Skip to main content

The Role of Human Chorionic Gonadotropin as Tumor Marker: Biochemical and Clinical Aspects

  • Chapter
Advances in Cancer Biomarkers

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 867))

Abstract

Tumor markers are biological substances that are produced/released mainly by malignant tumor cells, enter the circulation in detectable amounts and are potential indicators of the presence of a tumor. The most useful biochemical markers are the tumor-specific molecules, i.e., receptors, enzymes, hormones, growth factors or biological response modifiers that are specifically produced by tumor cells and not, or minimally, by the normal counterpart (Richard et al. Principles and practice of gynecologic oncology. Wolters Kluwer Health, Philadelphia, 2009). Based on their specificity and sensitivity in each malignancy, biomarkers are used for screening, diagnosis, disease monitoring and therapeutic response assessment in clinical management of cancer patients.

This chapter is focused on human chorionic gonadotropin (hCG), a hormone with a variety of functions and widely used as a tumor biomarker in selected tumors. Indeed, hCG is expressed by both trophoblastic and non-trophoblastic human malignancies and plays a role in cell transformation, angiogenesis, metastatization, and immune escape, all process central to cancer progression. Of note, hCG testing is crucial for the clinical management of placental trophoblastic malignancies and germ cell tumors of the testis and the ovary. Furthermore, the production of hCG by tumor cells is accompanied by varying degrees of release of the free subunits into the circulation, and this is relevant for the management of cancer patients (Triozzi PL, Stevens VC, Oncol Rep 6(1):7–17, 1999).

The name chorionic gonadotropin was conceived: chorion derives from the latin chordate meaning afterbirth, gonadotropin indicates that the hormone is a gonadotropic molecule, acting on the ovaries and promoting steroid production (Cole LA, Int J Endocrinol Metab 9(2):335–352, 2011). The function, the mechanism of action and the interaction between hCG and its receptor continue to be the subject of intensive investigation, even though many issues about hCG have been well documented (Tegoni M et al., J Mol Biol 289(5):1375–1385, 1999).

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

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
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 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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

Similar content being viewed by others

Abbreviations

hCGβcf :

Core fragment of hCGβ

References

  1. Bahl OP, Carlsen RB, Bellisario R, Swaminathan N (1972) Human chorionic gonadotropin: amino acid sequence of the alpha and beta subunits. Biochem Biophys Res Commun 48(2):416–422

    Article  CAS  PubMed  Google Scholar 

  2. Banerjee P, Fazleabas AT (2011) Extragonadal actions of chorionic gonadotropin. Rev Endocr Metab Disord 12(4):323–332

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Pierce JG, Parsons TF (1981) Glycoprotein hormones: structure and function. Annu Rev Biochem 50:465–495

    Article  CAS  PubMed  Google Scholar 

  4. McFarland KC, Sprengel R, Phillips HS, Köhler M, Rosemblit N, Nikolics K, Segaloff DL, Seeburg PH (1989) Lutropin-horiogonadotropin receptor: an unusual member of the G protein-coupled receptor family. Science 245(4917):494–499

    Article  CAS  PubMed  Google Scholar 

  5. Minegishi T, Nakamura K, Takakura Y, Miyamoto K, Hasegawa Y, Ibuki Y, Igarashi M, Minegish T (1990) Cloning and sequencing of human LH/hCG receptor cDNA corrected to Minegishi T. Biochem Biophys Res Commun 172(3):1049–1054

    Article  CAS  PubMed  Google Scholar 

  6. Handschuh K, Guibourdenche J, Tsatsaris V, Guesnon M, Laurendeau I, Evain-Brion D et al (2007) Human chorionic gonadotropin expression in human trophoblasts from early placenta: comparative study between villous and extravillous trophoblastic cells. Placenta 28(2–3):175–184

    Article  CAS  PubMed  Google Scholar 

  7. Cole LA (2010) Structures of free a-subunit and free b-subunit. In: Cole LA (ed) Human chorionic gonadotropin (hCG). Elsevier, Oxford

    Google Scholar 

  8. Handschuh K, Guibourdenche J, Tsatsaris V, Guesnon M, Laurendeau I, Evain-Brion D, Fournier T (2007) Human chorionic gonadotropin produced by the invasive trophoblast but not the villous trophoblast promotes cell invasion and is down-regulated by peroxisome proliferator-activated receptor-a. Endocrinology 148:5011–5019

    Article  CAS  PubMed  Google Scholar 

  9. Morgan FJ, Birken S, Canfield RE (1975) The amino acid sequence of human chorionic gonadotropin. The alpha subunit and beta subunit. J Biol Chem 250(13):5247–5258

    CAS  PubMed  Google Scholar 

  10. Elliott MM, Kardana A, Lustbader JW, Cole LA (1997) Carbohydrate and peptide structure of the alphaand beta-subunits of human chorionic gonadotropin from normal and aberrant pregnancy and choriocarcinoma. Endocrine 7(1):15–32

    Article  CAS  PubMed  Google Scholar 

  11. Wu H, Lustbader JW, Liu Y, Canfield RE, Hendrickson WA (1994) Structure of human chorionic gonadotropin at 2.6 å resolution from MAD analysis of the selenomethionyl protein. Structure 2:545–558

    Article  CAS  PubMed  Google Scholar 

  12. Aschner B (1912) Ueber die function der hypophyse. Pflugers Arch Gesamte Physiol 146:1–147

    Article  Google Scholar 

  13. Aschheim S, Zondek B (1927) Das Hormon des hypophysenvorderlappens: testobjekt zum Nachweis des hormons. Klin Wochenschr 6:248–252

    Article  Google Scholar 

  14. Rao CV, Griffin LP, Carman FR Jr (1977) Prostaglandin F2 alpha binding sites in human corpora lutea. J Clin Endocrinol Metab 44:1032–1037

    Article  CAS  PubMed  Google Scholar 

  15. Rao CV (1979) Differential properties of human chorionic gonadotropin and human luteinizing hormone binding to plasma membranes of bovine corpora luteal. Acta Endocrinol 90:696–710

    CAS  PubMed  Google Scholar 

  16. Cole LA (2010) Biological functions of hCG and hCG-related molecules. Reprod Biol Endocrinol 8:102

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Toth P, Lukacs H, Gimes G, Sebestyen A, Pasztor N, Paulin F, Rao CV (2001) Clinical importance of vascular hCG/LH receptors – a review. Reprod Biol 1:5–11

    CAS  PubMed  Google Scholar 

  18. Berndt S, Blacher S, d’Hauterive PS, Thiry M, Tsampalas M, Cruz A, Pequeux C, Lorquet S, Munaut C, Noel A, Foidart JM (2009) Chorionic gonadotropin stimulation of angiogenesis and pericyte recruitment. J Clin Endocrinol Metab 94:4567–4574

    Article  CAS  PubMed  Google Scholar 

  19. Licht P, Russu V, Wildt L (2001) On the role of human chorionic gonadotropin (hCG) in the embryo-endometrial microenvironment: implications for differentiation and implantation. Semin Reprod Med 19:37–47

    Article  CAS  PubMed  Google Scholar 

  20. Carmichael DN, Morgan NG, Scarpello JHB (1994) Human chorionic-gonadotropin stimulates the growth of retinal vascular cells. Diabetologia 38:A275

    Google Scholar 

  21. Dukic-Stefanovic S, Walther J, Wosch S, Zimmermann G, Wiedemann P, Alexander H, Claudepierre T (2012) Chorionic gonadotropin and its receptor are both expressed in human retina, possible implications in normal and pathological conditions. PLoS One 7(12), e52567

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Akoum A, Metz CN, Morin M (2005) Marked increase in macrophage migration inhibitory factor synthesis and secretion in human endometrial cells in response to human chorionic gonadotropin hormone. J Clin Endocrinol Metab 90:2904–2910

    Article  CAS  PubMed  Google Scholar 

  23. Wan H, Marjan A, Cheung VW, Leenen PJM, Khan NA, Benner R, Kiekens RCM (2007) Chorionic gonadotropin can enhance innate immunity by stimulating macrophage function. J Leukoc Biol 82:926–933

    Article  CAS  PubMed  Google Scholar 

  24. Cole LA, Dai D, Butler SA, Leslie KK, Kohorn EI (2006) Gestational trophoblastic diseases: 1. Pathophysiology of hyperglycosylated hCG-regulated neoplasia. Gynecol Oncol 102:144–149

    Google Scholar 

  25. Sasaki Y, Ladner DG, Cole LA (2008) Hyperglycosylated hCG the source of pregnancy failures. Fertil Steril 89:1781–1786

    Article  CAS  PubMed  Google Scholar 

  26. Cole LA, Butler SA, Khanlian SA, Giddings A, Muller CY, Seckl MJ et al (2006) Gestational trophoblastic diseases: 2.Hyperglycosylated hCG as a reliable marker of active neoplasia. Gynecol Oncol 102:150–158

    Google Scholar 

  27. Lei ZM, Taylor DD, Gercel-Taylor C, Rao CV (1999) Human chorionic gonadotropin promotes tumorigenesis of choriocarcinoma JAR cells. Troph Res 13:147–159

    CAS  Google Scholar 

  28. Hamade AL, Nakabayashi K, Sato A, Kiyoshi K, Takamatsu Y, Laoag-Fernandez JB, Ohara N, Maruo T (2005) Transfection of antisense chorionic gonadotropin β gene into choriocarcinoma cells suppresses the cell proliferation and induces apoptosis. J Clin Endocrinol Metab 90:4873–4879

    Article  CAS  Google Scholar 

  29. Cole LA, Perini F, Birken S, Ruddon RW (1984) An oligosaccharide of the O-linked type distinguishes the free from the combined form of hCG alpha-subunit. Biochem Biophys Res Commun 122:1260–1267

    Article  CAS  PubMed  Google Scholar 

  30. Khoo NK, Bechberger JF, Shepherd T, Bond SL, McCrae KR, Hamilton GS, Lala PK (1998) SV40 Tag transformation of the normal invasive trophoblast results in a premalignant phenotype I Mechanisms responsible for hyperinvasiveness and resistance to anti-invasive action of TGFβ. Intl J Cancer 77:429–439

    Article  CAS  Google Scholar 

  31. Butler SA, Ikram MS, Mathieu S, Iles RK (2000) The increase in bladder carcinoma cell population induced by the free beta subunit of hCG is a result of an anti-apoptosis effect and not cell proliferation. Br J Cancer 82:1553–1556

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Staun-Ram E, Shaleu E (2005) Human trophoblast function during implantation process. Reprod Biol Endocrinol 3:56

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Butler SA, Staite EM, Iles RK (2003) Reduction of bladder cancer cell growth in response to hCG beta CTP37 vaccinated mouse serum. Oncol Res 14:93–100

    CAS  PubMed  Google Scholar 

  34. Hoshina M, Boime I, Mochizuki M (1984) Cytological localization of hPL, hCG, and mRNA in chorionic tissue using in situ hybridization. Acta Obstet Gynaecol Jpn 36:397–404

    CAS  Google Scholar 

  35. Butler SA, Iles RK (2003) Ectopic human chorionic gonadotrophin β secretion by epithelial tumors and human chorionic gonadotrophin β-induced apoptosis in Karposi’s sarcoma is there a connection? Clin Cancer Res 9:4666–4673

    CAS  PubMed  Google Scholar 

  36. Iles RK (2007) Ectopic hCGβ expression by epithelial cancer: malignant behavior metastasis and inhibition of tumor cell apoptosis. Mol Cell Endocrinol 260:264–270

    Article  PubMed  CAS  Google Scholar 

  37. Carter WB, Sekharem M, Coppola D (2006) Human chorionic gonadotropin induces apoptosis in breast cancer. Breast Cancer Res Treat 100:S243–S244

    Google Scholar 

  38. Li D, Wen X, Ghali L, Al-Shalabi FM, Docherty SM, Purkis P, Iles RK (2008) hCGβ expression by cervical squamous carcinoma – in vivo histological association with tumor invasion and apoptosis. Histopathology 53:147–155

    Article  CAS  PubMed  Google Scholar 

  39. Moulton HM, Yoshihara PH, Mason DH, Iversen PL, Triozzi PL (2002) Active specific immunotherapy with b-human chorionic gonadotropin peptide vaccine in patients with metastatic colorectal cancer: antibody response is associated with improved survival. Clin Cancer Res 8:2044–2051

    CAS  PubMed  Google Scholar 

  40. Iversen PL, Mourich DV, Moulton HM (2003) Monoclonal antibodies to two epitopes of b-human chorionic gonadotropin for the treatment of cancer. Curr Opin Mol Ther 5:156–160

    CAS  PubMed  Google Scholar 

  41. Delves PJ, Roitt IM (2005) Vaccines for the control of reproduction–status in mammals and aspects of comparative interest. Dev Biol 121:265–273

    CAS  Google Scholar 

  42. Delves PJ, Iles RK, Roitt IM, Lund T (2007) Designing a new generation of antihCG vaccines for cancer therapy. Mol Cell Endocrinol 260:276–281

    Article  PubMed  CAS  Google Scholar 

  43. Guan QD, Wang Y, Chu YW, Wang LX, Ni J, Guo Q, Xiong SD (2007) The distinct effects of three tandem repeats of C3d in the immune responses against tumor-associated antigen hCGbeta by DNA immunization. Cancer Immunol Immunother 56:875–884

    Article  CAS  PubMed  Google Scholar 

  44. Stenman U-H, Alfthan H, Hotakainen K (2004) Human chorionic gonadotropin in cancer. Clin Biochem 37:549–561

    Article  CAS  PubMed  Google Scholar 

  45. Bagshawe KD (1992) Choriocarcinoma. A model for tumor markers. Acta Oncol 31:99–106

    Article  CAS  PubMed  Google Scholar 

  46. Fisher RA (1993) Newlands ES. Rapid diagnosis and classification of hydatidiform moles with polymerase chain reaction. Am J Obstet Gynecol 168:563–569

    Article  CAS  PubMed  Google Scholar 

  47. Szulman AE, Surti U (1982) The syndromes of hydatidiform mole: I. Cytogenetic and morphologic correlations. Am J Obstet Gynecol 131:665

    Google Scholar 

  48. Cole LA, Khanlian SA, Riley JM, Butler SA (2006) Hyperglycosylated hCG (hCG-H) in gestational implantation, and in choriocarcinoma and testicular germ cell malignancy tumorigenesis. J Reprod Med 51:919–929

    CAS  PubMed  Google Scholar 

  49. Cole LA, Butler SA (2008) Hyperglycosylated hCG and its free β-subunit, tumor markers and tumor promoters: a review. J Reprod Med 53:499–510

    CAS  PubMed  Google Scholar 

  50. Vartiainen J, Alfthan H, Lehtovirta P, Stenman U-H (1998) Identification of choriocarcinoma by the hCG beta-to-hCG proportion in patients with delayed diagnosis caused by contraceptive use. Contraception 57:257–260

    Article  CAS  PubMed  Google Scholar 

  51. Korhonen J, Alfthan H, Ylostalo P, Veldhuis J, Stenman U-H (1997) Disappearance of human chorionic gonadotropin and its alpha- and beta-subunits after term pregnancy. Clin Chem 43:2155–2163

    CAS  PubMed  Google Scholar 

  52. Yedema KA, Verheijen RH, Kenemans P, Schijf CP, Borm GF, Segers MF et al (1993) Identification of patients with persistent trophoblastic disease by means of a normal human chorionic gonadotropin regression curve. Am J Obstet Gynecol 168:787–792

    Article  CAS  PubMed  Google Scholar 

  53. Matsui H, Iitsuka Y, Yamazawa K, Tanaka N, Mitsuhashi A, Seki K et al (2003) Criteria for initiating chemotherapy in patients after evacuation of hydatidiform mole. Tumour Biol 24:140–146

    Article  PubMed  Google Scholar 

  54. Feltmate CM, Genest DR, Goldstein DP, Berkowitz RS (2002) Advances in the understanding of placental site trophoblastic tumor. J Reprod Med 47:337–341

    PubMed  Google Scholar 

  55. Papadopoulos AJ, Foskett M, Seckl MJ, McNeish I, Paradinas FJ, Rees H et al (2002) Twenty-five years’ clinical experience with placental site trophoblastic tumors. J Reprod Med 47:460–464

    PubMed  Google Scholar 

  56. Talerman A (1985) Germ cell tumours. Ann Pathol 5:145–157

    CAS  PubMed  Google Scholar 

  57. Mayordomo JI, Paz-Ares L, Rivera F, Lopez-Brea M, Lopez Martin E, Mendiola C et al (1994) Ovarian and extragonadal malignant germ-cell tumors in females: a single-institution experience with 43 patients. Ann Oncol 5:225–231

    CAS  PubMed  Google Scholar 

  58. Bosl GJ, Motzer RJ (1997) Testicular germ-cell cancer. N Engl J Med 337:242–253

    Article  CAS  PubMed  Google Scholar 

  59. Mostofi FK, Sesterhenn IA, Davis CJ Jr (1988) Developments in histopathology of testicular germ cell tumors. Semin Urol 6:171–188

    CAS  PubMed  Google Scholar 

  60. Ruther U, Rothe B, Grunert K, Bader H, Sessler R, Nunnensiek C et al (1994) Role of human chorionic gonadotropin in patients with pure seminoma. Eur Urol 26:129–133

    CAS  PubMed  Google Scholar 

  61. Mann K, Saller B, Hoermann R (1993) Clinical use of HCG and hCG beta determinations. Scand J Clin Lab Invest Suppl 216:97–104

    Article  CAS  PubMed  Google Scholar 

  62. Saller B, Clara R, Spottl G, Siddle K, Mann K (1990) Testicular cancer secretes intact human choriogonadotropin (hCG) and its free betasubunit: evidence that hCG (+hCG-beta) assays are the most reliable in diagnosis and follow-up. Clin Chem 36:234–239

    CAS  PubMed  Google Scholar 

  63. Braunstein GD (1979) Use of chorionic gonadotropin as a tumor marker in cancer. In: Herberman RB, McIntire KR (eds) Immunodiagnosis of cancer. Marcel Dekker Inc, New York, pp 383–409

    Google Scholar 

  64. Zalel Y, Piura B, Elchalal U, Czernobilsky B, Antebi S, Dgani R (1996) Diagnosis and management of malignant germ cell ovarian tumors in young females. Int J Gynaecol Obstet 55:1–10

    Article  CAS  PubMed  Google Scholar 

  65. Harms D, Janig U (1986) Germ cell tumours of childhood. Report of 170 cases including 59 pure and partial yolk-sac tumours. Virchows Arch A Pathol Anat Histopathol 409:223–239

    Article  CAS  PubMed  Google Scholar 

  66. Kurman RJ, Norris HJ (1976) Embryonal carcinoma of the ovary: a clinicopathologic entity distinct from endodermal sinus tumor resembling embryonal carcinoma of the adult testis. Cancer 38:2420–2433

    Article  CAS  PubMed  Google Scholar 

  67. Roger M, Chaussain JL, Blacker C, Feinstein MC (1984) Tumors secreting choriogonadotropin in children. Ann Med Intern (Paris) 135:381–384

    CAS  Google Scholar 

  68. Stenman U-H, Alfthan H (2002) Markers for testicular cancer. In: Diamandis E, Fritsche H, Lilja H, Chan D, Schwartz M (eds) Tumor markers. Physiology, pathobiology, technology, and clinical applications. AACC Press, Washington, DC, pp 351–359

    Google Scholar 

  69. Sobin L, Wittekind C (1997) TNM classification of malignant tumors, 5th edn. Wiley-Liss, New York

    Google Scholar 

  70. Sturgeon CM, Duffy MJ, Stenman UH et al (2008) National academy of clinical biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem 54(12):e11–e79

    Article  CAS  PubMed  Google Scholar 

  71. Vogelzang NJ (1987) Prognostic factors in metastatic testicular cancer. Int J Androl 10:225–237

    Article  CAS  PubMed  Google Scholar 

  72. Mead GM, Stenning SP (1993) Prognostic factors in metastatic non-seminomatous germ cell tumours: the medical research council studies. Eur Urol 23:196–200

    CAS  PubMed  Google Scholar 

  73. Kohn J (1978) The dynamics of serum alpha-fetoprotein in the course of testicular teratoma. Scand J Immunol 8(Suppl 8):103

    Article  Google Scholar 

  74. Lange PH, Vogelzang NJ, Goldman A, Kennedy BJ, Fraley EE (1982) Marker half-life analysis as a prognostic tool in testicular cancer. J Urol 128:708–711

    CAS  PubMed  Google Scholar 

  75. Pierotti MA, van Harten W, Licitra L, Lombardo C (2011) European options and recommendations for cancer diagnosis and therapy, 1st edn. Organisation of European Cancer Institutes European Economic Interest Grouping Publisher, OECI-EEIG Reg. , Brussels

    Google Scholar 

  76. Mazumdar M, Bajorin DF, Bacik J, Higgins G, Motzer RJ, Bosl GJ (2001) Predicting outcome to chemotherapy in patients with germ cell tumors: the value of the rate of decline of human chorionic gonadotrophin and alpha-fetoprotein during therapy. J Clin Oncol 19:2534–2541

    CAS  PubMed  Google Scholar 

  77. Coogan CL, Foster RS, Rowland RG, Bihrle R, Smith ER Jr, Einhorn LH et al (1997) Postchemotherapy retroperitoneal lymph node dissection is effective therapy in selected patients with elevated tumor markers after primary chemotherapy alone. Urology 50:957–962

    Article  CAS  PubMed  Google Scholar 

  78. Toner G (1990) Serum tumor-marker half-life during chemotherapy allows early prediction of complete response and survival in nonseminomatous germ cell tumors. Cancer Res 50:5904–5910

    CAS  PubMed  Google Scholar 

  79. Czaja JT, Ulbright TM (1992) Evidence for the transformation of seminoma to yolk sac tumor, with histogenetic considerations. Am J Clin Pathol 97:468–477

    CAS  PubMed  Google Scholar 

  80. Banfi G, Casari E, Murone M, Bonini P (1990) La coriogonadotropina umana. Medical systems S.P.A

    Google Scholar 

  81. Alfthan H, Haglund C, Dabek J, Stenman U-H (1992) Concentrations of human chorionic gonadotropin, its h-subunit and the core fragment of the h-subunit in serum and urine of men and nonpregnant women. Clin Chem 38:1981–1987

    CAS  PubMed  Google Scholar 

  82. Alfthan H, Haglund C, Roberts P, Stenman U-H (1992) Elevation of free h-subunit of human choriogonadotropin and core h fragment of human choriogonadotropin in the serum and urine of patients with malignant pancreatic and biliary disease. Cancer Res 52:4628–4633

    CAS  PubMed  Google Scholar 

  83. Marcillac I, Troalen F, Bidart JM, Ghillani P, Ribrag V, Escudier B et al (1992) Free human chorionic gonadotropin beta subunit in gonadal and nongonadal neoplasms. Cancer Res 52:3901–3907

    CAS  PubMed  Google Scholar 

  84. Braunstein GD, Vaitukaitis JL, Carbone PP, Ross GT (1973) Ectopic production of human chorionic gonadotrophin by neoplasms. Ann Intern Med 78:39–45

    Article  CAS  PubMed  Google Scholar 

  85. Lazar V, Diez SG, Laurent A, Giovangrandi Y, Radvanyi F, Chopin D et al (1995) Expression of human chorionic gonadotropin beta subunit genes in superficial and invasive bladder carcinomas. Cancer Res 55:3735–3738

    CAS  PubMed  Google Scholar 

  86. Crawford RA, Iles RK, Carter PG, Caldwell CJ, Shepherd JH, Chard T (1998) The prognostic significance of beta human chorionic gonadotrophin and its metabolites in women with cervical carcinoma. J Clin Pathol 51:685–688

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Hotakainen K, Ljungberg B, Paju A, Rasmuson T, Alfthan H, Stenman UH (2002) The free beta-subunit of human chorionic gonadotropin as a prognostic factor in renal cell carcinoma. Br J Cancer 86:185–189

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Iles RK, Chard T (1989) Immunochemical analysis of the human chorionic gonadotrophin-like material secreted by ‘normal’ and neoplastic urothelial cells. J Mol Endocrinol 2:107–112

    Article  CAS  PubMed  Google Scholar 

  89. Fukutani K, Libby JM, Panko WB, Scardino PT (1983) Human chorionic gonadotropin detected in urinary concentrates from patients with malignant tumors of the testis, prostate, bladder, ureter and kidney. J Urol 129:74–77

    CAS  PubMed  Google Scholar 

  90. Kuida CA, Braunstein GD, Shintaku P, Said JW (1988) Human chorionic gonadotropin expression in lung, breast, and renal carcinomas. Arch Pathol Lab Med 112:282–285

    CAS  PubMed  Google Scholar 

  91. Hotakainen K, Haglund C, Paju A, Nordling S, Alfthan H, Rintala E et al (2002) Chorionic gonadotropin beta-subunit and core fragment in bladder cancer: mRNA and protein expression in urine, serum and tissue. Eur Urol 41:677–685

    Article  CAS  PubMed  Google Scholar 

  92. Hotakainen K, Ljungberg B, Haglund C, Nordling S, Paju A, Stenman UH (2003) Expression of the free beta-subunit of human chorionic gonadotropin in renal cell carcinoma: prognostic study on tissue and serum. Int J Cancer 104:631–635

    Article  CAS  PubMed  Google Scholar 

  93. Purnell DM, Heatfield BM, Trump BF (1984) Immunocytochemical evaluation of human prostatic carcinomas for carcinoembryonic antigen, nonspecific cross-reacting antigen, beta- chorionic gonadotrophin, and prostate-specific antigen. Cancer Res 44:285–292

    CAS  PubMed  Google Scholar 

  94. Span PN, Thomas CM, Heuvel JJ, Bosch RR, Schalken JA, vd Locht L et al (2002) Analysis of expression of chorionic gonadotrophin transcripts in prostate cancer by quantitative Taqman and a modified molecular beacon RT-PCR. J Endocrinol 172:489–495

    Article  CAS  PubMed  Google Scholar 

  95. Papapetrou PD, Sakarelou NP, Braouzi H, Fessas P (1980) Ectopic production of human chorionic gonadotropin (hCG) by neoplasms: the value of measurements of immunoreactive hCG in the urine as a screening procedure. Cancer 45:2583–2592

    Article  CAS  PubMed  Google Scholar 

  96. Birken S, Agosto G, Amr S, Nisula B, Cole L, Lewis J et al (1988) Characterization of antisera distinguishing carbohydrate structures in the beta-carboxyl-terminal region of human chorionic gonadotropin. Endocrinology 122:2054–2063

    Article  CAS  PubMed  Google Scholar 

  97. Louhimo J, Carpelan-Holmstrom M, Alfthan H, Stenman U-H, Jarvinen HJ, Haglund C (2002) Serum HCG beta, CA 72-4 and CEA are independent prognostic factors in colorectal cancer. Int J Cancer 101:545–548

    Article  PubMed  CAS  Google Scholar 

  98. Louhimo J, Finne P, Alfthan H, Stenman U-H, Haglund C (2002) Combination of hCGb, CA 19-9 and CEA with logistic regression improves accuracy in gastrointestinal malignancies. Anticancer Res 22:1759–1764

    CAS  PubMed  Google Scholar 

  99. Carpelan-Holmström M, Haglund C, Lundin J, Alfthan H, Stenman U-H, Roberts P (1996) Independent prognostic value of preoperative serum markers CA 242, specific tissue polypeptide antigen and human chorionic gonadotrophin beta, but not of carcinoembryonic antigen or tissue polypeptide antigen in colorectal cancer. Br J Cancer 74:925–929

    Article  PubMed Central  PubMed  Google Scholar 

  100. Lundin M, Nordling S, Lundin J, Alfthan H, Stenman UH, Haglund C (2001) Tissue expression of human chorionic gonadotropin beta predicts outcome in colorectal cancer: a comparison with serum expression. Int J Cancer 95:18–22

    Article  CAS  PubMed  Google Scholar 

  101. Webb A, Scott-Mackie P, Cunningham D, Norman A, Andreyev J, O’Brien M et al (1995) The prognostic value of CEA, beta HCG, AFP, CA125, CA19-9 and C-erb B-2, beta HCG immunohistochemistry in advanced colorectal cancer. Ann Oncol 6:581–587

    CAS  PubMed  Google Scholar 

  102. Louhimo J, Kokkola A, Alfthan H, Stenman UH, Haglund C (2004) Preoperative hCGbeta and CA 72-4 are independent prognostic factors in gastric cancer. Int J Cancer 111(6):929–933

    Article  CAS  PubMed  Google Scholar 

  103. Yamaguchi A, Ishida T, Nishimura G, Kumaki T, Katoh M, Kosaka T, Yonemura Y, Miyazaki I (1989) Human chorionic gonadotropin in colorectal cancer and its relationship to prognosis. Br J Cancer 60(3):382–384

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Zseli J, Csillag J, Tulassay Z, Tarjan G, Moksony I (1984) Gonadotropinsecreting liver cancer in ulcerative colitis. Wien Klin Wochenschr 96:5–8

    CAS  PubMed  Google Scholar 

  105. Louhimo J, Nordling S, Alfthan H, von Boguslawski K, Stenman U-H, Haglund C (2001) Specific staining of hCGh in benign and malignant gastrointestinal tissue with monoclonal antibodies. Histopathology 38:418–424

    Article  CAS  PubMed  Google Scholar 

  106. Kahn CR, Rosen SW, Weintraub BD, Fajans SS, Gorden P (1977) Ectopic production of chorionic gonadotropin and its subunits by islet-cell tumors. A specific marker for malignancy. N Engl J Med 297:565–569

    Article  CAS  PubMed  Google Scholar 

  107. Oberg K, Wide L (1981) hCG and hCG subunits as tumour markers in patients with endocrine pancreatic tumours and carcinoids. Acta Endocrinol (Copenh) 98:256–260

    CAS  Google Scholar 

  108. Grossmann M, Trautmann ME, Poertl S, Hoermann R, Berger P, Arnold R et al (1994) Alpha-subunit and human chorionic gonadotropinbeta immunoreactivity in patients with malignant endocrine gastroenteropancreatic tumours. Eur J Clin Invest 24:131–136

    Article  CAS  PubMed  Google Scholar 

  109. Ridgway EC, Klibanski A, Ladenson PW, Clemmons D, Beitins IZ, McArthur JW et al (1981) Pure alpha-secreting pituitary adenomas. N Engl J Med 304:1254–1259

    Article  CAS  PubMed  Google Scholar 

  110. Oppenheim DS, Kana AR, Sangha JS, Klibanski A (1990) Prevalence of alpha-subunit hypersecretion in patients with pituitary tumors: clinically nonfunctioning and somatotroph adenomas. J Clin Endocrinol Metab 70:859–864

    Article  CAS  PubMed  Google Scholar 

  111. Tachibana O, Yamashima T, Yamashita J, Takabatake Y (1994) Immunohistochemical expression of human chorionic gonadotropin and pglycoprotein in human pituitary glands and craniopharyngiomas. J Neurosurg 80:79–84

    Article  CAS  PubMed  Google Scholar 

  112. Bepler G, Jaques G, Oie HK, Gazdar AF (1991) Human chorionic gonadotropin and related glycoprotein hormones in lung cancer cell lines. Cancer Lett 58(1-2):145–150

    Article  CAS  PubMed  Google Scholar 

  113. Yoshimura M, Nishimura R, Murotani A, Miyamoto Y, Nakagawa T, Hasegawa K et al (1994) Assessment of urinary beta-core fragment of human chorionic gonadotropin as a new tumor marker of lung cancer. Cancer 73:2745–2752

    Article  CAS  PubMed  Google Scholar 

  114. Wilson TS, McDowell EM, McIntire KR, Trump BF (1981) Elaboration of human chorionic gonadotropin by lung tumors: an immunocytochemical study. Arch Pathol Lab Med 105:169–173

    CAS  PubMed  Google Scholar 

  115. Slodkowska J, Szturmowicz M, Rudzinski P, Giedronowicz D, Sakowicz A, Androsiuk W et al (1998) Expression of CEA and trophoblastic cell markers by lung carcinoma in association with histological characteristics and serum marker levels. Eur J Cancer Prev 7:51–60

    CAS  PubMed  Google Scholar 

  116. Szturmowicz M, Wiatr E, Sakowicz A, Slodkowska J, Roszkowski K, Filipecki S et al (1995) The role of human chorionic gonadotropin beta subunit elevation in small-cell lung cancer patients. J Cancer Res Clin Oncol 121:309–312

    Article  CAS  PubMed  Google Scholar 

  117. Szturmowicz M, Slodkowska J, Zych J, Rudzinski P, Sakowicz A, Rowinska-Zakrzewska E (1999) Frequency and clinical significance of beta- subunit human chorionic gonadotropin expression in non-small cell lung cancer patients. Tumour Biol 20:99–104

    Article  CAS  PubMed  Google Scholar 

  118. Bieche I, Lazar V, Nogues C, Poynard T, Giovangrandi Y, Bellet D et al (1998) Prognostic value of chorionic gonadotropin beta gene transcripts in human breast carcinoma. Clin Cancer Res 4:671–676

    CAS  PubMed  Google Scholar 

  119. Span PN, Manders P, Heuvel JJ, Thomas CM, Bosch RR, Beex LV et al (2003) Molecular beacon reverse transcription-PCR of human chorionic gonadotropin-beta-3,-5, and-8 mRNAs has prognostic value in breast cancer. Clin Chem 49:1074–1080

    Article  CAS  PubMed  Google Scholar 

  120. Tormey DC, Waalkes TP, Simon RM (1977) Biological markers in breast carcinoma: II. Clinical correlations with human chorionic gonadotrophin. Cancer 39:2391–2396

    Article  CAS  PubMed  Google Scholar 

  121. Castro A, Buschbaum P, Nadji M, Voigt W, Tabei S, Morales A (1979) Ectopic human chorionic gonadotropin in breast carcinoma. Experientia 35:1392–1393

    Article  CAS  PubMed  Google Scholar 

  122. Caffier H, Brandau H (1983) Serum tumor markers in metastatic breast cancer and course of disease. Cancer Detect Prev 6:451–457

    CAS  PubMed  Google Scholar 

  123. Borkowski A, Puttaert V, Gyling M, Muquardt C, Body JJ (1984) Human chorionic gonadotropin-like substance in plasma of normal nonpregnant subjects and women with breast cancer. J Clin Endocrinol Metab 58:1171–1178

    Article  CAS  PubMed  Google Scholar 

  124. Monteiro JC, Ferguson KM, McKinna JA, Greening WP, Neville AM (1984) Ectopic production of human chorionic gonadotrophin-like material by breast cancer. Cancer 53:957–962

    Article  CAS  PubMed  Google Scholar 

  125. Sjöström J, Alfthan H, Joensuu H, Stenman UH, Lundin J, Blomqvist C (2001) Serum tumour markers CA 15-3, TPA, TPS, hCGbeta and TATI in the monitoring of chemotherapy response in metastatic breast cancer. Scand J Clin Lab Invest 61:431–441

    Article  PubMed  Google Scholar 

  126. Birken S, Armstrong EG, Kolks MA, Cole LA, Agosto GM, Krichevsky A et al (1988) Structure of the human chorionic gonadotropin beta-subunit fragment from pregnancy urine. Endocrinology 123:572–583

    Article  CAS  PubMed  Google Scholar 

  127. Carter PG, Iles RK, Neven P, Ind TE, Shepherd JH, Chard T (1994) The prognostic significance of urinary beta core fragment in premenopausal women with carcinoma of the cervix. Gynecol Oncol 55:271–276

    Article  CAS  PubMed  Google Scholar 

  128. Alberti C, Sacchini P, Coltellini P (1990) Occult carcinoma in urology. Nosografy and diagnosis. Minerva Urol Nefrol 42:85–93

    CAS  PubMed  Google Scholar 

  129. Schwartz BF, Auman R, Peretsman SJ, Moul JW, Deshon GE, Hernandez J et al (1996) Prognostic value of BHCG and local tumorinvasion in stage I seminoma of the testis. J Surg Oncol 61:131–133

    Article  CAS  PubMed  Google Scholar 

  130. Kinugasa M, Nishimura R, Koizumi T, Morisue K, Higashida T, Natazuka T et al (1995) Combination assay of urinary beta-core fragment of human chorionic gonadotropin with serum tumor markers in gynecologic cancers. Jpn J Cancer Res 86:783–789

    Article  CAS  PubMed  Google Scholar 

  131. Bhalang K, Kafrawy AH, Miles DA (1999) Immunohistochemical study of the expression of human chorionic gonadotropin-beta in oral squamous cell carcinoma. Cancer 85:757–762

    Article  CAS  PubMed  Google Scholar 

  132. Hedstrom J, Grenman R, Ramsay H, Finne P, Lundin J, Haglund C et al (1999) Concentration of free hCGbeta subunit in serum as a prognostic marker for squamous-cell carcinoma of the oral cavity and oropharynx. Int J Cancer 84:525–528

    Article  CAS  PubMed  Google Scholar 

  133. Abramson DH, Schefler AC (2004) Update on retinoblastoma. Retina 24:828–848

    Article  PubMed  Google Scholar 

  134. Anteby I, Cohen E, Anteby E, BenEzra D (2001) Ocular manifestations in children born after in vitro fertilization. Arch Ophthalmol 119:1525–1529

    Article  CAS  PubMed  Google Scholar 

  135. Marees T, Dommering CJ, Imhof SM, Kors WA, Ringens PJ et al (2009) Incidence of retinoblastoma in Dutch children conceived by IVF: an expanded study. Hum Reprod 24:3220–3224

    Article  CAS  PubMed  Google Scholar 

  136. Moll AC, Imhof SM, Cruysberg JR, Schouten-van Meeteren AY, Boers M (2003) Incidence of retinoblastoma in children born after in-vitro fertilisation. Lancet 361:309––310

    Article  PubMed  Google Scholar 

  137. Stenman U-H, Bidart JM, Birken S, Mann K, Nisula B, O’Connor J (1993) Standardization of protein immunoprocedures. Choriogonadotropin (CG). Scand J Clin Lab Invest 216(Suppl):42–78

    Article  CAS  Google Scholar 

  138. Vaitukaitis JL (1977) Human chorionic gonadotropin. In: Fuchs F, Klopper A (eds) Endocrinology of pregnancy. Harper and Row, New York

    Google Scholar 

  139. Hussa RO, Rinke ML, Schweitzer PG (1985) Discordant human chorionic gonadotropin results, causes and solutions. Obstet Gynecol 65:211

    CAS  PubMed  Google Scholar 

  140. Vaitukaitis JL, Braunstein GD, Ross GT (1972) A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Am J Obstet Gynecol 113:751–758

    CAS  PubMed  Google Scholar 

  141. Morgan FJ, Canfield RE (1971) Nature of the subunits of human chorionic gonadotropin. Endocrinology 88:1045

    Article  CAS  PubMed  Google Scholar 

  142. Bidart JM, Ozturk M, Bellet DH, Jolivet M, Gras-Masse H, Troalen F et al (1985) Identification of epitopes associated with hCG and the beta hCG carboxyl terminus by monoclonal antibodies produced against a synthetic peptide. J Immunol 134:457–464

    CAS  PubMed  Google Scholar 

  143. Ehrlich PH, Moustafa ZA, Krichevsky A, Birken S, Armstrong EG, Canfield RE (1985) Characterization and relative orientation of epitopes for monoclonal antibodies and antisera to human chorionic gonadotropin. Am J Reprod Immunol Microbiol 8:48–54

    Article  CAS  PubMed  Google Scholar 

  144. Norman RJ, Poulton T, Gard T, Chard T (1985) Monoclonal antibodies to human chorionic gonadotropin: implications for antigenic mapping, immunoradiometric assays, and clinical applications. J Clin Endocrinol Metab 61:1031–1038

    Article  CAS  PubMed  Google Scholar 

  145. Schwarz S, Berger P, Wick G (1985) Epitope-selective, monoclonal-antibody-based immunoradiometric assays of predictable specificity for differential measurement of choriogonadotropin and its subunits. Clin Chem 31:1322–1328

    CAS  PubMed  Google Scholar 

  146. Schwarz S, Krude H, Klieber R, Dirnhofer S, Lottersberger C, Merz WE et al (1991) Number and topography of epitopes of human chorionic gonadotropin (hCG) are shared by desialylated and deglycosylated hCG. Mol Cell Endocrinol 80:33–40

    Article  CAS  PubMed  Google Scholar 

  147. Birken S, Krichevsky A, O’Connor J, Schlatterer J, Cole L, Kardana A et al (1999) Development and characterization of antibodies to a nicked and hyperglycosylated form of hCG from a choriocarcinoma patient: generation of antibodies that differentiate between pregnancy hCG and choriocarcinoma hCG. Endocrine 10:137–144

    Article  CAS  PubMed  Google Scholar 

  148. Cole LA (1997) Immunoassay of human chorionic gonadotropin, its free subunits, and metabolites. [see comments]. Clin Chem 43:2233–2243

    CAS  PubMed  Google Scholar 

  149. Cole LA, Wang YX, Elliott M, Latif M, Chambers JT, Chambers SK et al (1988) Urinary human chorionic gonadotropin free beta-subunit and beta-core fragment: a new marker of gynecological cancers. Cancer Res 48:1356–1360

    CAS  PubMed  Google Scholar 

  150. Iles RK, Persad R, Trivedi M, Sharma KB, Dickinson A, Smith P et al (1996) Urinary concentration of human chorionic gonadotrophin and its fragments as a prognostic marker in bladder cancer. Br J Urol 77:61–69

    Article  CAS  PubMed  Google Scholar 

  151. Stenman UH, Alfthan H, Ranta T, Vartiainen E, Jalkanen J, Seppälä M (1987) Serum levels of human chorionic gonadotropin in nonpregnant women and men are modulated by gonadotropin-releasing hormone and sex steroids. J Clin Endocrinol Metab 64:730–736

    Article  CAS  PubMed  Google Scholar 

  152. Bellet D, Lazar V, Bieche I, Paradis V, Giovangrandi Y, Paterlini P et al (1997) Malignant transformation of nontrophoblastic cells is associated with the expression of chorionic gonadotropin beta genes normally transcribed in trophoblastic cells. Cancer Res 57:516–523

    CAS  PubMed  Google Scholar 

  153. Norman RJ, Menabawey M, Lowings C, Buck RH, Chard T (1987) Relationship between blood and urine concentrations of intact human chorionic gonadotropin and its free subunits in early pregnancy. Obstet Gynecol 69:590–593

    CAS  PubMed  Google Scholar 

  154. Papapetrou PD, Nicopoulou SC (1986) The origin of a human chorionic gonadotropin beta-subunit-core fragment excreted in the urine of patients with cancer. Acta Endocrinol (Copenh) 112:415–422

    CAS  Google Scholar 

  155. Cole LA (2011) hCG, the centerpiece of life and death. Int J Endocrinol Metab 9(2):335–352

    Article  CAS  Google Scholar 

  156. Barakat RR, Markman M, Randall ME (2009) Principles and practice of gynecologic oncology. Wolters Kluwer Health, Philadelphia

    Google Scholar 

  157. Tegoni M, Spinelli S, Verhoeyen M, Davis P, Cambillau C (1999) Crystal structure of a ternary complex between human chorionic gonadotropin (hCG) and two Fv fragments specific for the alpha and beta-subunits. J Mol Biol 289(5):1375–1385

    Article  CAS  PubMed  Google Scholar 

  158. Triozzi PL, Stevens VC (1999) Human chorionic gonadotropin as a target for cancer vaccines. Oncol Rep 6(1):7–17

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC, IG13128) and from the Italian Ministry of Health (GR-2010-2310057) to ML.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Matteo Landriscina .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Sisinni, L., Landriscina, M. (2015). The Role of Human Chorionic Gonadotropin as Tumor Marker: Biochemical and Clinical Aspects. In: Scatena, R. (eds) Advances in Cancer Biomarkers. Advances in Experimental Medicine and Biology, vol 867. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-7215-0_11

Download citation

Publish with us

Policies and ethics