Biological function of the free β -subunit: expression and treatment target in cancer.

Reports of ectopic hCG molecules expressed in vivo by nongestational tumors were noted as early as 1904 [1] . A rare case of a bladder tumor expressing biologically active gonadotropin (called chorioepithelioma ) contained syncytiotrophoblast elements and had widely metastasized. The tumor occurred in a postmenopausal woman whose ovaries were atrophic, despite a hyperplastic endometrium. Therefore, 23 years before the discovery of hCG by Aschheim and Zondeck [2] , it was correctly concluded that these changes were due to a gonadotrophic hormone produced by the tumor. Ectopic production of biologically active hCG produced by non-germ-cell tumors was next reported in 1946 [3] . It is not uncommon for ectopic hCG β production to be explained by dedifferentiation (trophoblastic differentiation), where it is assumed that the tissue has reverted to pluripotence, taking on the characteristics of the syncytiotrophoblast and thus expressing hCG. In almost all cases, however, the sole criterion for the trophoblastic differentiation claim is the detection of hCG; this detection is often a result of a misinterpreted hCG β -positive assay. Because common epithelial tumors will express hCG β [4] , most of these claims are the result of false dogma. It is, in fact, quite distinct, as germ-cell tumors will express both hCG α and hCG β . Resulting in the production of the gonadotropic holo-hormone hCG, ectopic expression by common epithelial tumors consists almost exclusively of the free β -subunit. Only rarely is the holo-hormone found in advanced-stage carcinomatosis [5] , and it has been only sporadically noted in liver and lung cancers [6] . Thus, such de-differentiation is a much rarer event than has been claimed, and has more to do with confusion over assay specificity and hCG/hCG β terminology than de-differentiation or carcinomatosis. Although the holo-hormone hCG is produced by placental and germ-cell tumors, the free β -subunit (hCG β ) is produced by epithelial tumors and is (more often than not) independent of glycoprotein hormone alpha gene expression [7,8] . Ectopic production of free hCG β by bladder carcinoma is well described, and the majority of our work has been concentrated in this field [9] ; however, expression of hCG β is not exclusive to bladder carcinoma. It has also been shown in cervical and endometrial carcinoma, as well as many other non-germ-cell tumors of the breast, colon, lung, ovary, oral/facial tissue, prostate, pancreas, vulva/vagina, kidney, and neuroendocrine tissue ( Table 14.1 )