O-GLYCOSYLATION OF HCG AND CANCER

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Human chorionic gonadotropin (hCG) is produced by the trophoblast in pregnancy, mole and choriocarcinoma. Studies in this and other laboratories have shown that a specific O-linked oligosaccharide structure, NeuAc alpha2,3Ga1 beta1,3(NeuAc alpha2,3Gal beta1,4GlcNAc beta1,6)GalNAc, and N-linked oligosacchrides of the GlcNAc beta1,4Man alpha1,3 triantennary-type are consistently found on choriocarcinoma hCG molecules. Studies here show that these same structures may also be present on early pregnancy hCG, from 1-3 weeks following implantation, or the time of trophoblast invasion of the uterus. This led to the hypothesis that these structures are characteristic of invasive cells. Our objectives are: 1) To confirm the hypothesis that these structures are characteristic of invasive cells, we will examine the carbohydrate structures on further samples of hCG from early pregnancy and from testicular and other cancer patients. 2) To determine if these same oligosaccharides are more abundant on cancer cell plasma membranes, where they may effect cell-cell interaction and possibly cell invasiveness. 3) To compare pertinent glycosyltransferase activities, GlcNAc beta1,6GalNAc transferase, GlcNAc transferase-IV, and NeuAc alpha2,3 transferase in normal and malignant cells. 4) Trophoblast has CSF-I and PDGF receptors. Recent experiments suggest that CSF-I may promote trophoblast invasiveness in early pregnancy. The effect of CSF-1 and PDGF on hCG glycosylation and on trophoblast glycosyltransferase activities will be investigated. 5) Cytotrophoblast cells predominate and produce hCG in very early pregnancy, differentiated sycytial structures then take-over this function. Using culture models, the effects of trophoblast differentiation on hCG glycosylation will be examined. 6) To use immunoassays and chromatofocusing methods to monitor the levels of "invasive cell" hCG, in trophoblast disease (to follow the progression of hydatidiform mole to malignant disease), in early pregnancy (from women having persistent and spontaneously- aborting pregnancies), and in women with invasive placental disease (placenta accreta, increta or percreta). 7) Thyrotoxicosis and gynecomastia can develop from the "invasive cell" hCG production that occurs in choriocarcinoma and testicular cancer. To determine if "invasive cell" hCG has altered or additional biologic activities, the steroidogenic, cAMP-promoting, thyrotropic, receptor-binding and metabolic clearance rates of normal pregnancy and "invasive cell hormone will be compared.