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