Review
Ectopic hCGβ expression by epithelial cancer: Malignant behaviour, metastasis and inhibition of tumor cell apoptosis

https://doi.org/10.1016/j.mce.2006.02.019Get rights and content

Abstract

Ectopic expression of the β-subunit of human chorionic gonadotropin (hCG) is now a recognized phenomenon in 20–40% of all common epithelial carcinoma arising from mucosal epithelia such as bladder, cervix, lung and naso-pharynx. Recent studies have shown that it acts as an autocrine growth factor by inhibiting apoptosis. Structural homology and in vitro studies suggest that it may achieve this by inhibition of the transforming growth factor β (TGFβ) receptor complex. Such a molecular mechanism would go some way to explaining ectopic hCGβ's association with poor prognosis and tumors that will rapidly progress to metastasis.

Introduction

Ectopic human chorionic gonadotropin (hCG) expression by non-gestational tumours was noted as early as 1904 (DeJewitzi reported a case in which he concluded that a gonadotropin was produced by a bladder cancer—reviewed by Iles and Chard, 1991) and was reported by Ascheim and Zondek following the introduction of their seminal bio-assay for hCG in 1927 (Ascheim and Zondek, 1927, Ascheim and Zondek, 1928, Zondek, 1930, Zondek, 1935). Up to the late 1970s, the incidence of ectopic hCG expression by common epithelial cancers could be counted in terms of the number of case reports. By the end of the 1980s the incidence had grown exponentially and is now reported in terms of the percentage of hCG positive tumors in any given type of epithelial cancers (reviewed by Iles and Butler, 1998). The reason for this apparently dramatic change was the introduction of the β-subunit hCG radio-immunoassay by Vaitukaitis et al. (1972). This immunoassay detected free β-subunit hCG as well as the intact hormone. Extensive immunochemical characterisation has shown that, whilst intact hCG was abundantly produced by the placenta and germ cell tumours, the free β-subunit (hCGβ) – independent of the common glycoprotein hormone α-subunit (GPHα) – is produced by common epithelial tumours (Iles and Chard, 1989, Iles et al., 1990a, Iles et al., 1990b). Intact hCG may be expressed by various common epithelial tumors in an unpredictable fashion, most often by lung cancer and hepatoblastoma (Stenman et al., 2004). In bladder cancer this is associated with carcinomatosis. However, the free β-subunit (hCGβ) is the most abundant form of immunoreactive hCG expressed (Iles and Chard, 1991).

Ectopic production of free hCGβ by bladder carcinoma is well described (reviewed by Iles and Butler, 1998). Expression of hCGβ has also been shown in cervical and endometrial carcinoma as well as many other non-germ cell tumours of the ovary, vulva, breast, prostate, lung, colon, oral/facial tissue and stomach (see Table 1). As hCGβ expression by bladder cancers has been extensively reported it serves as a good model for ectopic expression by other common epithelial cancers.

Section snippets

Ectopic hCGβ expression and poor prognosis

The common consensus of multiple studies is that 30–40% of bladder cancer patients have elevated immunoreactive hCGβ in serum and urine or immunohistochemically positive tumours (see Table 1) (reviewed by Iles and Butler, 1998). Although the incidence is too low for screening purposes there is a strong correlation between free hCGβ expression and tumour grade, stage and patient survival (Iles and Chard, 1991, Iles, 1995, Moutzouris et al., 1993). An association between hCGβ expression and

Biological action of hCGβ on epithelial tumors

Why hCGβ expression by bladder cancers should be associated with the tendency for the tumour to resist radiotherapy and develop metastases had been largely ignored as an epiphenomenona of no molecular consequence. Expression of fetal proteins by cancers is well recognised and an established understanding exists that cancer is a form of cellular regression; a legacy of the Luterian/Trophoblast theory of cancer (Krebs and Krebs, 1950, Acevedo, 2002). Thus, hCG and by association hCGβ, expression

hCG and the cystine knot growth factor/TGFβ superfamily

Lapthorn et al. (1994) determined the three-dimensional structure of hCG. The most striking feature was the arrangement of three disulphide bridges in the centre of each subunit. The positions of the three cystines are almost identical in both subunits, where two disulphides bridge the anti-parallel strands of the peptide chain forming a central loop, through which the third disulphide passes. This structure has been identified before in a group of growth factors which are designated by its

hCGβ and cross-talk with the TGFβ receptor

The absence of a receptor for free hCGβ, but structural homology with the cystine knot growth factors, suggests that free hCGβ cross-interaction with other cystine knot growth factor receptors may occur. Given that the growth modulation action of hCGβ on epithelial cancer occurs via inhibition of apoptosis, whilst the induction of epithelial cell apoptosis is a well-established action of TGFβ and that we have previously highlighted the topological homology of hCGβ with TGFβ (Gillott et al., 1996

References (64)

  • H.F. Acevedo

    Human chorionic gonadotropin (hCG), the hormone of life and death: a review

    J. Exp. Ther. Oncol.

    (2002)
  • S. Ascheim et al.

    Hypophysenworderlappen hormon und ovarialhormon im Harn von Schwangeren

    Klin. Wochenschr.

    (1927)
  • C. Ascheim et al.

    Die Schwangerschaftsdiagnose aus dem Harn durch Nachweis der HypophysevordemLappenhormon

    Klin. Wochenschr.

    (1928)
  • M.H. Barcellos-Hoff et al.

    Transforming growth factor B and breast cancer: mammary gland development

    Breast Cancer Res.

    (2000)
  • F. Berzal-Cantalejo et al.

    Syncytial giant cell component. Review of 55 renal cell carcinomas

    Histol. Histopathol.

    (2004)
  • K. Bhalang et al.

    Immunohistochemical study of the expression of human chorionic gonadotropin-beta in oral squamous cell carcinomas

    Cancer

    (1999)
  • I. Bieche et al.

    Prognostic value of chorionic gonadotropin beta gene transcripts in human breast carcinoma

    Clin. Cancer Res.

    (1998)
  • S.A. Butler et al.

    The increase in bladder carcinoma cell population induced by the free beta subunit of human chorionic gonadotrophin is a result of an anti-apoptosis effect and not cell proliferation

    Br. J. Cancer

    (2000)
  • P.G. Carter et al.

    Measurement of urinary β-core fragment of human chorionic gonadotrohin in women with vulvovaginal malignancy and its prognostic significance

    Br. J. Cancer

    (1995)
  • L.M. Coombs et al.

    Reduced expression of TGFβ is associated with advanced disease in transitional cell carcinoma

    Br. J. Cancer

    (1993)
  • R.A. Crawford et al.

    The prognostic significance of beta human chorionic gonadotrophin and its metabolites in women with cervical carcinoma

    J. Clin. Pathol.

    (1998)
  • M.M. Daja et al.

    Beta-human chorionic gonadotropin in semen: a marker for early detection of prostate cancer?

    Mol. Urol.

    (2000)
  • Davies, S. 2001. Ectopic expression of glycoprotein hormones and their receptors by urogenital cancers. Ph.D. Thesis....
  • H.W. De Bruijn et al.

    Rising serum values of beta-subunit human chorionic gonadotrophin (hCG) in patients with progressive vulvar carcinomas

    Br. J. Cancer

    (1997)
  • Z.F. Dobrowolski et al.

    Prognostic value of β human chorionic gonadotrophin in blood serum of patients with urinary bladder tumors

    Int. Urol. Nephrol.

    (1994)
  • O. El-Ahmady et al.

    Urinary gonadotropin peptide (UGP) in Egyptian patients with benign and advanced malignant urological disease

    Br. J. Cancer

    (1996)
  • I.E. Eder et al.

    Expression of transforming growth factors-β1, β2 and β3 in human bladder carcinomas

    Br. J. Cancer

    (1997)
  • D. Fujii

    Transforming growth factor β gene maps to human chromosome 19 long arm and to mouse chromosome 7

    Somat. Cell Mol. Genet.

    (1986)
  • D.J. Gillott et al.

    The effects of β-human chorionic gonadotrophin on the in vitro growth of bladder cancer cell lines

    Br. J. Cancer

    (1996)
  • M. Grossmann et al.

    Measurement of human chorionic gonadotrophin-related immunoreactivity in serum, ascites and tumor cysts of patients with gynaecologic malignancies

    Eur. J. Clin. Invest.

    (1995)
  • A.-B. Halim et al.

    Urinary β-hCG in benign and malignant urinary tract disease

    Dis. Markers

    (1995)
  • J. Hedstrom et al.

    Concentration of free hCGbeta subunit in serum as a prognostic marker for squamous-cell carcinoma of the oral cavity and oropharynx

    Int. J. Cancer

    (1999)
  • Cited by (0)

    View full text