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At least 181 records · Page 10Linked to original sources
PubMed2001

SNRPN methylation patterns in germ cell tumors as a reflection of primordial germ cell development.

Studies examining altered imprinted gene expression in cancer compare the observed expression pattern to the normal expression pattern for a given tissue of origin, usually the somatic expression pattern for the imprinted gene. Germ cell tumors (GCTs), however, require a developmental stage-dependent comparison. To explore using methylation as an indicator of germ cell development, we determined the pattern of methylation at the 5' untranslated region of SNRPN in 89 GCTs from both children and adults. Fifty-one of 84 tumors (60.7%) (12/30 (40%) of cultured pediatric GCTs, 23/36 (63.9%) of frozen adult GCTs, and 16/23 (69.5%) of frozen pediatric GCTs, with five samples having results from both cultured and uncultured material) demonstrated a nonsomatic methylation pattern after dual digestion with XbaI, NotI, and Southern blot analysis. In contrast, only 2 of 18 (11%) control samples (16 non-GCTs and 2 normal ovaries) exhibited a nonsomatic pattern. In both cases, the result was shown to be due to copy number differences between maternal and paternal homologs, unlike the GCTs in which there was no evidence of an uneven homolog number. A comparison of the data for only the gonadal GCTs and the control data showed a highly significant difference in the proportion of tumors with methylation alterations at this locus (P = 0.0000539). Since there is no published evidence of the involvement of SNRPN methylation changes in the development of malignancy, the data suggest that the methylation pattern of SNRPN in GCTs reflects that of the primordial germ cell giving rise to the tumor.

Adolescent↗
PubMed1990

Cytogenetic and immunohistochemical evidence for the germ cell origin of a subset of acute leukemias associated with mediastinal germ cell tumors.

Most acute leukemias occurring in patients with mediastinal germ cell tumors (MGCTs) appear to be primary rather than therapy-related; however, no data have been obtained to date to confirm the hypothesized germ cell origin of the leukemias in this syndrome. We identified six male patients with this syndrome treated at Memorial Sloan-Kettering Cancer Center: in all six, the leukemia was studied immunohistochemically for various hematologic and germ cell antigens; in four, the karyotype of the leukemia was available; in one, the MGCT had also been karyotyped. In three patients, we found evidence of a germ cell origin of the acute leukemias. A 19-year-old male developed an acute myeloblastic leukemia 11 months after presenting with an MGCT; karyotypes of the two tumors showed them to be clonally related, both showing an i(12p), a cytogenetic marker of germ cell tumors. A 16-year-old male with probable Klinefelter's syndrome presented simultaneously with acute monocytic leukemia and an MGCT; although the MGCT was not karyotyped, the leukemia showed an i(12p). A 23-year-old male developed concurrently an MGCT and acute myelomonocytic leukemia; the leukemia cells coexpressed myelomonocytic antigens (HAM56, My4, My9) and cytokeratin, suggesting dual differentiation, myeloid and germ cell. Evidence for a germ cell origin of the acute leukemias in the three other patients was not obtained, although in all three the MGCT and the leukemia occurred simultaneously, supporting an etiologic relationship. Hence, these leukemias may represent another form of non-germ cell malignancy developing in germ cell tumors. All patients died of the leukemia, with a median survival of less than 2 months. This syndrome may be a useful pathologic model for the study of germ cell differentiation and hematopoietic ontogeny.

Adolescent↗
PubMed2000

Paclitaxel-based chemotherapy for patients with refractory or relapsed nonseminomatous germ cell tumors.

Germ cell tumors have been the paradigm for successful solid tumor therapy. With multimodality treatment including surgery and/or chemotherapy and/or radiation therapy 75% of all patients with germ cell tumors will be cured of their malignancy. However, in patients who have primary refractory or relapsed disease, the cure rate is less than 20%. Treatment strategies in this patient population have included: (1) dose intense therapies such as alternating sequential chemotherapy with multiple active regimens given in short intervals, (2) dose dense therapy with high-dose chemotherapy and stem cell support, (3) new agents, and (4) salvage surgery. Prognostic stratification of patients in a salvage setting can help to determine which therapeutic modalities may provide the greatest opportunity for success. The evaluation of new agents has historically occurred in the salvage setting followed by the development of combinations and then advancement to nonsalvage therapy. The introduction of paclitaxel, with its novel mechanism of action and preclinical activity, resulted in its evaluation as a single agent in patients with refractory or relapsed nonseminomatous germ cell tumors. As a single agent, paclitaxel has an overall response rate of 13.3% in a heavily pretreated salvage population. The preclinical evaluation of the combination of paclitaxel and cisplatin allowed for the most appropriate sequencing and dosing of the two agents. In addition, preclinical evaluation suggests that these agents are synergistic as well as active in cisplatin-refractory disease. The combination of paclitaxel and cisplatin was evaluated clinically and demonstrated an overall response rate of 30%. Doxorubicin is an active agent in germ cell tumors and has nonoverlapping toxicity with pactitaxel and cisplatin. The majority of patients treated in a community setting have not had prior exposure to this agent. Therefore, the regime of doxorubicin, paclitaxel, and cisplatin (ATP) was developed and in a small number of patients was utilized in the salvage setting with a 25% response rate. A pilot study with ATP therapy for patients with nonseminomatous germ cell tumors who have disease progression during induction therapy or first and second salvage regimens and who have received a total of more than six courses of prior chemotherapy is ongoing.

Journal Article↗
PubMed2003

Epidermal growth factor receptor is a marker for syncytiotrophoblastic cells in testicular germ cell tumors.

The epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis, therapy and prognosis of various tumor types. The aim of this study was to investigate EGFR expression in a large series of testicular germ cell tumors (TGCTs). A total of 88 TGCTs (37 of pure type and 51 of mixed type) comprising a total of 44 seminoma, 49 embryonal carcinoma, 32 yolk sac tumor, 28 teratoma and 7 choriocarcinoma components were immunostained for EGFR. EGFR reactivity was observed in the stromal cells of embryonal carcinoma (29%) and in epithelial compartments of teratoma (71%). In addition, EGFR staining was consistently detected in syncytiotrophoblastic cells of choriocarcinoma, seminoma, embryonal carcinoma and yolk sac tumor components. EGFR staining, similar to beta-human chorionic gonadotropin (HCG) immunohistochemistry, was efficiently able to identify syncytiotrophoblastic cells in TGCTs. This study shows that EGFR is expressed in a subset of testicular germ cell tumors and suggests that EGFR may be a useful marker for syncytiotrophoblastic cells.

Biomarkers, Tumor↗
PubMed1997

Time series analysis supporting the hypothesis that enhanced cosmic radiation during germ cell formation can increase breast cancer mortality in germ cell cohorts.

Techniques from cancer epidemiology and time series analysis were used to explore the hypothesis that cosmic radiation can induce germ cell changes leading to increases in future breast cancer mortality. A birth cohort time series for female breast cancer mortality was obtained using a model-independent, age-period-cohort analysis on age-specific mortality data for 1940-1990. The birth cohort series contained several oscillatory components, which were isolated and compared to the corresponding frequency components of a cosmic ray surrogate time series-Greenland ice-core 10Be concentrations. A technique, referred to as component wave-train alignment, was used to show that the breast cancer and cosmic ray oscillations were phase-locked approx. 25 years before the time of birth. This is consistent with the time of germ cell formation, which occurs during the fetal development stage of the preceding generation. Evidence is presented that the observable oscillations in the birth cohort series were residues of oscillations of much larger amplitude in the germ cell cohort, which were attenuated by the effect of the broad maternal age distribution. It is predicted that a minimum of 50% of breast cancer risk is associated with germ cell damage by cosmic radiation (priming event), which leads to the development of individuals with a higher risk of breast cancer. It is proposed that the priming event, by preceding other steps of carcinogenesis, works in concert with risk factor exposure during life. The priming event is consistent with epigenetic changes such as imprinting.

Adult↗
PubMed1996

Mono-(2-ethylhexyl) phthalate rapidly alters both Sertoli cell vimentin filaments and germ cell apoptosis in young rat testes.

Mono-(2-ethylhexyl) phthalate (MEHP) is a widely studied Sertoli cell toxicant. Here we describe alterations in Sertoli cell vimentin filament distribution and the incidence of testicular germ cell apoptosis in young (28-day-old) Fischer rats that were treated with MEHP (2 microgram/kg, po) and killed 0, 3, 6, or 12 hr after exposure. A collapse in vimentin filaments was observed 3 hr after MEHP exposure without accompanying changes in the pattern of Sertoli cell tubulin or actin. A progressive increase in the perinuclear condensation of the vimentin filaments was observed from 6 to 12 hr after exposure. To evaluate the consequences of these Sertoli cell changes on germ cells, the role of apoptosis in MEHP-induced testicular toxicity was examined. DNA isolated from testis of rats 6 and 12 hr after MEHP exposure showed a marked increase in low-molecular-weight DNA resulting from internucleosomal cleavage. In addition, DNA fragmentation visualized in frozen testis cross sections by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick end label (TUNEL) staining demonstrated a progressive increase in germ cell apoptosis from 6 to 12 hr after MEHP exposure. However, 3 hr after MEHP exposure, the incidence of TUNEL-positive germ cells was significantly decreased compared to that seen in controls. Taken together, the early collapse in Sertoli cell vimentin filaments and the concurrent decrease in germ cell apoptosis suggests that MEHP engenders Sertoli cell dysfunction resulting in the disruption of the physiological mechanism of germ cell apoptosis.

Animals↗
PubMed2003

Cell migration and programmed cell death of Drosophila germ cells.

Cell migration and programmed cell death are essential components of animal development and homeostasis, and the germ cells of Drosophila provide a simple genetic system to study the molecular mechanisms that govern these important cellular processes. Detailed descriptions of germ cell migration in Drosophila were accomplished long ago, but most genetic and molecular analyses of the process have occurred within the past 10 years. A few of the genes required for germ cell migration have been identified, and a very interesting picture is emerging. However, a process as complex as cell migration must involve the functions of many more molecules. In addition, cell migration and cell death mechanisms are often linked, as it is important to eliminate cells that are misplaced and could present a danger to the organism. In Drosophila, genes involved in germ cell migration can also affect programmed cell death. Currently, very little is known about how germ cells ectopic to the gonads are eliminated. To date, only four genes have been reported with roles in germ cell death, and three of these have additional functions in germ cell pathfinding. The nature of the cell death program has not been elucidated. Here, I provide a brief review of Drosophila germ cell migration and programmed cell death at both the descriptive and molecular levels. Many questions remain to be answered, but advances made in recent years are providing useful insights into these critical biological phenomena.

Animals↗
PubMed2000

Regulation of tissue inhibitor of metalloproteinases-1 in rat Sertoli cells: induction by germ cell residual bodies, interleukin-1alpha, and second messengers.

In the testis, FSH has been shown to induce the expression and secretion of tissue inhibitor of metalloproteinases-1 (TIMP-1) from Sertoli cells in vitro. This study was performed to elucidate further the cellular origin of testicular TIMP-1 and its expression by hormonal and paracrine factors. This is the first report on the expression of testicular TIMP-1 in vivo. TIMP-1 mRNA in whole testis was decreased after hypophysectomy and strongly increased by the injection of FSH-S17 to hypophysectomized rats. Primary cultures of both peritubular and Sertoli cells showed basal expression of TIMP-1 mRNA. In contrast, we were unable to detect TIMP-1 mRNA in Leydig cells, freshly isolated immature germ cells (primary spermatocytes and spermatids), or residual bodies. We further show that treatment of Sertoli cells with 8-(4-chlorophenyl)thio-cAMP (8-CPTcAMP) in combination with 12-O-tetradecanoylphorbol 13-acetate (TPA) or Ca(2+) inducers (calcium ionophore A23187 or thapsigargin) had additive (TPA) and synergistic effects (Ca(2+)) on the level of TIMP-1 mRNA and secreted protein. We also show that both the level of TIMP-1 mRNA and secreted protein from Sertoli cells were strongly increased by residual bodies, as well as by the cytokine interleukin-1alpha. TIMP-1 was not up-regulated by either 8-CPTcAMP or interleukin-1alpha in peritubular cells. In contrast to the regulated secretory fraction of TIMP-1, we also detected constitutively expressed immunoreactive TIMP-1 in the nucleus of Sertoli cells, suggesting a role of nuclear TIMP-1 in these cells. In conclusion, our data show that secretion of TIMP-1 from Sertoli cells is highly regulated by hormonal and local processes in the testis, indicating that TIMP-1 is of physiological importance during both testicular development and spermatogenesis.

Animals↗
PubMed1983

Possible liver cell differentiation in testicular germ cell tumours.

Germ cell tumours may imitate various structures of the developing embryo and foetus. Certain structures have, however, very rarely or never been observed in these tumours. Thus the presence of hepatic tissue in testicular germ cell tumours has not been reported. In a series of 37 non-seminomatous testicular tumours seven tumours contained epithelial structures showing morphological and functional resemblance to liver cell trabeculae. These structures were present in tumours with yolk sac tumour (YST) components and most of the tumours also contained teratoid elements. With the immunoperoxidase technique the epithelial structures were heavily stained for alpha-foetoprotein (AFP) and ferritin in all cases, while positive staining for albumin, prealbumin and transferrin was occasionally found. Alpha-I-antitrypsin and haemoglobin F were demonstrated in few scattered cells. Whether or not these epithelial structures should be included among the various patterns of YST or considered to be teratoid components is uncertain. It is suggested that examinations of the heterogeneity of the concomitant serologic AFP may support one or other assumption.

Cell Differentiation↗
PubMedDate not supplied

Immunostaining of stage-specific embryonic antigen-4 in intratubular germ cell neoplasia unclassified and in testicular germ-cell tumors.

Stage-specific embryonic antigen-4 (SSEA-4) is expressed in testicular germ-cell tumors (GCT) according to studies using thin-layer chromatography (TLC) immunostaining. To further understand the relationship between SSEA-4 and the histogenesis of testicular GCT, we examined the expression of SSEA-4 in 43 samples of testicular GCT either by immunohistochemical staining or by TLC immunostaining. Immunohistochemical staining detected SSEA-4 in spermatogonia from the non-tumor parts of the testis and in all of 8 samples of intratubular germ cell neoplasia unclassified (IGCNU). Immunohistochemical staining was SSEA-4 positive in all 9 seminomas, and in one yolk sac tumor and in 5 embryonal carcinomas among 9 non-seminomas. Immunostaining with TLC showed that SSEA-4 was retained in 15 of 16 seminomas and in 4 of 8 non-seminomas. These results demonstrate an antigenic link between spermatogonia, IGCNU, and testicular GCT. We suggest that SSEA-4 is associated with the histogenesis of testicular GCT.

Adult↗
PubMed1991

Testicular germ cell tumor seven years after a retroperitoneal germ cell tumor.

A 44-year-old male was diagnosed in August 1980 as having a retroperitoneal germ cell tumor (classic seminoma with anaplastic areas). After treatment with cisplatin-based chemotherapy, he reached complete clinical and pathological remission. Eighty-eight months later, in December 1987, he was diagnosed as having a testicular mixed germ cell tumor (embryonal carcinoma with anaplastic seminoma areas) after right orchiectomy. The potential mechanisms by which the latter tumor could have developed are discussed.

Adult↗
PubMed1998

Spontaneous germ cell apoptosis in humans: evidence for ethnic differences in the susceptibility of germ cells to programmed cell death.

Spontaneous death of certain classes of germ cells has been shown to be a constant feature of normal spermatogenesis in a variety of mammalian species, including the human. Recent studies on various animal models have demonstrated that apoptosis is the underlying mechanism of germ cell death during normal spermatogenesis. Withdrawal of gonadotropins and/or testosterone further accelerates the germ cell apoptosis. We examined the involvement of apoptosis in the spontaneous loss of germ cells in men. Testicular samples obtained at autopsy from 5 Chinese and 9 non-Hispanic Caucasian men were analyzed. To identify individual germ cells undergoing apoptosis, we used a modified terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling technique that detects germ cell apoptosis with high sensitivity and specificity. Testicular sections from all 14 subjects exhibited spontaneous occurrence of germ cell apoptosis involving spermatogonia, spermatocytes, and spermatids (apoptotic indexes, 1.6 +/- 0.4 2.5 +/- 0.6, and 5.5 +/- 1.2, respectively). The incidence of spermatogonial (2.8 +/- 0.8 vs. 1.0 +/- 0.2) as well as spermatid (9.3 +/- 2.1 vs. 8.4 +/- 0.9) apoptosis was higher in Chinese than in Caucasian men. A higher incidence of spermatocyte apoptosis was also noted for Chinese (4.4 +/- 1.4) compared to Caucasian (1.9 +/- 0.4) men, but the difference was not statistically significant. These results suggest that germ cell death during normal spermatogenesis in men occurs via apoptosis and provide evidence for ethnic differences in the inherent susceptibility of germ cells to programmed cell death. Our data may also help to explain the greater efficacy of testosterone-induced spermatogenic suppression to azoospermia observed in Asian compared to non-Asian men.

Adult↗
PubMed2006

Male germ cells.

Primordial germ cells, which carry the responsibility for perpetuation of the species, are set aside from their somatic neighbors very early in mammalian embryonic development. The founder population of germ cells is rare and difficult to identify and isolate in quantities suitable for molecular and biochemical analysis, thereby highlighting the importance of an in vitro system for deriving germ cells from embryonic stem cells. This chapter details methods for in vitro derivation of germ lineage elements and discusses potential applications of these techniques in germ cell research.

Animals↗
PubMed2006

Feasibility and usefulness of high-dose chemotherapy (high-dose ifosfamide, carboplatin and etoposide) combined with peripheral blood stem cell transplantation for male germ cell tumor: a single-institute experience.

Although the usefulness of high-dose chemotherapy with peripheral blood stem cell transplantation for advanced germ cell tumor is still under evaluation in phase III randomized controlled studies, this approach is currently used as one treatment option for relapsed or advanced male germ cell tumor. Clinical outcomes of high-dose chemotherapy for a single institute from Japan are presented herein. We administered 63 courses of high-dose ifosfamide, carboplatin and etoposide chemotherapy (1250 mg/m carboplatin; 1500 mg/m etoposide; 7.5 g/m ifosfamide) to 34 men with germ cell tumors. Of these, 27 patients underwent high-dose ifosfamide, carboplatin and etoposide as first-line therapy after 2-3 courses of conventional bleomycin, etoposide and cisplatin chemotherapy, and seven patients underwent high-dose ifosfamide, carboplatin and etoposide for relapsed germ cell tumor. Peripheral blood stem cells were harvested during previous chemotherapy and sufficient CD34 cells were harvested for transplantation. Although all patients experienced grade 4 hemotoxicity, leukocyte counts recovered to above 1000/mul within 8-11 days after peripheral blood stem cell transplantation. No treatment-related deaths occurred. After a mean follow-up of 45 months (range 12-118 months), 23 of 34 patients (67.6%) remained disease-free. High-dose ifosfamide, carboplatin and etoposide could be performed safely, and could offer an effective means of treating advanced or refractory germ cell tumors in men.

Adolescent↗
PubMed2002

A 3'-truncated transferrin messenger RNA is expressed in rat testicular germ cells.

Rat germ cells express a 0.9-kilobase (kb) message with a sequence similar to that of the 3' portion of mammalian transferrins. The sequence of this transcript, called hemiferrin, was considered unique, suggesting that it was encoded by a gene different from that of rat transferrin. Difficulties in conducting experiments using hemiferrin sequence primers led us to question the original sequence. Ribonuclease protection assays revealed that the hemiferrin sequence provided protection only for bovine sequences and not for rat mRNA. Conversely, a 3' rat transferrin sequence protected only rat liver and testis RNA sequences and not bovine sequences, indicating that the 0.9-kb transcript in germ cells is a truncated form of rat transferrin. Western analysis and immunoprecipitation of germ cell proteins metabolically radiolabeled in vitro and in vivo failed to detect a protein of the predicted size regardless of whether anti-rat transferrin or anti-hemiferrin antibodies were used. The findings suggest that a foreshortened transcript of the transferrin gene is produced in rat germ cells and that little or no protein is made from that transcript.

Animals↗
PubMed2003

Turning germ cells into stem cells.

Primordial germ cells (PGCs), the embryonic precursors of the gametes of the adult animal, can give rise to two types of pluripotent stem cells. In vivo, PGCs can give rise to embryonal carcinoma cells, the pluripotent stem cells of testicular tumors. Cultured PGCs exposed to a specific cocktail of growth factors give rise to embryonic germ cells, pluripotent stem cells that can contribute to all the lineages of chimeric embryos including the germline. The conversion of PGCs into pluripotent stem cells is a remarkably similar process to nuclear reprogramming in which a somatic nucleus is reprogrammed in the egg cytoplasm. Understanding the genetics of embryonal carcinoma cell formation and the growth factor signaling pathways controlling embryonic germ cell derivation could tell us much about the molecular controls on developmental potency in mammals.

Animals↗