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Journal of Ovarian Research
Published in: Journal of Ovarian Research 1/2011

Open Access 01-12-2011 | Research

The hen model of human ovarian cancer develops anti-mesothelin autoantibodies in response to mesothelin expressing tumors

Authors: Yi Yu, Seby L Edassery, Animesh Barua, Jacques S Abramowicz, Janice M Bahr, Ingegerd Hellstrom, Judith L Luborsky

Published in: Journal of Ovarian Research | Issue 1/2011

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Abstract

Objective

Study of the hen immune system led to seminal contributions to basic immunological principles. Recent studies of spontaneous ovarian cancer in the laying hen show strikingly similar tumor types and antigen expression compared to human ovarian cancer, suggesting hens would be valuable for studies of tumor immunology and pre-clinical vaccine development. Circulating mesothelin is a relatively specific marker for human ovarian cancer and autoantibodies to mesothelin were reported. We hypothesized that hen tumors express mesothelin and that circulating anti-mesothelin antibodies occur in response to tumors.

Methods

Mesothelin mRNA expression was analyzed by RT-PCR in hen ovarian tumors and normal ovaries. Mesothelin protein expression was evaluated by immunohistochemistry (IHC) and two-dimensional SDS-PAGE Western blots. Anti-mesothelin antibodies were assessed by immunoassay of sera from hens with normal ovaries and with ovarian tumors.

Results

Significant mesothelin mRNA expression was observed in 57% (12/21) of hen ovarian tumors but not in normal ovaries and was found predominantly in serous tumors as in humans. Mesothelin protein was detected in tumors with mesothelin mRNA by IHC and 2D Western blots, but not in normal ovaries or tumors without mesothelin mRNA. Circulating anti-mesothelin antibodies occurred in 44% (n = 4/9) of hens with ovarian tumors which express mesothelin mRNA and were not found in hens with tumors that did not express mesothelin (n = 0/5) or normal ovaries (n = 0/5).

Conclusion

The results support the utility of the hen as a novel model for preclinical studies of mesothelin as a biomarker and a target for immunotherapy.
Appendix
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Literature
1.
2.
3.
Urick ME, Giles JR, Johnson PA: Dietary aspirin decreases the stage of ovarian cancer in the hen. Gynecol Oncol 2009, 112: 166–170. 10.1016/j.ygyno.2008.09.032PubMedCrossRef
4.
Hakim AA, Barry CP, Barnes HJ, Anderson KE, Petitte J, Whitaker R, Lancaster JM, Wenham RM, Carver DK, Turbov J, et al.: Ovarian adenocarcinomas in the laying hen and women share similar alterations in p53, ras, and HER-2/neu. Cancer Prev Res (Phila) 2009, 2: 114–121. 10.1158/1940-6207.CAPR-08-0065CrossRef
5.
Barua A, Bitterman P, Abramowicz JS, Dirks AL, Bahr JM, Hales DB, Bradaric MJ, Edassery SL, Rotmensch J, Luborsky JL: Histopathology of ovarian tumors in laying hens: a preclinical model of human ovarian cancer. Int J Gynecol Cancer 2009, 19: 531–539. 10.1111/IGC.0b013e3181a41613PubMedCentralPubMedCrossRef
6.
Hales DB, Zhuge Y, Lagman JA, Ansenberger K, Mahon C, Barua A, Luborsky JL, Bahr JM: Cyclooxygenases expression and distribution in the normal ovary and their role in ovarian cancer in the domestic hen (Gallus domesticus). Endocrine 2008, 33: 235–244. 10.1007/s12020-008-9080-zPubMedCentralPubMedCrossRef
7.
Hawkridge AM, Wysocky RB, Petitte JN, Anderson KE, Mozdziak PE, Fletcher OJ, Horowitz JM, Muddiman DC: Measuring the intra-individual variability of the plasma proteome in the chicken model of spontaneous ovarian adenocarcinoma. Anal Bioanal Chem 398, 737–749.
8.
Gonzalez Bosquet J, Peedicayil A, Maguire J, Chien J, Rodriguez GC, Whitaker R, Petitte JN, Anderson KE, Barnes HJ, Shridhar V, Cliby WA: Comparison of gene expression patterns between avian and human ovarian cancers. Gynecol Oncol 120: 256–264.
9.
10.
Rodriguez-Burford C, Barnes MN, Berry W, Partridge EE, Grizzle WE: Immunohistochemical expression of molecular markers in an avian model: a potential model for preclinical evaluation of agents for ovarian cancer chemoprevention. Gynecol Oncol 2001, 81: 373–379. 10.1006/gyno.2001.6191PubMedCrossRef
11.
Jackson E, Anderson K, Ashwell C, Petitte J, Mozdziak PE: CA125 expression in spontaneous ovarian adenocarcinomas from laying hens. Gynecol Oncol 2007, 104: 192–198. 10.1016/j.ygyno.2006.07.024PubMedCrossRef
12.
Stammer K, Edassery SL, Barua A, Bitterman P, Bahr JM, Hales DB, Luborsky JL: Selenium-Binding Protein 1 expression in ovaries and ovarian tumors in the laying hen, a spontaneous model of human ovarian cancer. Gynecol Oncol 2008, 109: 115–121. 10.1016/j.ygyno.2007.12.030PubMedCentralPubMedCrossRef
13.
Urick ME, Johnson PA: Cyclooxygenase 1 and 2 mRNA and protein expression in the Gallus domesticus model of ovarian cancer. Gynecol Oncol 2006, 103: 673–678. 10.1016/j.ygyno.2006.05.012PubMedCrossRef
14.
Ansenberger K, Zhuge Y, Lagman JA, Richards C, Barua A, Bahr JM, Hales DB: E-cadherin expression in ovarian cancer in the laying hen, Gallus domesticus, compared to human ovarian cancer. Gynecol Oncol 2009, 113: 362–369. 10.1016/j.ygyno.2009.02.011PubMedCentralPubMedCrossRef
15.
Urick ME, Giles JR, Johnson PA: VEGF expression and the effect of NSAIDs on ascites cell proliferation in the hen model of ovarian cancer. Gynecol Oncol 2008, 110: 418–424. 10.1016/j.ygyno.2008.05.018PubMedCrossRef
16.
Barua A, Bitterman P, Bahr JM, Bradaric MJ, Hales DB, Luborsky JL, Abramowicz JS: Detection of tumor-associated neoangiogenesis by Doppler ultrasonography during early-stage ovarian cancer in laying hens: a preclinical model of human spontaneous ovarian cancer. J Ultrasound Med 29: 173–182.
17.
Zhuge Y, Lagman JA, Ansenberger K, Mahon CJ, Daikoku T, Dey SK, Bahr JM, Hales DB: CYP1B1 expression in ovarian cancer in the laying hen Gallusdomesticus. Gynecol Oncol 2009, 112: 171–178. 10.1016/j.ygyno.2008.09.026PubMedCentralPubMedCrossRef
18.
Barua A, Bradaric MJ, Kebede T, Espinosa S, Edassery SL, Bitterman P, Rotmensch J, Luborsky JL: Anti-ovarian and anti-tumor antibodies in women with ovarian cancer. Am J Reprod Immunol 2007, 57: 243–249. 10.1111/j.1600-0897.2007.00470.xPubMedCrossRef
19.
Barua A, Edassery SL, Bitterman P, Abramowicz JS, Dirks AL, Bahr JM, Hales DB, Bradaric MJ, Luborsky JL: Prevalence of antitumor antibodies in laying hen model of human ovarian cancer. Int J Gynecol Cancer 2009, 19: 500–507. 10.1111/IGC.0b013e3181a39db1PubMedCentralPubMedCrossRef
20.
Chang K, Pastan I: Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci USA 1996, 93: 136–140. 10.1073/pnas.93.1.136PubMedCentralPubMedCrossRef
21.
Frierson HF, Moskaluk CA, Powell SM, Zhang H, Cerilli LA, Stoler MH, Cathro H, Hampton GM: Large-scale molecular and tissue microarray analysis of mesothelin expression in common human carcinomas. Hum Pathol 2003, 34: 605–609. 10.1016/S0046-8177(03)00177-1PubMedCrossRef
22.
Ordonez NG: Application of mesothelin immunostaining in tumor diagnosis. Am J Surg Pathol 2003, 27: 1418–1428. 10.1097/00000478-200311000-00003PubMedCrossRef
23.
Chang K, Pastan I: Molecular cloning and expression of a cDNA encoding a protein detected by the K1 antibody from an ovarian carcinoma (OVCAR-3) cell line. Int J Cancer 1994, 57: 90–97. 10.1002/ijc.2910570117PubMedCrossRef
24.
Hough CD, Sherman-Baust CA, Pizer ES, Montz FJ, Im DD, Rosenshein NB, Cho KR, Riggins GJ, Morin PJ: Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer. Cancer Res 2000, 60: 6281–6287.PubMed
25.
Argani P, Iacobuzio-Donahue C, Ryu B, Rosty C, Goggins M, Wilentz RE, Murugesan SR, Leach SD, Jaffee E, Yeo CJ, et al.: Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res 2001, 7: 3862–3868.PubMed
26.
27.
Obulhasim G, Fujii H, Matsumoto T, Yasen M, Abe M, Matsuoka S, Ohtsuji N, Hino O: Mesothelin gene expression and promoter methylation/hypomethylation in gynecological tumors. Eur J Gynaecol Oncol 2010, 31: 63–71.PubMed
28.
Muminova ZE, Strong TV, Shaw DR: Characterization of human mesothelin transcripts in ovarian and pancreatic cancer. BMC Cancer 2004, 4: 19. 10.1186/1471-2407-4-19PubMedCentralPubMedCrossRef
29.
Zhang Y, Pastan I: High shed antigen levels within tumors: an additional barrier to immunoconjugate therapy. Clin Cancer Res 2008, 14: 7981–7986. 10.1158/1078-0432.CCR-08-0324PubMedCrossRef
30.
Rosen DG, Wang L, Atkinson JN, Yu Y, Lu KH, Diamandis EP, Hellstrom I, Mok SC, Liu J, Bast RC Jr: Potential markers that complement expression of CA125 in epithelial ovarian cancer. Gynecol Oncol 2005, 99: 267–277. 10.1016/j.ygyno.2005.06.040PubMedCrossRef
31.
Hassan R, Bera T, Pastan I: Mesothelin: a new target for immunotherapy. Clin Cancer Res 2004, 10: 3937–3942. 10.1158/1078-0432.CCR-03-0801PubMedCrossRef
32.
Hellstrom I, Raycraft J, Kanan S, Sardesai NY, Verch T, Yang Y, Hellstrom KE: Mesothelin variant 1 is released from tumor cells as a diagnostic marker. Cancer Epidemiol Biomarkers Prev 2006, 15: 1014–1020. 10.1158/1055-9965.EPI-05-0334PubMedCrossRef
33.
Ho M, Hassan R, Zhang J, Wang QC, Onda M, Bera T, Pastan I: Humoral immune response to mesothelin in mesothelioma and ovarian cancer patients. Clin Cancer Res 2005, 11: 3814–3820. 10.1158/1078-0432.CCR-04-2304PubMedCrossRef
34.
Hassan R, Remaley AT, Sampson ML, Zhang J, Cox DD, Pingpank J, Alexander R, Willingham M, Pastan I, Onda M: Detection and quantitation of serum mesothelin, a tumor marker for patients with mesothelioma and ovarian cancer. Clin Cancer Res 2006, 12: 447–453. 10.1158/1078-0432.CCR-05-1477PubMedCrossRef
35.
Hellstrom I, Friedman E, Verch T, Yang Y, Korach J, Jaffar J, Swisher E, Zhang B, Ben-Baruch G, Tan MC, et al.: Anti-mesothelin antibodies and circulating mesothelin relate to the clinical state in ovarian cancer patients. Cancer Epidemiol Biomarkers Prev 2008, 17: 1520–1526. 10.1158/1055-9965.EPI-08-0039PubMedCrossRef
36.
McIntosh MW, Drescher C, Karlan B, Scholler N, Urban N, Hellstrom KE, Hellstrom I: Combining CA 125 and SMR serum markers for diagnosis and early detection of ovarian carcinoma. Gynecol Oncol 2004, 95: 9–15. 10.1016/j.ygyno.2004.07.039PubMedCentralPubMedCrossRef
37.
Huang CY, Cheng WF, Lee CN, Su YN, Chien SC, Tzeng YL, Hsieh CY, Chen CA: Serum mesothelin in epithelial ovarian carcinoma: a new screening marker and prognostic factor. Anticancer Res 2006, 26: 4721–4728.PubMed
38.
39.
Hellstrom KE, Hellstrom I: Vaccines to treat cancer--an old approach whose time has arrived. J Cell Biochem 2007, 102: 291–300. 10.1002/jcb.21468PubMedCrossRef
40.
Bera TK, Pastan I: Mesothelin is not required for normal mouse development or reproduction. Mol Cell Biol 2000, 20: 2902–2906. 10.1128/MCB.20.8.2902-2906.2000PubMedCentralPubMedCrossRef
41.
Scholler N, Garvik B, Hayden-Ledbetter M, Kline T, Urban N: Development of a CA125-mesothelin cell adhesion assay as a screening tool for biologics discovery. Cancer Lett 2007, 247: 130–136. 10.1016/j.canlet.2006.03.029PubMedCentralPubMedCrossRef
42.
Rump A, Morikawa Y, Tanaka M, Minami S, Umesaki N, Takeuchi M, Miyajima A: Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion. J Biol Chem 2004, 279: 9190–9198. 10.1074/jbc.M312372200PubMedCrossRef
43.
Gubbels JA, Belisle J, Onda M, Rancourt C, Migneault M, Ho M, Bera TK, Connor J, Sathyanarayana BK, Lee B, et al.: Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors. Mol Cancer 2006, 5: 50. 10.1186/1476-4598-5-50PubMedCentralPubMedCrossRef
44.
McLemore MR, Aouizerat B: Introducing the MUC16 gene: implications for prevention and early detection in epithelial ovarian cancer. Biol Res Nurs 2005, 6: 262–267. 10.1177/1099800404274445PubMedCrossRef
45.
Goodman MT, Howe HL: Descriptive epidemiology of ovarian cancer in the United States, 1992–1997. Cancer 2003, 97: 2615–2630. 10.1002/cncr.11339PubMedCrossRef
46.
Goodman MT, Correa CN, Tung KH, Roffers SD, Cheng Wu X, Young JL, Wilkens LR, Carney ME, Howe HL: Stage at diagnosis of ovarian cancer in the United States, 1992–1997. Cancer 2003, 97: 2648–2659. 10.1002/cncr.11347PubMedCrossRef
47.
Lu KH, Yates MS, Mok SC: The monkey, the hen, and the mouse: models to advance ovarian cancer chemoprevention. Cancer Prev Res (Phila) 2009, 2: 773–775. 10.1158/1940-6207.CAPR-09-0156CrossRef
48.
Liu J, Yang G, Thompson-Lanza JA, Glassman A, Hayes K, Patterson A, Marquez RT, Auersperg N, Yu Y, Hahn WC, et al.: A genetically defined model for human ovarian cancer. Cancer Res 2004, 64: 1655–1663. 10.1158/0008-5472.CAN-03-3380PubMedCrossRef
49.
Stakleff KD, Von Gruenigen VE: Rodent models for ovarian cancer research. Int J Gynecol Cancer 2003, 13: 405–412. 10.1046/j.1525-1438.2003.13317.xPubMedCrossRef
50.
Dinulescu DM, Ince TA, Quade BJ, Shafer SA, Crowley D, Jacks T: Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med 2005, 11: 63–70. 10.1038/nm1173PubMedCrossRef
51.
Kojima T, Oh-eda M, Hattori K, Taniguchi Y, Tamura M, Ochi N, Yamaguchi N: Molecular cloning and expression of megakaryocyte potentiating factor cDNA. J Biol Chem 1995, 270: 21984–21990. 10.1074/jbc.270.37.21984PubMedCrossRef
52.
Hassan R, Kreitman RJ, Pastan I, Willingham MC: Localization of mesothelin in epithelial ovarian cancer. Appl Immunohistochem Mol Morphol 2005, 13: 243–247. 10.1097/01.pai.00000141545.36485.d6PubMedCrossRef
53.
Ordonez NG: Value of mesothelin immunostaining in the diagnosis of mesothelioma. Mod Pathol 2003, 16: 192–197. 10.1097/01.MP.0000056981.16578.C3PubMedCrossRef
Metadata
Title
The hen model of human ovarian cancer develops anti-mesothelin autoantibodies in response to mesothelin expressing tumors
Authors
Yi Yu
Seby L Edassery
Animesh Barua
Jacques S Abramowicz
Janice M Bahr
Ingegerd Hellstrom
Judith L Luborsky
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2011
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/1757-2215-4-12

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