Sage Journals: Discover world-class research

Abstract

Objective: Elevated serum haptoglobin (Hp) concentrations have been reported in patients with malignant diseases. We have shown that Hp is produced by and localizes only in the stroma and not the epithelium of endometriotic lesions, which share many characteristics of carcinoma. Furthermore, Hp mRNA and protein are found exclusively in the stroma of eutopic endometrium from women with endometriosis and not those without endometriosis. We hypothesized that characteristic patterns of Hp gene expression and protein localization in endometrioid adenocarcinoma of the uterus may provide insight into the clinical utility of Hp as a tumor marker or alternative therapeutic approach. Methods: Biopsies of endometrioid adenocarcinoma tumors of the uterus and their adjacent nonaffected endometrium were collected. Normal endometrium was collected from healthy women. Haptoglobin messenger RNA (mRNA) levels were quantified by quantitative polymerase chain reaction (Q-PCR). Haptoglobin protein cell-specific localization was identified by immunohistochemistry. Results: Haptoglobin mRNA levels were significantly greater (P < .005) in endometrioid adenocarcinoma and adjacent nonaffected endometrial tissues than normal endometrium. No correlation was found between Hp levels and cancer stage (P = .673) or grade (P = .739). Haptoglobin protein localized in both stromal and glandular epithelial cells of endometrioid adenocarcinoma and their adjacent nonaffected tissue but not in control endometrium. Conclusions: Our results have identified, for the first time, unique patterns of Hp mRNA expression and protein localization in the stromal and glandular epithelial cells of endometrioid adenocarcinoma of the uterus. We propose that this unique pattern of endometrioid adenocarcinoma Hp expression may be developed as a novel diagnostic marker. Modulation of Hp, with its immunomodulatory and angiogenic properties, may generate novel methods of prevention or treatment for endometrial cancer.

Keywords

Haptoglobin endometrioid adenocarcinoma endometrium tumor marker.

Get full access to this article

View all access options for this article.

References

Cancer Trends Progress Report (http://progressreport.cancer.gov), in 2004 dollars, based on methods described in Medical Care 2002 Aug; 40 (8 Suppl): IV-104-17.

Amant F. , Moerman P. , Neven P. , Timmerman D. , Van Limbergen E. , Vergote I. Endometrial cancer. Lancet. 2005; 366(9484):491-505.

Bokhman JV Two pathogenetic types of endometrial carcinoma. Gynecol Oncol . 1983;15(1):10-17.

Hecht JL , Mutter GL Molecular and pathologic aspects of endometrial carcinogenesis. J Clin Oncol. 2006;24(29): 4783-4791.

Cristofano AD , Ellenson LH Endometrial carcinoma. Annu Rev Pathol Mech Dis. 2007;2(2):57-85.

Fleming GF , Filiaci VL , Bentley RC , et al. Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study. Ann Oncol. 2004; 15(8):1173-1178.

Nori D. , Hilaris BS , Tome M. , Lewis JL Jr , Birnbaum S. , Fuks Z. Combined surgery and radiation in endometrial carcinoma: an analysis of prognostic factors. Int J Radiat Oncol Biol Phys. 1987;13(4):489-498.

Neale EJ , Wong WS , Arumanayagam M. , et al. The clinical significance of the serum haptoglobin concentration in patients with invasive cervical carcinoma. Aust N Z J Obstet Gynaecol. 1989;29(3 pt 1):197-199.

Tatra G. , Moesers C. Haptoglobin in gynecologic tumors [in German]. Strahlentherapie . 1978;154(5):323-327.

10.

Zhao C. , Annamalai L. , Guoy C. , et al. Circulating haptoglobin is an independent prognostic factor in the sera of patients with epithelial ovarian cancer. Neoplasia . 2007;9(1):1-7.

11.

Dowling P. , O’Driscoll L. , Meleady P. , et al. 2-D difference gel electrophoresis of the lung squamous cell carcinoma versus normal sera demonstrates consistent alterations in the levels of ten specific proteins. Electrophoresis. 2007;28(23): 4302-4310.

12.

Onizuka K. , Mihara K. , Tukino H. , Mizoguchi N. , Migita S. Studies on serum protein fractions of patients with breast cancer undergoing radiotherapy. Nippon Igaku Hoshasen Gakkai Zasshi . 1987;47(8):1064-1075.

13.

Sharpe KL , Vernon MW Polypeptides synthesized and released by rat ectopic uterine implants differ from those of the uterus in culture. Biol Reprod. 1993;48(6):1334-1340.

14.

Sharpe KL , Zimmer RL , Griffin WT , Penny LL Polypeptides synthesized and released by human endometriosis differ from those of the uterine endometrium in cell and tissue explant culture. Fertil Steril. 1993;60(5):839-851.

15.

Sharpe-Timms KL , Piva M. , Ricke EA , et al. Endometriotic lesions synthesize and secrete a haptoglobin-like protein. Biol Reprod. 1998;58(4):988-994.

16.

Piva M. , Sharpe-Timms KL Peritoneal endometriotic lesions differentially express a haptoglobin-like gene. Mol Hum Reprod. 1999;5(1):71-78.

17.

Sharpe-Timms KL , Zimmer RL , Ricke EA , et al. Endometriotic haptoglobin binds peritoneal macrophages and alters their function in endometriosis . Fertil Steril. 2002;78(4): 810-819.

18.

Piva M. , Horwitz G. , Sharpe-Timms KL Interleukin-6 differentially stimulates haptoglobin production by peritoneal and endometriotic cells in vitro: a model for endometrial-peritoneal interaction in endometriosis. J Clin Endocrinol Metab. 2001;86(6):2553-2561.

19.

Sharpe-Timms KL Haptoglobin expression by shed endometrial tissue fragments found in peritoneal fluid. Fertil Steril . 2005;84(1):22-30.

20.

Sharpe-Timms KL , Ricke EA , Piva M. , Horowitz GM Differential expression and localization of de-novo synthesized endometriotic haptoglobin in endometrium and endometriotic lesions. Hum Reprod. 2000;15(10):2180-2185.

21.

Livak KJ , Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T) method. Methods . 2001;25(4):402-408.

22.

Berkova N. , Lemay A. , Dresser DW , Fontaine JY , Kerizit J. , Goupil S. Haptoglobin is present in human endometrium and shows elevated levels in the decidua during pregnancy. Mol Hum Reprod. 2001;7(8):747-754.

23.

Piva MA , Moreno I. , Sharpe-Timms KL Glycosylation and over-expression of endometriosis-associated peritoneal haptoglobin . Glycoconj J. 2003;19(1):33-41.

24.

Dobryszycka W. Biological functions of haptoglobin-new pieces to an old puzzle. Eur J Clin Chem Clin Biochem. 1997;35(9):647-654.

25.

Langlois MR , Delanghe JR Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem. 1996;42(10):1589-1600.

26.

Cockerill GW , Gamble JR , Vadas MA Angiogenesis: models and modulators. Int Rev Cytol. 1995;159:113-160.

27.

Cid MC , Grant DS , Hoffman GS , Auerbach R. , Fauci AS , Kleinman HK Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculitis. J Clin Invest. 1993 ;91(3):977-985.

28.

Smeets MB , Pasterkamp G. , Lim SK , Velema E. , van Middelaar B. , de Kleijn DP Nitric oxide synthesis is involved in arterial haptoglobin expression after sustained flow changes. FEBS Lett. 2002 ;529(2-3):221-224.

29.

de Kleijn DPV , Smeets MB , Kemmeren Ppcw , et al. Acute-phase protein haptoglobin is a cell migration factor involved in arterial restructuring . FASEB J. 2002;16(9):1123-1125.

30.

Oh S. , Very D. , Walker J. , Raam S. , Ju ST An analogy between fetal haptoglobin and a potent immunosuppressant in cancer . Cancer Res. 1987;47(19):5120-5126.

31.

Samak R. , Edelstein R. , Israel L. Immunosuppressive effect of acute-phase reactant proteins in vitro and its relevance to cancer. Cancer Immunol Immunother. 1982;13(1):38-43.

32.

Turner GA Haptoglobin. A potential reporter molecule for glycosylation changes in disease . Adv Exp Med Biol. 1995; 376:231-238.

33.

Ye B. , Cramer DW , Skates SJ , et al. Haptoglobin-α subunit as potential serum biomarker in ovarian cancer: identification and characterization using proteomic profiling and mass spectrometry. Clin Cancer Res. 2003;9(8):2904-2911.

34.

Saldova R. , Royle L. , Radcliffe CM , et al. Ovarian cancer is associated with changes in glycosylation in both acute-phase proteins and IgG. Glycobiology. 2007;17(12):1344-1356.

35.

Thompson S. , Turner GA Elevated levels of abnormally-fucosylated haptoglobin in cancer sera. Br J Cancer. 1987 ; 56(5):605-610.

36.

Thompson S. , Cantwell BM , Cornell C. , Turner GA Abnormally-fucosylated haptoglobin: a cancer marker for tumor burden but not gross liver metastasis . Br J Cancer. 1991;64(2):386-390.

37.

Jayanthi M. , Habibullah CM , Ishaq M. , Ali H. , Babu PS , Ali MM Distribution of haptoglobin phenotypes in esophageal and gastric cancer. J Med Genet. 1989; 26(3):172-173.

38.

Dobryszycka W. , Warwas M. Haptoglobin types in ovarian tumors . Neoplasma. 1983;30(2):169-172.

Haptoglobin Expression in Endometrioid Adenocarcinoma of the Uterus

Abstract

Keywords

Get full access to this article

References