit for a particular anticancer regimen, which is very crucial for experimental treatment efficacy. In addition, anticancer agents may well inhibit subcutaneous tumor growth without effecting overall animal survival. Herein, we describe a peritoneal dissemination mouse xenograft model for survival outcome analysis with intraperitoneal injection of human esophageal adenocarcinoma cell lines.

Key words

Esophageal adenocarcinoma Xenograft model Survival model Metastatic model Peritoneal dissemination OE19 



The Indiana University internal funding supported this work.


  1. 1.
    Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29. CrossRefPubMedGoogle Scholar
  2. 2.
    Liu DS, Read M, Cullinane C, Azar WJ, Fennell CM, Montgomery KG, Haupt S, Haupt Y, Wiman KG, Duong CP, Clemons NJ, Phillips WA (2015) APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of esophageal adenocarcinoma. Gut 64(10):1506–1516. CrossRefPubMedGoogle Scholar
  3. 3.
    Fujihara S, Kato K, Morishita A, Iwama H, Nishioka T, Chiyo T, Nishiyama N, Miyoshi H, Kobayashi M, Kobara H, Mori H, Okano K, Suzuki Y, Masaki T (2015) Antidiabetic drug metformin inhibits esophageal adenocarcinoma cell proliferation in vitro and in vivo. Int J Oncol 46(5):2172–2180. CrossRefPubMedGoogle Scholar
  4. 4.
    Dodbiba L, Teichman J, Fleet A, Thai H, Starmans MH, Navab R, Chen Z, Girgis H, Eng L, Espin-Garcia O, Shen X, Bandarchi B, Schwock J, Tsao MS, El-Zimaity H, Der SD, Xu W, Bristow RG, Darling GE, Boutros PC, Ailles LE, Liu G (2015) Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers. PLoS One 10(3):e0121872. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kambhampati S, Rajewski RA, Tanol M, Haque I, Das A, Banerjee S, Jha S, Burns D, Borrego-Diaz E, Van Veldhuizen PJ, Banerjee SK (2013) A second-generation 2-Methoxyestradiol prodrug is effective against Barrett’s adenocarcinoma in a mouse xenograft model. Mol Cancer Ther 12(3):255–263. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ford SJ, Obeidy P, Lovejoy DB, Bedford M, Nichols L, Chadwick C, Tucker O, Lui GY, Kalinowski DS, Jansson PJ, Iqbal TH, Alderson D, Richardson DR, Tselepis C (2013) Deferasirox (ICL670A) effectively inhibits esophageal cancer growth in vitro and in vivo. Br J Pharmacol 168(6):1316–1328. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lange T, Nentwich MF, Luth M, Yekebas E, Schumacher U (2011) Trastuzumab has anti-metastatic and anti-angiogenic activity in a spontaneous metastasis xenograft model of esophageal adenocarcinoma. Cancer Lett 308(1):54–61. CrossRefGoogle Scholar
  8. 8.
    Liu DS, Hoefnagel SJ, Fisher OM, Krishnadath KK, Montgomery KG, Busuttil RA, Colebatch AJ, Read M, Duong CP, Phillips WA, Clemons NJ (2016) Novel metastatic models of esophageal adenocarcinoma derived from FLO-1 cells highlight the importance of E-cadherin in cancer metastasis. Oncotarget 7(50):83342–83358. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sehdev V, Peng D, Soutto M, Washington MK, Revetta F, Ecsedy J, Zaika A, Rau TT, Schneider-Stock R, Belkhiri A, El-Rifai W (2012) The aurora kinase A inhibitor MLN8237 enhances cisplatin-induced cell death in esophageal adenocarcinoma cells. Mol Cancer Ther 11(3):763–774. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Gros SJ, Dohrmann T, Rawnaq T, Kurschat N, Bouvet M, Wessels J, Hoffmann RM, Izbicki JR, Kaifi JT (2010) Orthotopic fluorescent peritoneal carcinomatosis model of esophageal cancer. Anticancer Res 30(10):3933–3938PubMedGoogle Scholar
  11. 11.
    Sicklick JK, Leonard SY, Babicky ML, Tang CM, Mose ES, French RP, Jaquish DV, Hoh CK, Peterson M, Schwab R, Lowy AM (2014) Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor. J Transl Med 12:41. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hassan MS, Awasthi N, Li J, Schwarz MA, Schwarz RE, Holzen UV (2017) A novel intraperitoneal metastatic xenograft mouse model for survival outcome assessment of esophageal adenocarcinoma. PLoS One 12(2):e0171824. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, Thompson IR, Luo X, Soares J, Liu Q, Iorio F, Surdez D, Chen L, Milano RJ, Bignell GR, Tam AT, Davies H, Stevenson JA, Barthorpe S, Lutz SR, Kogera F, Lawrence K, McLaren-Douglas A, Mitropoulos X, Mironenko T, Thi H, Richardson L, Zhou W, Jewitt F, Zhang T, O’Brien P, Boisvert JL, Price S, Hur W, Yang W, Deng X, Butler A, Choi HG, Chang JW, Baselga J, Stamenkovic I, Engelman JA, Sharma SV, Delattre O, Saez-Rodriguez J, Gray NS, Settleman J, Futreal PA, Haber DA, Stratton MR, Ramaswamy S, McDermott U, Benes CH (2012) Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483(7391):570–575. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wilding JL, Bodmer WF (2014) Cancer cell lines for drug discovery and development. Cancer Res 74(9):2377–2384. CrossRefGoogle Scholar
  15. 15.
    Niu N, Wang L (2015) In vitro human cell line models to predict clinical response to anticancer drugs. Pharmacogenomics 16(3):273–285. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kresty LA, Weh KM, Zeyzus-Johns B, Perez LN, Howell AB (2015) Cranberry proanthocyanidins inhibit esophageal adenocarcinoma in vitro and in vivo through pleiotropic cell death induction and PI3K/AKT/mTOR inactivation. Oncotarget 6(32):33438–33455. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lin YS, Hu L, Yin MC (2017) Apoptotic effects of rotundic acid on human esophagus and lung cancer cells. Integr Cancer Ther.
  18. 18.
    Boonstra JJ, Tilanus HW, Dinjens WN (2015) Translational research on esophageal adenocarcinoma: from cell line to clinic. Dis Esophagus 28(1):90–96. CrossRefGoogle Scholar
  19. 19.
    Hasina R, Surati M, Kawada I, Arif Q, Carey GB, Kanteti R, Husain AN, Ferguson MK, Vokes EE, Villaflor VM, Salgia R (2013) O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer. J Carcinog 12:20. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Johnson JI, Decker S, Zaharevitz D, Rubinstein LV, Venditti JM, Schepartz S, Kalyandrug S, Christian M, Arbuck S, Hollingshead M, Sausville EA (2001) Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer 84(10):1424–1431. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kerbel RS (2003) Human tumor xenografts as predictive preclinical models for anticancer drug activity in humans: better than commonly perceived-but they can be improved. Cancer Biol Ther 2(4 Suppl 1):S134–S139PubMedGoogle Scholar
  22. 22.
    Gros SJ, Kurschat N, Dohrmann T, Reichelt U, Dancau AM, Peldschus K, Adam G, Hoffman RM, Izbicki JR, Kaifi JT (2010) Effective therapeutic targeting of the overexpressed HER-2 receptor in a highly metastatic orthotopic model of esophageal carcinoma. Mol Cancer Ther 9(7):2037–2045. CrossRefPubMedGoogle Scholar
  23. 23.
    Harada K, Ferdous T, Kobayashi H, Ueyama Y (2014) Paclitaxel in combination with cetuximab exerts antitumor effect by suppressing NF-kappaB activity in human oral squamous cell carcinoma cell lines. Int J Oncol 45(6):2439–2445. CrossRefPubMedGoogle Scholar
  24. 24.
    Karginova O, Siegel MB, Van Swearingen AE, Deal AM, Adamo B, Sambade MJ, Bazyar S, Nikolaishvili-Feinberg N, Bash R, O’Neal S, Sandison K, Parker JS, Santos C, Darr D, Zamboni W, Lee YZ, Miller CR, Anders CK (2015) Efficacy of Carboplatin alone and in combination with ABT888 in intracranial murine models of BRCA-mutated and BRCA-wild-type triple-negative breast cancer. Mol Cancer Ther 14(4):920–930. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Awasthi N, Zhang C, Ruan W, Schwarz MA, Schwarz RE (2012) Evaluation of poly-mechanistic antiangiogenic combinations to enhance cytotoxic therapy response in pancreatic cancer. PLoS One 7(6):e38477. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Zamai M, VandeVen M, Farao M, Gratton E, Ghiglieri A, Castelli MG, Fontana E, D’Argy R, Fiorino A, Pesenti E, Suarato A, Caiolfa VR (2003) Camptothecin poly[n-(2-hydroxypropyl) methacrylamide] copolymers in antitopoisomerase-I tumor therapy: intratumor release and antitumor efficacy. Mol Cancer Ther 2(1):29–40CrossRefPubMedGoogle Scholar
  27. 27.
    Awasthi N, Yen PL, Schwarz MA, Schwarz RE (2012) The efficacy of a novel, dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer. J Cell Biochem 113(3):784–791. CrossRefPubMedGoogle Scholar
  28. 28.
    Awasthi N, Kirane A, Schwarz MA, Toombs JE, Brekken RA, Schwarz RE (2011) Smac mimetic-derived augmentation of chemotherapeutic response in experimental pancreatic cancer. BMC Cancer 11:15. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Zhang C, Awasthi N, Schwarz MA, Schwarz RE (2013) Establishing a peritoneal dissemination xenograft mouse model for survival outcome assessment of experimental gastric cancer. J Surg Res 182(2):227–234. CrossRefPubMedGoogle Scholar
  30. 30.
    Boonstra JJ, van der Velden AW, Beerens EC, van Marion R, Morita-Fujimura Y, Matsui Y, Nishihira T, Tselepis C, Hainaut P, Lowe AW, Beverloo BH, van Dekken H, Tilanus HW, Dinjens WN (2007) Mistaken identity of widely used esophageal adenocarcinoma cell line TE-7. Cancer Res 67(17):7996–8001. CrossRefPubMedGoogle Scholar
  31. 31.
  32. 32.
    Risinger AL, Giles FJ, Mooberry SL (2009) Microtubule dynamics as a target in oncology. Cancer Treat Rev 35(3):255–261. CrossRefPubMedGoogle Scholar
  33. 33.
    Rowinsky EK, Cazenave LA, Donehower RC (1990) Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst 82(15):1247–1259CrossRefPubMedGoogle Scholar
  34. 34.
    Stanton RA, Gernert KM, Nettles JH, Aneja R (2011) Drugs that target dynamic microtubules: a new molecular perspective. Med Res Rev 31(3):443–481. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2018

Authors and Affiliations

  1. 1.Department of SurgeryIndiana University School of MedicineSouth BendUSA
  2. 2.Goshen Center for Cancer Care, GoshenGoshenUSA
  3. 3.Harper Cancer Research InstituteSouth BendUSA
  4. 4.University of BaselBaselSwitzerland

Personalised recommendations