Lenhard et al. BMC Cancer 2012, 12:2 http://www.biomedcentral.com/1471-2407/12/2 Page 6 of 8 Table 3 Ovarian cancer patient survival: 5-year survival for hCG positive and negative tumors with regard to LH receptor (LH-R) and FSH receptor (FSH-R) expression Ovarian cancer patient 5-year survival (%) LH-R positive and FSH-R negative FSR-R and LH-R positive/FSH-R and LH-R FSH-R positive and LH-R negative negative hCG negative hCG positive 50.5 75.0 patients with gynecological cancers [31]. Still, hCG serum levels seem not to be useful in the diagnosis or therapy monitoring of non-trophoblastic gynecological malignancies [32,33]. But since there is evidence sup- porting that hCG is produced by gynecological cancers themselves [34-36], hCG production can be suspected to have an influence on gonadotropin receptor expres- sion in cancer tissue. The fact that we observed a posi- tive correlation of hCG to LH-receptor expression supports this assumption. Among non-trophoblastic cancers, hCG expression is best analyzed in the transitional cell carcinoma of the bladder and urinary tract. The appearance of human chorionic gonadotropin within the tumor cells is described to be an evidence of dedifferentiation, since it is more commonly expressed in poorly differentiated tumors [37]. In this study, we also observed significant differences in hCG expression related to tumor grade (p = 0.022) but no differences with regard to the histologi- cal subtype. In addition, mucinous ovarian carcinomas showed significantly increased hCG expression at FIGO stage 3 (p = 0.018). There is in vitro data with uterine microvascular endothelial cells showing hCG to increase capillary formation and migration of endothelial cells with no effect on cell proliferation [38]. In the same study by Zygmunt et al., hCG was found to induce neo- vascularization even in ovarian cancer in an in vivo ani- mal model. Therefore, hCG was thought to be an important angiogenetic factor [38]. This finding may in part explain higher hCG expression in dedifferentiated tumors or higher stages in the mucinous ovarian cancer subgroup as observed in our own study. Still, there was no significant difference in patient survival relating to tumor hCG expression as it was found for transitional cell cancer of the bladder [39]. Therefore, we assume hCG to have varying functions in ovarian cancer, e.g. neovascularization or LH-R regulation, which might explain the partly contradictory findings of hCG effects in relation to histological results on the one hand and patient survival on the other. Interestingly, we found a difference in 5-year survival rate between hCG-positive and hCG-negative tumors depending on LH-R or FSH-R expression. As demon- strated in our previous study, the LH-R and FSH-R themselves have prognostic value for patient’s survival [17]. Our results showed a positive correlation of hCG 44.9 39.8 30.0 25.0 tissue expression and LH-R expression. Therefore we assume hCG also to have an LH-R regulative function. The role of hCG and its receptors in cancer is discussed controversially in literature [15,40]. We have demon- strated here, that the contradictory findings in literature may also be explained by variable gonadotropin hor- mone and hormone receptor expression. Gonadotropins bind to extracellular receptors, the LH- R and FSH-R. The LH-R receptor binds not only the gonadotropin LH but also hCG, and is therefore often referred to as LH/hCG-R. It is mainly found in gonadal tissue. Apart from gonadal tissue, it is known to be expressed in a variety of non-gonadal tissues in humans and rodents, like fetal tissues [41], the placenta [42], mammary gland [43], the salpinx, the uterus [44] or the cervix [45]. Most research on this receptor focuses on fertility-related treatments. Nonetheless, new therapeutic fields are evolving regarding this receptor since the LH/ hCG-R is expressed in human cancer cells like breast cancer [46] or ovarian cancer [17]. To reduce the side- effects of chemotherapy, receptor-mediated therapies might be a new approach in anticancer treatment. Rah- man et al. have developed a lytic peptide, hecate-CGbeta, which selectively kills cancer cells by changing their membrane potential [47]. Its effect on tumor cells has already been proven for breast cancer [46-48] and testi- cular tumors [49], but also for ovarian cancer [49,50]. Gebauer et al. have analyzed the effect of human chor- ionic gonadotropin-doxorubicin on ovarian cancer cells and observed an increased activity of doxorubicin when conjugated to hCG [51]. This finding was also described for breast cancer cells [52]. The combination of cyto- static agents with hormones like hCG for the treatment of LH/hCG-R positive cells might be a promising approach to reduce morbidity and mortality in antican- cer therapy. New therapeutic agents like lytic peptides or chemotherapeutic agents binding to the LH-R offer less toxic, but effective and selective anticancer treat- ment options, either alone or in combination with stan- dard chemotherapeutic agents, in ovarian cancer patients whose tumors express these receptors. Strengths of this study are the long follow-up time, the consistent pathologic histology review by expert gynecologic oncology pathologists and the large sample size. A limitation of this study is obviously the retro- spective study design.