Increased serum levels of human chorionic gonadotropin beta subunit (hCG beta) were described previously in patients with bladder cancer. To obtain insight into such production of hCG beta, the expression of hCG beta 7, 8, 5, and 3 genes in bladder carcinomas and normal urothelia was investigated by reverse transcription PCR. Surprisingly, hCG beta mRNAs were detected in both normal urothelial and carcinomatous cells. However, tumor progression was characterized by different patterns of transcription of the hCG beta genes; the beta 7 gene was the only gene transcribed in normal urothelia and Ta tumors included in this study, whereas in addition to beta 7, genes beta 5, 8, and 3 were transcribed in T1 to T4 tumors. Moreover, transcription levels of the latter three genes increased with the stage of the disease. These observations showed that dramatic modifications in the expression of hCG beta genes accompany progression of bladder carcinomas.
Immunointerruption of pregnancy consists of preventing pregnancy or terminating it at an early stage through antibodies. The antibodies may be obtained after administration of vaccine to induce their formation through active immunization, or by direct injection through passive immunization. Antigens that could potentially be used are found in sperm, the zona pellucida, and reproductive hormones, especially the chorionic gonadotropins. The sperm antigens are basically enzymes such as hyaluronidase and accrosine. 3 glucoproteins have been identified in the zona pellucida of mice and pigs. In vitro studies have shown that fertilization can be prevented if eggs are exposed to antizona-pellucida antibodies along with sperm. Active immunization could give longer term results, but ovarian function could also be affected if the antigens weren't purified. Much research has been devoted to identifying human embryonic antigens through analysis of the proteins of the cells of embryonic teratocarcinoma. Among placental antigens, the glucoprotein SP1 synthesized by the trophoblast is under study. Anti-SP1 antibodies appear to cause abortion in monkeys, but knowledge of these antigens is still fragmentary. Various reproductive hormones have been studied, but too many undesirable effects could result from the use of luteinizing hormone, luteinizing hormone releasing hormone, follicle stimulation hormone, or steroids. Human chorionic gonadotropin (hCG), however, is more promising. It is a glucoprotein formed of alpha and beta subunits, both of which are needed for hCG to interact with its receptor. The alpha subunit has the same sequence as that of other hormones of the same species, but the beta subunit is specific to each hormone. Studies are underway to determine the site of amino acids and peptide sequences capable of inducing an anti-hCG response which would inactivate the biological activity of hCG. Different teams have used synthetic peptides analogous to sequences of beta-hCG or fragments obtained by enzymatic cleavage of natural hCG to block pregnancy in rats and baboons. The presence of antibodies can block pregnancy without disturbing ovulation or modifying menstrual regularity. No toxic or secondary effect has been observed in animals. A multicenter phase 1 test using beta-hCG coupled with tetanus antitoxin caused almost all the women participating to develop antibeta-hCG and antitetanus anatoxin antibodies, but titres of antibodies varied greatly between different women, required 5-6 months to develop, and declined rapidly thereafter. Several pregnancies were observed, especially in women with low titres of antibodies. The approach of passive immunization through direct injection of antibodies has met with numerous obstacles, including lack of success in producing human monoclonal antibodies. Although a 2nd generation of vaccines in under study, the potential role of immunointerruption of pregnancy in fertility regulation remains to be clarified.
Early placenta insulin-like growth factor (EPIL) is expressed by a subpopulation of the Her2-positive SKBR3 breast cancer cell line displaying high motility and transendothelial invasiveness in vitro , as recently shown by our group. As a consequence of this, we established cellular models by generating an EPIL-overexpressing SKBR3 cell line, knocked down EPIL by adding specific small interfering RNA (siRNA) to those cells and produced EPIL-enriched and depleted serum-free culture media. EPIL-expressing cells as well as EPIL-induced SKBR3 cells acquired a high capacity for transendothelial invasiveness. We observed a thin and outspread morphology caused by enhanced formation of lamellipodia, i.e. protrusions in the initial phase of motility. In parallel, Her2-positive MDAHer2 breast cancer cells also showed increased invasiveness when induced by EPIL-conditioned medium. A downstream signaling impact of EPIL could be observed in the form of reduced phosphorylation of Her2, erk1/2 and akt, while phospholipase Cγ1 phophorylation remained unaffected. As an in vivo model for highly motile tumor cells, Paget’s disease of the nipple showed simultaneous EPIL and Her2 expression upon immunohistochemical examination using specific antibodies. Such experimental data have been translated to a clinical setting by using a prognostic tissue microarray established from 603 breast cancer cases. Survival data analysis found a significant association between expression levels of EPIL and 5-year overall survival that was dose dependent: EPIL (negative) 84%, EPIL (moderately positive) 77%, EPIL (strongly positive) 48% ( P <0.005). One particular subgroup (7.6% of the cases with full clinical records) that comprised tumors simultaneously expressing EPIL and Her2 represented patients with the poorest 5-year overall survival. The results suggested that EPIL might be a cancer cell-produced growth factor that influences lateral Her2 signaling. Moreover, EPIL may be induced by factors apart from Her2 and may independently provide signaling for cancer invasion and motility.
