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Differential gene expression pattern between normal human trophoblast and choriocarcinoma cell lines: downregulation of heat shock protein-27 in choriocarcinoma in vitro and in vivo.

OBJECTIVE: Our purpose was to identify potential differences in gene expression between normal trophoblast and choriocarcinoma cells. METHODS: The Atlas human cDNA expression array hybridization technique was used to study the gene expression pattern in normal trophoblast and choriocarcinoma cell lines. Furthermore, to confirm heat shock protein-27 (Hsp-27) expression data, reverse transcriptase-PCR (RT-PCR), Western blot, and immunohistochemical analyses were used in vitro with cell lines and in vivo with paraffin sections. RESULTS: The expression of nine genes was strongly different comparing a normal trophoblast cell line with choriocarcinoma cells on the Atlas membranes. Compared to normal trophoblast cells, six genes were upregulated and three were downregulated in choriocarcinoma cells. Furthermore, the downregulation of Hsp-27 in choriocarcinoma cells was confirmed both in vitro with cell lines and in vivo with paraffin sections using RT-PCR, Western blot, and immunohistochemical techniques. CONCLUSION: cDNA expression array is a useful technique for identifying differentially expressed gene patterns in normal trophoblast and choriocarcinoma cells. The strong expression of Hsp-27 in placental villous trophoblast cells may play a role in trophoblast differentiation. The downregulation of Hsp-27 in choriocarcinoma may contribute to the extreme sensitivity of trophoblastic tumors to chemotherapy.

Choriocarcinoma↗

Intraplacental choriocarcinoma: experience from a tertiary referral center and relationship with infantile choriocarcinoma.

The development of persistent gestational trophoblastic disease following an apparently uncomplicated term pregnancy is well-recognized; however, reports of confirmed intraplacental choriocarcinoma are rare. We report four cases of histologically reviewed intraplacental choriocarcinoma occurring in third-trimester pregnancies from the files of a regional trophoblastic disease unit. In all cases, macroscopic examination of the placenta appeared unremarkable, with small nondescript lesions being identified, thought to be fresh infarcts or intervillus thrombi. Histological examination demonstrated the presence of focal intraplacental choriocarcinoma. Review of the literature demonstrates primary intraplacental choriocarcinoma rarely may be associated with obstetric complications such as intrauterine death or fetal distress. But in most cases, the disease is initially asymptomatic, the diagnosis only being made following histopathological placental examination for other indications. Intraplacental choriocarcinoma may therefore manifest as a spectrum of clinical disease ranging from an incidental lesion diagnosed on placental pathological examination with no adverse effects on mother or baby, through to metastatic maternal disease that is present in about half of the cases, to disseminated fatal infantile choriocarcinoma.

Adult↗

Comparative genomic hybridization studies in hydatidiform moles and choriocarcinoma: amplification of 7q21-q31 and loss of 8p12-p21 in choriocarcinoma.

Comparative genomic hybridization (CGH) was utilized to investigate genetic changes from archived cases of choriocarcinoma (n = 12) and hydatidiform moles (n = 7). Test DNA was extracted from paraffin-embedded tissues, amplified using total universal PCR, and co-hybridized with control DNA to normal metaphases. Comparative genomic hybridization findings showed chromosomal imbalances in 9 of 12 cases of choriocarcinoma. By contrast, all hydatidiform moles showed normal CGH profiles. Consistent findings in choriocarcinoma included deletion at 8p (5 cases) and amplification at 7q (4 cases). A tumor suppressor gene (e.g., N33) at 8p and/or a growth regulator at 7q could play a role in the initiation of choriocarcinoma and its progression. This is the first study showing specific alterations in choriocarcinomas by CGH, and illustrates the utility of this technique in elucidating genetic changes in gynecological tumors.

Adult↗

Gastric choriocarcinoma shows characteristics of adenocarcinoma and gestational choriocarcinoma: a comparative genomic hybridization and fluorescence in situ hybridization study.

The authors report two cases of the rare primary gastric choriocarcinoma. These tumors showed an overwhelming predominance of cytotrophoblast- and syncytiotrophoblast-like tumor cells that were positive for beta-human chorionic gonadotrophin, with small foci of glandular differentiation. Beta-human chorionic gonadotrophin was also detected serologically in one patient. Comparative genomic hybridization study was performed on one specimen. Copy number gains of chromosomes 12, 17, 20, 22, and X, together with losses on 18q, were the major findings. Except for the gain of chromosome 12, which is known to be uncommon in primary gastric adenocarcinoma but frequently associated with choriocarcinoma, the remaining genomic imbalances were among the most common comparative genomic hybridization findings reported in primary gastric adenocarcinoma. Fluorescence in situ hybridization on paraffin sections of both specimens confirmed the presence of polysomy 17 and trisomy 12. These results suggest that primary gastric choriocarcinoma genetically possesses characteristics of both adenocarcinoma and gestational choriocarcinoma. The authors believe this is the first interphase cytogenetics study on this rare tumor, and that the results support the theory that gastric choriocarcinoma arises from alternate differentiation pathways of adenocarcinoma.

Adenocarcinoma↗

Trophoblastic tumors of the testis other than classic choriocarcinoma: "monophasic" choriocarcinoma and placental site trophoblastic tumor: a report of two cases.

We report two unusual forms of testicular trophoblastic tumor. One was a mixed germ cell tumor in a 19-year-old man that had a predominant component of nodules of cytotrophoblast cells with only rare syncytiotrophoblast cells. These nodules of "monophasic" choriocarcinoma were diffusely positive for human chorionic gonadotropin (hCG), which stained the syncytiotrophoblast cells more intensely; stains for human placental lactogen (HPL) highlighted only the latter cells. The second tumor occurred in a 16-month-old boy. It consisted of a pure proliferation of intermediate trophoblast cells and was identical to the placental site trophoblastic tumor of the uterus. The tumor cells showed diffuse immunoreactivity for HPL and patchy staining for hCG. Despite the occurrence of vascular wall invasion, the patient was alive and well at 8 years follow-up with no treatment other than orchiectomy. These cases show that trophoblastic tumors other than classic choriocarcinoma occur rarely in the testis. The differential diagnosis of the "monophasic" choriocarcinoma included seminoma and the solid variant of yolk sac tumor, but the tumor had larger, more irregular nuclei than those of seminoma and was not associated with distinctive yolk sac tumor patterns. The placental site trophoblastic tumor may be confused with Leydig cell tumor or choriocarcinoma, but awareness of its occurrence in the testis and the immunohistochemical findings should permit its recognition.

Adult↗

Investigation of choriocarcinoma clonal cell lines in vitro and choriocarcinoma transplants in the hamster for the secretion of a thyroid-stimulating factor.

Six choriocarcinoma cell lines that secrete chorionic gonadotropin (hCG) in tissue culture were investigated for the production of thyroid stimulators. In the mouse thyrotropin bioassay, no thyroid-stimulating activity was found in cell culture media even after 30-fold concentration by the method of Bates. Further, concentrates of culture media did not react in a porcine thyrotropin radioimmunoassay in which hCT cross-reacted completely. Thyroid function was also assessed in hamsters bearing hCG-secreting human choriocarinoma transplants. Even though the thyroid-stimulating factor present in commercial urinary hCG preparations caused an increase in PB131I in the hamster, the presence of the choriocarcinoma had no effect on PB131I. From these results, it appears that human choriocarcinoma cell lines maintained in tissue culture and human choriocarcinoma serially transplanted in the hamster are not suitable models for the study of the secretion of a thyroid-stimulating factor by trophoblastic tissues.

Animals↗

Interaction of choriocarcinoma cells and human peripheral blood lymphocytes. Resistance of cultured choriocarcinoma cells to cell-mediated cytotoxicity by mitogen-activated lymphocytes.

Cultured choriocarcinoma (Be Wo) cells exist that share many of the morphologic and bio-synthetic properties of normal human trophoblasts. In an attempt to develop a model for the immunologic relationship between a sensitized mother and fetus, we mixed Be Wo cells with mitogen-activated cytotoxic lymphocytes in vitro. Be Wo cells were resistant to the cytolytic effects of the activated lymphocytes despite 24-h exposure and intimate cell-to-cell contact as determined by microscopy. Control target cells, a line of human hepatoma cells, were readily destroyed. Cytotoxicity was measured by determining residual radioactivity of [(3)H]thymidine-labeled target cells after exposure to activated lymphocytes. Employing the quantitative assay, we confirmed the morphologic results and showed that Be Wo and a number of other choriocarcinoma cell lines were resistant to the cytotoxic effects of lymphocytes activated by phytohemagglutinin, pokeweed mitogen, and allogeneic cells in mixed lymphocyte cultures. Moreover, Be Wo cells were resistant to injury over a wide range of killer to target cell ratios. Significant killing of the Be Wo cells occurred only after prolonged exposure (48 and 72 h) to the activated lymphocytes. We suggest that one mechanism that may assist the fetus (or a choriocarcinoma) in its immunologic survival is the intrinsic resistance of trophoblast cells to lymphocyte-mediated cytotoxicity.

Cells, Cultured↗

[A case of a male gastric choriocarcinoma with massive mesenteric tumor and review of the literature on male choriocarcinoma].

A 32-year-old man was admitted to our hospital, complaining of an abdominal mass. An operation disclosed a large tumor, the size of a child's head, in the mesenterium of the transverse colon, with a multiple liver metastasis. A tumor resection was performed and, histologically, the tumor was diagnosed as being a choriocarcinoma. Gynecomastia was not observed. The patient died 2 months after this operation in spite of chemotherapy. An autopsy disclosed metastatic choriocarcinomas in the lungs, the liver, the peritoneum, the stomach, the adrenal glands and in the lymph nodes. The testis was found to be normal by a serial histological examination. Primary advanced adenocarcinoma, which is histologically similar to a choriocarcinoma, was found in the stomach. This case was finally diagnosed as being a gastric adenocarcinoma which showed choriocarcinomatous differentiation at various metastatic sites.

Adenocarcinoma↗

Enzymohistochemical study on the gestational choriocarcinoma: histochemistry of choriocarcinoma.

Histochemical investigation of Al-p, HSAP, Ac-p, and LDH was performed with tissues of normal chorionic villi, H. mole, invasive mole, and choriocarcinoma with the following conclusions: 1. In the normal villous tissues, Al-p, HSAP, and Ac-p are localized in syncytiotrophoblast, the former two in the rim of the cell, and the latter inside the cytoplasm. LDH displayed higher activity in cytotrophoblast than syncytiotrophoblast, especially in the former of cell column of initial chorionic villi. 2. In H. mole, Al-p, HSAP, and Ac-p are localized in syncytiotrophoblast of cystic epithelium, and in this layer and transitional cells of the chrioblastic part, the former two are localized in the rim of the cell, the latter within the cytoplasm. LDH is localized in cytotrophoblast and the transitional cell of the cystic epithelium and the chorioblastosis. 3. Localization and activities of Al-p, HSAP, Ac-p, and LDH in invasive mole are closely similar to those in H. mole. 4. Localization and activities of Al-p, HSAP, and Ac-p in choriocarcinoma presented various aspects, but more frequently they are localized in syncytiotrophoblasts in the periphery of focus and also partly in cytotrophoblasts and transitional cells. Also localization and activity of LDH showed diversity. However, the activity is stronger in cytotrophoblast. 5. From those findings, choriocarcinoma is hardly comparable with H. mole or invasive mole from an enzymohistochemical viewpoint and is assumed to have specific enzymic deviation invisible in the others and therefore to possess particular characteristics different from those of any other villous tissues.

Acid Phosphatase↗

Development and characterization of antibodies to a nicked and hyperglycosylated form of hCG from a choriocarcinoma patient: generation of antibodies that differentiate between pregnancy hCG and choriocarcinoma hCG.

Human chorionic gonadotropin (hCG) exists in blood and urine as a variety of isoforms one of which contains peptide bond cleavages within its beta-subunit loop 2 and is referred to as nicked hCG (hCGn). This hCG isoform appears to be more prevalent in the urine of patients with certain malignancies and possibly in some disorders of pregnancy. Until now, only indirect immunoassays could be used to quantify hCGn. We report the development of two monoclonal antibodies (MAbs) to a form of hCGn isolated from a choriocarcinoma patient. This hCG isoform was not only 100% nicked, but also contained 100% tetrasaccharide-core O-linked carbohydrate moieties in its beta COOH-terminal region. Two-site immunometric assays have been developed using these new antibodies, B151 and B152. The former exhibits good specificity for hCGn independent of the source of the hCGn, the form excreted by choriocarcinoma patients or the form of hCGn from normal pregnancies. The latter antibody, B152, is sensitive to the carbohydrate moieties and possibly other differences in hCG isoforms, but is not for nicking of the beta-subunit. These two immunometric assays provide potential novel diagnostic tools for direct measurement of hCG isoforms which could not be accurately quantified earlier before development of the assays using these newly generated antibodies.

Animals↗

[Choriocarcinoma: cerebral metastasis from choriocarcinoma--a successfully surgical treated case].

A surgical case of multiple cerebral metastases from choriocarcinoma was reported, who was a 26 year-old female. She had received treatment of hydatid mole on April 1979, and admitted to our hospital for the consciousness disturbance and right hemiparesis. CT scan showed two high density tumors with marked brain edema. Emergency craniotomy was performed and five tumors were completely removed. Following the operation, symptoms of increased intracranial pressure and disturbance of consciousness were markedly improved in about a week. She received radiation therapy. After radiochemotherapy, a metastatic lung tumor was removed. Now her chorionic gonadotropin titers remain normal and she is able to perform all her household responsibilities despite a mild right hemiparesis. Recently, surgical treatment has been getting done for cerebral metastasis of choriocarcinoma. Because most of the metastatic cerebral lesions occur in relatively easy position for the operation. If symptoms of cerebral metastasis appear, we should performed surgical treatment as soon as possible.

Adult↗

[Late pulmonary metastases of uterine choriocarcinoma: apropos of a case occurring 19 years after hysterectomy for choriocarcinoma. Review of the literature].

The authors report a case of pulmonary metastasis which exceptionally occurred 19 years after hysterectomy for uterine choriocarcinoma. They use this opportunity to take stock of our present knowledge concerning this subject by reviewing a vast literature. This case is of interest, as it provides a new element to the theoretical study of carcinogenesis.

Choriocarcinoma↗

Gamma-interferon enhances expression of Class I MHC antigens in the weakly HLA+ human choriocarcinoma cell line BeWo, but does not induce MHC expression in the HLA- choriocarcinoma cell line Jar.

PHA-activated lymphocyte supernatants and high doses of affinity-purified human gamma-interferon enhance the expression of apparently normal Class I histocompatibility antigens in a malignant human trophoblast cell line that expresses low amounts of these antigens under normal culture conditions. Another human choriocarcinoma cell line, Jar, which is normally HLA-, did not respond to this treatment. This system provides a model in which to study further the regulation and effects of MHC antigen expression in cells of trophoblastic origin.

Antibodies, Monoclonal↗

Intraplacental choriocarcinoma associated with viable pregnancy: pathologic features and implications for the mother and infant.

Choriocarcinoma arising in the placenta, or intraplacental choriocarcinoma, has seldom been reported, particularly in the absence of maternal metastases. Reluctance to diagnose choriocarcinoma in the presence of chorionic villi can delay diagnosis; however, timely diagnosis of choriocarcinoma is prognostically important, both for the mother and infant. We report the clinicopathologic findings in five mothers and infants in whom choriocarcinoma was identified in the placenta. None of the mothers had a history of gestational trophoblastic disease in previous pregnancies. Three placentas were similar with a single small lesion grossly suggesting a small infarct; microscopically these consisted of infarcted areas surrounded by choriocarcinoma. These three mothers were unusual in that none had metastatic choriocarcinoma; two were treated with chemotherapy and remained disease-free; the third was lost to follow-up shortly following delivery. The remaining two mothers had known pulmonary metastases at time of delivery. One of these latter two placentas contained a large marginal lesion microscopically identified as choriocarcinoma. The fifth placenta had rare microscopic foci of choriocarcinoma, and sheets of necrotic choriocarcinoma were identified in "blood clot" submitted with the placenta. In four of the five cases the choriocarcinoma appeared to be arising from otherwise normal chorionic villi, and in no case was there invasion of the villous stroma. All of the infants survived, and none had evidence of choriocarcinoma. These cases support the concept that choriocarcinoma associated with otherwise normal pregnancy arises in the placenta and may be more common than reported.

Adult↗