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At least 199 records · Page 11Linked to original sources
PubMed1998

The cell cycle program in germ cells of the Drosophila embryo.

The germ cells of metazoans follow a program of proliferation that is distinct from proliferation programs of somatic cells. Despite their developmental importance, the cell proliferation program in the metazoan primordial germ cells is not well characterized and the regulatory controls are not understood. In Drosophila melanogaster, germ cell precursors (called pole cells) proliferate early in embryogenesis and then enter a prolonged quiescence. We found that polar nuclear divisions are asynchronous and lag behind somatic nuclear divisions during syncytial cycles 9 and 10. Thus, the polar division program deviates from the somatic division program when pole nuclei and somatic nuclei still share a common cytoplasm, earlier than previously thought. The lag in polar nuclear divisions is independent of grapes, which is required for lengthening somatic cell cycles 10-13. Mapping of the last S phase in pole cells and measurement of their DNA content indicate that pole cells become quiescent in G2 phase of the cell cycle. We were able to drive quiescent pole cells into mitosis by induction of either an activator of Cdc2 (Cdc25string phosphatase) or a mutant form of Cdc2 that cannot be inhibited by phosphorylation. In contrast, induction of wild-type Cdc2 with a mitotic cyclin did not induce mitosis in pole cells. We propose that inhibition of Cdc2 by phosphorylation contributes to G2 arrest in pole cells during embryogenesis. Furthermore, pole cells enter G1 following induced mitoses, indicating that entry into both mitosis and S phase is blocked in quiescent pole cells. These studies represent the first molecular characterization of proliferation in embryonic germ cells of Drosophila.

Animals↗
PubMed1994

Stem cells from primordial germ cells can reenter the germ line.

Embryonic stem (ES) cells are totipotent cells derived from cultured preimplantation blastocysts. When injected into embryos, they can give rise to all somatic lineages as well as functional gametes. Embryonal carcinoma (EC) cells are pluripotent cells, derived from teratocarcinomas, which contribute to somatic lineages, but only rarely to the germ line. A novel source of pluripotent cells, remarkably similar to both ES and EC cells, has been identified. These are EG cells, derived by culturing primordial germ cells isolated from postimplantation embryos, but it is not known whether they resemble ES or EC cells in their ability to contribute to the germ line. Here we show that EG cells of both sexes can form functional gametes. The derivation of such cell lines offers a new route to deriving totipotent cells and also provides insights into the timing of X-chromosome inactivation/activation and genomic imprinting in the germ line.

Animals↗
PubMed1999

Reprogramming a somatic nucleus by trans-modification activity in germ cells.

The germ cell lineage is totipotent insofar as it provides a link between an individual and the subsequent generations. There is a series of characteristic genomic modifications in germ cells that distinguish this lineage from somatic cells. These modifications include extensive demethylation of the genome, erasure of allele-specific methylation of imprinted loci and re-activation of the silent X chromosome. To test if this is an active process capable of reprogramming a somatic nucleus, we prepared germ cell-somatic cell hybrids. A dominant trans modification activity was detected in germ cells that was capable of inducing similar modifications in the somatic nucleus. This experimental system can therefore be used to study how determined cell state can be reversed by specific genomic modifications.

Animals↗
PubMedDate not supplied

Differential expression of clusterin in the testis and epididymis of postnatal and germ cell deficient mice.

Clusterin is found in a wide variety of tissues and is expressed in a number of physiological and pathological contexts. It is expressed constitutively in the adult male reproductive tract, specifically the testes and caput of the epididymis. The gene is also induced during apoptotic cell death in the kidney and hormone-dependent tissues such as the prostate and mammary gland. The mechanisms controlling the expression of clusterin gene expression in these tissues are still unknown, although it has been suggested that interactions between the Sertoli cells and germ cells in the testis, or epithelial cells and germ cells in the epididymis, may be required for clusterin expression. To investigate the importance of germ cells in the induction of clusterin expression in these tissues, we have used in situ hybridization to determine the developmental regulation and germ cell dependence of clusterin expression in the reproductive tract of the normal and germ cell deficient male mice. Clusterin mRNA is present in the supporting cells in the testes of normal mice and in both atrichosis (at) and dominant spotting mutant (Wv) mice, both of which are germ cell deficient. On the other hand, the expression of clusterin in the epididymis appears to be at least partially dependent of the presence of germ cells, because segmental localization of clusterin mRNA within the caput of the epididymis that is seen in normal mice is disrupted in the at and Wv mutants. In these germ cell deficient mutants, the steady-state level of clusterin mRNA, which is repressed in segment 1 and 2 of the adult wild type mouse, is expressed at levels similar to those seen at days 7 and 17 during the development of the normal epididymis.

Animals↗
PubMed2000

[Stem cell transplantation in germ cell tumors].

High dose chemotherapy (HDCT) with autologous stem cell transplantation in patients with relapsed or refractory non-seminomatous germ cell tumors seems to be the only therapeutic option with curative intention. Evaluation of a scored risk profile before HDCT might significantly support the precise estimation of results after HDCT. Patients with a negative or low score could achieve long-lasting complete remissions or might be cured, whereas patients with absolutely refractory disease do not benefit from HDCT. Ongoing prospective randomised trials in Europe and USA comparing standard therapy with HDCT will hopefully contribute to the right therapeutic decision in the future.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Pagetoid spread of intratubular germ cell neoplasia into rete testis: a morphologic and histochemical study of 100 orchiectomy specimens with invasive germ cell tumors.

Intratubular germ cell neoplasia (ITGCN) is now considered to be the preinvasive phase of testicular germ cell tumors with the exceptions of spermatocytic seminoma, pure yolk sac tumor, and mature teratoma. Pagetoid spread of ITGGN into rete testis is a common yet unpublished finding in these cases. We reviewed 100 cases of testicular germ cell tumors from the Surgical Pathology service of Parkland Memorial Hospital (Dallas, TX) to evaluate the frequency of this pattern of spread. Additional sections were obtained from selected cases and were stained with anti-placental alkaline phosphatase, anti-low molecular weight keratin (clone AE1), and various lectins to highlight the process. Pagetoid spread of ITGCN into rete testis was identified in 24 of 60 cases (40%) in which histologic sections contained both ITGCN and rete testis. The incidence of pagetoid ITGCN involvement of the rete testis was lower in pure seminoma (seven of 25 cases [28%]) than in testes containing nonseminomatous germ cell tumors (17 of 35 cases [49%]). AE1 stained the epithelial cells of the rete testis but not the cells of the ITGCN, whereas placental alkaline phosphatase stained the neoplastic cells but not the epithelial cells of the rete testis. These stains were useful in delineating two cases in which the pagetoid involvement was so extensive that they were misdiagnosed as invasive seminomas. Pagetoid spread of ITGCN is a relatively common finding in testicular germ cell tumors and rarely can be mistaken for invasive seminoma. Immunohistochemistry can be helpful in distinguishing florid pagetoid spread from invasive seminoma.

Adolescent↗
PubMed2006

The role of exogenous fibroblast growth factor-2 on the reprogramming of primordial germ cells into pluripotent stem cells.

The germ cell lineage is a specified cell population that passes through a series of differentiation steps before giving rise, eventually, to either eggs or sperm. We have investigated the manner in which primordial germ cells (PGCs) are reprogrammed in vitro to form pluripotent stem cells in response to exogenous fibroblast growth factor-2 (FGF-2). The response is dependent on time of exposure and concentration of FGF-2. PGCs isolated in culture show a motile phenotype and lose any expression of a characteristic germ cell marker, mouse vasa homolog. Subsequently, some but not all of the cells show further changes of phenotype, accompanied by changes in expression of endogenous FGF-2 and up-regulation of its receptor, fibroblast growth factor receptor-3, in the nucleus. We propose that it is from this reprogrammed component of the now heterogeneous PGC population that pluripotent stem cells arise.

Animals↗
PubMed1996

Fate of germ cells in 2,5-hexanedione-induced testicular injury. I. Apoptosis is the mechanism of germ cell death.

2,5-hexanedione (2,5-HD) is a Sertoli cell toxicant which causes germ cell loss and testicular atrophy in the rat. The mechanism of germ cell death over the course of 2,5-HD treatment is not known nor is the reason why residual germ cells do not repopulate the seminiferous epithelium following toxicant withdrawal. In the current study, the role of apoptosis in germ cell loss was studied. Male Fischer rats were treated for up to 5 weeks with 1% 2,5-HD in the drinking water and killed between 0 and 12 weeks after the start of toxicant exposure. Apoptosis was assessed in control and treated animals by (1) DNA fragmentation detected by gel electrophoresis, (2) cellular morphology on plastic sections, and (3) DNA fragmentation in situ by terminal deoxy-nucleotidyl transferase-mediated digoxigenin-UTP nick end label (TUNEL) staining of testis cross sections. All three indices demonstrated a substantial increase in apoptosis which peaked at 5 weeks of 2,5-HD treatment. Morphological analysis determined that apoptosis occurred in germ cells of the seminiferous epithelium. DNA fragmentation determined by gel electrophoresis was barely detectable until 5-6 weeks of toxicant exposure. However, TUNEL staining of testis cross sections indicated that germ cell apoptosis increased after as early as 2 weeks of toxicant exposure, providing a highly sensitive biological marker of toxicant-induced testicular injury. These data also suggested a differential sensitivity of germ cells to toxicant exposure with spermatid apoptosis occurring first at 4-5 weeks of treatment followed by apoptosis of spermatocytes and spermatogonia between 6 and 12 weeks. Together, these data demonstrate that apoptosis is the mechanism of germ cell loss in 2,5-HD-induced testicular injury.

Animals↗
PubMed1984

Benign Leydig cell tumour and germ cell carcinoma in situ in a young man with gynaecomastia.

A 21-year-old man presented with a 16-year history of recurrent pyrexial episodes and a 5-year history of gynaecomastia. Blood and urinary oestrogen levels were elevated and a mass was found in the upper pole of a retractile right testis. After orchidectomy, oestrogen levels fell, gynaecomastia regressed and the pyrexial episodes ceased. Histological examination of the right testis showed a benign Leydig cell tumour in the upper pole and a germinal cell carcinoma in situ in the remaining part of the testis. Thus a potentially lethal condition was detected at an early pre-malignant phase by virtue of a benign, endocrinologically active tumour. This would seem to be the first report of the co-existence of a Leydig cell tumour and germ cell carcinoma in the same testis.

Adult↗
PubMed1997

Germ cell tumors.

Germ cell tumors are relatively uncommon childhood tumors. Several interesting characteristics distinguish them from other tumors. (1) Abnormal migration of primordial germ cells results in the frequent occurrence of extragonadal germ cell tumors in children. (2) Serum markers exist to allow evaluation of extent of resection and development of recurrent tumor. (3) The introduction of modern chemotherapy including cisplatin, etoposide, and bleomycin has significantly improved survival of these children. Optimal therapy includes complete surgical resection, accurate histological examination, and selective use of chemotherapy. Mature and immature teratomas at any site and stage I testicular cancers are managed by observation alone, whereas all other tumors require chemotherapy.

Chemotherapy, Adjuvant↗
PubMed1991

Hyperplasia and hypertrophy of Leydig cells associated with testicular germ cell tumours containing syncytiotrophoblastic giant cells.

In patients with seminomas and non-seminomatous germ cell tumours of the testis syncytiotrophoblastic giant cells (STGC) are largely responsible for elevated levels of chorionic gonadotropin. In searching for these cells, the question arises whether hyperplasia and/or hypertrophy of Leydig cells in the adjacent testicular tissue is a relevant finding. To elucidate this problem we analysed the tumour-free testicular tissue of 20 seminomas and 20 combined seminomatous and non-seminomatous germ cell tumours with or without immunohistochemically demonstrable STGC morphometrically. Extension of Leydig cell areas and the surface areas of Leydig cells per tubule are increased significantly in seminomas and combined tumours when STGC are present. There is also an apparent increase in the number of Leydig cells per tubule in seminomas and combined germ cell tumours with STGC. The difference, however, is not significant statistically in the group of seminomas. Hypertrophy and/or hyperplasia of Leydig cells must be considered as a relevant finding in germ cell tumours with STGC. It is most easily recorded by evaluating the surface area of Leydig cells per test area or per tubule.

Dysgerminoma↗
PubMed2000

The treatment of cranial germ cell tumours.

Germ cell tumours of the central nervous system (CNS) include many subtypes whose response to treatment varies, even though the symptoms and radiological appearances are similar. Five-year survival rates are 96% for germinomas, 100% for mature teratomas, 67% for immature teratomas and 69% for immature teratomas mixed with germinomas; for beta-HCG secreting germinomas the rate is only 38%. Patients with choriocarcinoma, embryonal carcinoma, or yolk sac tumour have the lowest survival rates; patients with germinoma or mature teratoma have longer survival rates. Although a wider resection is associated with a higher rate of survival for patients with non-germinomatous germ cell (NGGC) tumours, to date an aggressive surgical approach has been advocated only for pineal region tumours, but not for hypothalamic/neurohypophyseal tumours. Beside the delayed injury induced by radiotherapy, the late injury induced by chemotherapy is becoming increasingly evident. Cisplatin is considered an indispensable drug, but it may cause renal damage, ototoxicity, peripheral neuropathy and sterility, while etoposide is associated with an excess frequency of second neoplasms. Taking into account all of the published literature, the following therapeutic options are suggested: in pure germinoma tumours (GT) radiotherapy alone will usually ensure adequate control of the disease, and the long-term sequelae may be limited by reducing the dose delivered, as was proposed for germ cell testicular tumours, to 30 Gy to limited fields plus 25-30 Gy to the spinal axis if there is disseminated disease. In cases of recurrence, which should be uncommon, patients may be rescued with both radiotherapy and chemotherapy. In NGGC tumours, the prognosis is more unfavourable and there is often dissemination to the spine at diagnosis; however, the tumour's high chemosensitivity suggests neoadjuvant treatment chemotherapy with cisplatin and etoposide for three cycles followed by consolidation radiotherapy with 40 Gy to the limited fields plus 30 Gy to the spinal axis if disseminated. In our opinion, a higher dose of radiotherapy in cases in which chemotherapy does not achieve a radiological complete remission is not advisable, because very often the residual radiological abnormality does not represent biologically active tumour but differentiated forms such as mature teratoma. The challenge for 2000 is to both cure these patients, and avoid the late and permanent sequelae of radiation and/or chemotherapy that may subsequently impair quality of life.

Brain Neoplasms↗
PubMed2006

A novel transforming growth factor-beta superfamily member expressed in gonadal somatic cells enhances primordial germ cell and spermatogonial proliferation in rainbow trout (Oncorhynchus mykiss).

Our understanding of the molecular mechanisms of primordial germ cell (PGC) proliferation in fish is rudimentary, but it is thought to be controlled by the surrounding somatic cells. We assumed that growth factors that are specifically involved in PGC proliferation are expressed predominantly in the surrounding genital ridge somatic cells. In order to isolate these growth factors, we compiled a complementary DNA (cDNA) subtractive library using cDNA from the genital ridges of 40-dpf rainbow trout embryos as the tester and cDNA from embryos without genital ridges as the driver. This approach identified a novel cytokine, designated gonadal soma-derived growth factor (GSDF), which is a member of the transforming growth factor (TGF)-beta superfamily. GSDF was expressed in the genital ridge somatic cells surrounding the PGCs during embryogenesis, and in both the granulosa and Sertoli cells at later stages. Inhibition of GSDF translation by antisense oligonucleotides suppressed PGC proliferation. Moreover, isolated testicular cells that were cultured with recombinant GSDF demonstrated dose-dependent proliferation of type-A spermatogonia; this effect was completely blocked by antiserum against GSDF. These results denote that GSDF, a novel member of the TGF-beta superfamily, plays an important role for proliferation of PGC and spermatogonia.

Animals↗
PubMed1995

Immunoaffinity purification of migratory mouse primordial germ cells.

Primordial germ cells (PGCs) are the earliest identifiable germ cells in the embryo. It has not previously been possible to purify PGCs from mammalian embryos at early stages of development (before they arrive in the gonads), when such cells are very low in number, are moving along different tissues toward the gonadal ridges, and are not identifiable by morphological criteria alone. We report here that the use of PGC-specific TG-1 antibody in combination with immunoaffinity adhesion to plastic plates coated with anti-mouse IgM secondary antibody allows the isolation of reasonably pure yields of migratory PGCs from 9.5- to 11.5-dpc mouse embryos.

Animals↗
PubMed2001

Comparison of two standard chemotherapy regimens for good-prognosis germ-cell tumours: a randomised trial. Australian and New Zealand Germ Cell Trial Group.

BACKGROUND: Most patients with metastatic germ-cell tumours are cured with chemotherapy. However, the optimum chemotherapy regimen is uncertain, and there is variation in international practice. We did a multicentre randomised trial to compare two standard chemotherapy regimens for men with good-prognosis germ-cell tumours. METHODS: Good prognosis was defined by modified Memorial Sloan-Kettering criteria. The first regimen (regimen A) was based on treatment recommendations from Indiana University and comprised three cycles of 20 mg/m2 cisplatin on days 1-5, 100 mg/m2 etoposide on days 1-5, and 30 kU bleomycin on days 1, 8, and 15, repeated every 21 days. The second regimen (regimen B) was based on the control regimen of a published randomised clinical trial and comprised four cycles of 100 mg/m2 cisplatin on day 1, 120 mg/m2 etoposide on days 1-3, and 30 kU bleomycin on day 1, repeated every 21 days. The primary outcome measure was overall survival. Analysis was by intention to treat. FINDINGS: 166 patients were randomised, 83 to each regimen. The trial was stopped when the second planned interim analysis met predefined stopping rules. The median follow-up was 33 months. Overall survival was substantially better with regimen A (three vs 13 deaths, hazard ratio 0.22 [95% CI 0.06-0.77], p=0.008). This difference was due to deaths from cancer (one vs nine), and not deaths from treatment (two vs two) and remained significant after adjustment for other prognostic factors (0.25 [0.07-0.88], p=0.03). INTERPRETATION: In men with good-prognosis germ-cell tumours, the regimen developed at Indiana University is superior to the alternative regimen studied in this trial. The lower total dose and dose-intensity of bleomycin and the lower dose-intensity of etoposide in regimen B could be responsible for the worse outcome.

Adolescent↗
PubMed2006

Transforming growth factor beta inhibits proliferation of somatic cells without influencing germ cell number in the chicken embryonic ovary.

The gonadal development of chicken embryo is regulated by hormones and growth factors. Transforming growth factor beta (TGF-beta) isoforms may play a critical role in the regulation of growth in chicken gonads. We have investigated the effect of the TGF-beta isoforms on the number of germ and somatic cells in the ovary of the chicken embryo. Ovaries were obtained from chicken embryos at 9 days of incubation. They were organ-cultured for 72 h in groups treated with TGF-beta1, TGF-beta2, soluble betaglycan, TGF-beta1 plus soluble betaglycan, or TGF-beta2 plus soluble betaglycan, and untreated (control). TGF-beta1 and TGF-beta2 diminished the somatic cell number in the ovary of the chicken embryo at this age by inhibiting the proliferation of the somatic cells without increasing apoptosis. On the other hand, TGF-beta1 and TGF-beta2 did not affect the number of germ cells in the cultured ovary. The capacity of TGF-beta1 and TGF-beta2 to diminish the number of somatic cells in the ovary was blocked with soluble betaglycan, a natural TGF-beta antagonist. However, changes in the location of germ cells within the ovary suggested that TGF-beta promoted the migration of the germ cells from the ovarian cortex to the medulla. Thus, TGF-beta affects germ and somatic cells in the ovary of the 9-day-old chicken embryo and inhibits the proliferation of somatic cells.

Animals↗
PubMed2004

Sertoli-Sertoli and Sertoli-germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis.

Spermatogenesis is the process by which a single spermatogonium develops into 256 spermatozoa, one of which will fertilize the ovum. Since the 1950s when the stages of the epithelial cycle were first described, reproductive biologists have been in pursuit of one question: How can a spermatogonium traverse the epithelium, while at the same time differentiating into elongate spermatids that remain attached to the Sertoli cell throughout their development? Although it was generally agreed upon that junction restructuring was involved, at that time the types of junctions present in the testis were not even discerned. Today, it is known that tight, anchoring, and gap junctions are found in the testis. The testis also has two unique anchoring junction types, the ectoplasmic specialization and tubulobulbar complex. However, attention has recently shifted on identifying the regulatory molecules that "open" and "close" junctions, because this information will be useful in elucidating the mechanism of germ cell movement. For instance, cytokines have been shown to induce Sertoli cell tight junction disassembly by shutting down the production of tight junction proteins. Other factors such as proteases, protease inhibitors, GTPases, kinases, and phosphatases also come into play. In this review, we focus on this cellular phenomenon, recapping recent developments in the field.

Animals↗
PubMed1995

Adenocarcinomatous transformation of intracranial germ cell tumors.

Germ cell tumors arising in the gonads, retroperitoneum, and mediastinum are occasionally overgrown by cancers of somatic type that are widely assumed to derive from the "malignant transformation" of included teratomatous tissues. These malignant, nongerminal neoplasms are typically chemoresistant, and their emergence is often associated with fatal treatment failure. Only rare, well-documented reports of sarcomatous transformation complicating intracranial germ cell neoplasia are on record. We describe two nongerminomatous germ cell tumors of the pineal region that underwent transformation into enteric-type adenocarcinoma. Both recurred in a locally aggressive fashion, one proving rapidly fatal owing to the development of multiple cerebral and cerebellar metastases and spinal leptomeningeal adenocarcinomatosis.

Adenocarcinoma↗