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Testicular Germ Cell Tumours (testicular + germ_cell_tumour)
Selected AbstractsKIT and RAS signalling pathways in testicular germ cell tumours: new data and a review of the literatureINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 4 2007N. C. Goddard Summary Testicular germ cell tumours (TGCTs) are the leading cause of cancer deaths in young male Caucasians. Identifying changes in DNA copy number can pinpoint genes involved in tumour development. We defined the smallest overlapping regions of imbalance in TGCTs using array comparative genomic hybridization analysis. Novel regions, or regions which refined those previously reported, were identified. The expression profile of genes from 12p, which is invariably gained in TGCTs, and amplicons defined at 12p11.2-12.1 and 4q12, suggest KRAS and KIT involvement in TGCT and seminoma development, respectively. Amplification of these genes was not found in intratubular germ cell neoplasia adjacent to invasive disease showing these changes, suggesting their involvement in tumour progression. Activating mutations of RAS genes (KRAS or NRAS) and overexpression of KRAS were mutually exclusive events. These, correlations between the expression levels of KIT, KRAS and GRB7 (which encodes an adapter molecule known to interact with the KIT tyrosine kinase receptor) and other reported evidence reviewed here, are consistent with a role for activation of KIT and RAS signalling in TGCT development. In order to assess a role for KIT in seminomas, we modulated the level of KIT expression in TCam-2, a seminoma cell line. The likely seminomatous origin of this cell line was supported by demonstrating KIT and OCT3/4 overexpression and gain of 12p material. Reducing the expression of KIT in TCam-2 through RNA inhibition resulted in decreased cell viability. Further understanding of KIT and RAS signalling in TGCTs may lead to novel therapeutic approaches for these tumours. [source] Increased expression and nuclear localization of the centrosomal kinase Nek2 in human testicular seminomas,THE JOURNAL OF PATHOLOGY, Issue 3 2009Federica Barbagallo Abstract Protein kinases that regulate the centrosome cycle are often aberrantly controlled in neoplastic cells. Changes in their expression or activity can lead to perturbations in centrosome duplication, potentially leading to chromosome segregation errors and aneuploidy. Testicular germ cell tumours (TGCTs) are characterized by amplification of centrosomes through unknown mechanisms. Herein, we report that Nek2, a centrosomal kinase required for centrosome disjunction and formation of the mitotic spindle, is up-regulated in human testicular seminomas as compared to control testes or other types of testicular germ cell tumours. In addition, Nek2 activity is also increased in human seminomas, as demonstrated by immunokinase assays. Analysis by immunohistochemistry indicated that Nek2 is prevalently localized in the nucleus of neoplastic cells of primary human seminomas. Such nuclear localization and the up-regulation of Nek2 protein were also observed in the Tcam-2 seminoma cell line. We demonstrate that nuclear localization of Nek2 is a feature of the more undifferentiated germ cells of mouse testis and correlates with expression of the stemness markers OCT4 and PLZF. These studies suggest that up-regulation of Nek2 is a frequent event in human seminomas and that this may participate in the onset or progression of neoplastic transformation through deregulation of centrosome duplication and/or nuclear events in germ cells. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] The role of the histopathologist in the management of testicular germ cell tumour in adultsHISTOPATHOLOGY, Issue 3 2001M C Parkinson In the last 20,30 years the availability of effective chemotherapy and more accurate clinical staging has greatly improved the prognosis for patients with testicular germ cell tumours. Initially, such treatment appeared to diminish the role of histopathology to the distinction between seminoma and nonseminomatous germ cell tumour (NSGCT) in the primary specimen. However, histopathology has evolved as a prognostic tool indicating the risk of relapse in various defined clinical contexts thereby facilitating therapeutic decisions. The clinical emphasis has been on quality of life and reduction of therapy both in terms of the number of patients treated and the number of chemotherapy courses given to each patient. The treatment of adult testicular germ cell tumours may differ between countries but protocols are established. Therefore it is appropriate to discuss the role of histopathology during this era of relative therapeutic stability. [source] Lipoprotein lipase and endothelial lipase in human testis and in germ cell neoplasmsINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 1 2010J. E. Nielsen Summary The aim of this study was to investigate endothelial lipase (EL, LIPG) and lipoprotein lipase (LPL) mRNA and protein expression in normal human testis and testicular germ cell tumours (GCT). Both EL and LPL were expressed in normal seminiferous tubules and in the interstitial compartment. EL mRNA and protein were found in all germ cells as well as in Sertoli and Leydig cells. EL mRNA was abundant in pre-invasive carcinoma in situ (CIS) cells and GCTs, and EL protein was present in the cytoplasm of these cells. LPL mRNA was also relatively abundant in germ cells, Sertoli cells, CIS cells and GCTs. The LPL protein, however, was restricted to the cell membranes of pachytene spermatocytes and spermatids in normal tubules, absent from CIS cells and scarcely represented in tumours. The distribution of LPL protein in non-seminomas resembled the distribution of OCT3/4, a marker of embryonal carcinoma. The results suggest that both EL and LPL participate in the supply of nutrients and steroidogenesis in the testes, and that especially EL may be important for the supply of cholesterol for testosterone production in the Leydig cells. The partial cellular separation of the expression of the two lipases in normal testis suggests the existence of distinct biological roles, perhaps developmentally regulated, as indicated by the LPL expression in GCTs with embryonic features. A high expression of EL and abundance of lipid in tubules with CIS may have a diagnostic value. [source] Expression of Fas and Fas ligand in human testicular germ cell tumoursINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 2 2009E. Baldini Summary In the present study, we analysed the expression of Fas ligand (FasL) and its cognate receptor Fas in 14 seminomatous testicular germ cell tumours (TGCT) and six normal testicular tissues obtained following orchiectomy. Tissue samples have been processed to prepare either total RNA or protein extracts or fixed and embedded in paraffin for immunohistochemistry (IHC) experiments. Quantitative RT-PCR experiments demonstrated in TGCT a significant (p < 0.01) increase of the FasL mRNA expression of 21.1 ± 5.4 fold, with respect to normal tissues. On the contrary, in the same cancer tissues, the levels of Fas mRNA were significantly (p < 0.01) reduced to 0.27 ± 0.06 fold. These observations were confirmed in western blot experiments showing a significant increase of FasL and a concomitant decrease of Fas proteins in testicular cancer tissues, with respect to normal testis. Moreover, IHC experiments showed a strong FasL immuno-reactivity in six out of eight TGCT samples analysed, while Fas immuno-positivity was found in cancer cells of only two TGCT tissues. In addition, in all tumour samples, infiltrating lymphocytes were Fas positive. However, no correlation could be observed between Fas or FasL mRNA variations and clinical parameters such as patient's age, TNM stage or tumour size. We also compared the serum levels of soluble FasL (sFasL) of 15 patients affected by seminomatous TGCT, of four patients with non-seminomatous TGCT and six age-matched healthy males. No significant differences in sFasL serum level could be identified. In conclusion, our data demonstrated that the majority of seminomas are characterized by an increased expression of FasL and a concomitant reduction of Fas, with respect to human normal testis, and that sFasL serum level is not a tumour marker for patients affected by TGCT. [source] KIT and RAS signalling pathways in testicular germ cell tumours: new data and a review of the literatureINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 4 2007N. C. Goddard Summary Testicular germ cell tumours (TGCTs) are the leading cause of cancer deaths in young male Caucasians. Identifying changes in DNA copy number can pinpoint genes involved in tumour development. We defined the smallest overlapping regions of imbalance in TGCTs using array comparative genomic hybridization analysis. Novel regions, or regions which refined those previously reported, were identified. The expression profile of genes from 12p, which is invariably gained in TGCTs, and amplicons defined at 12p11.2-12.1 and 4q12, suggest KRAS and KIT involvement in TGCT and seminoma development, respectively. Amplification of these genes was not found in intratubular germ cell neoplasia adjacent to invasive disease showing these changes, suggesting their involvement in tumour progression. Activating mutations of RAS genes (KRAS or NRAS) and overexpression of KRAS were mutually exclusive events. These, correlations between the expression levels of KIT, KRAS and GRB7 (which encodes an adapter molecule known to interact with the KIT tyrosine kinase receptor) and other reported evidence reviewed here, are consistent with a role for activation of KIT and RAS signalling in TGCT development. In order to assess a role for KIT in seminomas, we modulated the level of KIT expression in TCam-2, a seminoma cell line. The likely seminomatous origin of this cell line was supported by demonstrating KIT and OCT3/4 overexpression and gain of 12p material. Reducing the expression of KIT in TCam-2 through RNA inhibition resulted in decreased cell viability. Further understanding of KIT and RAS signalling in TGCTs may lead to novel therapeutic approaches for these tumours. [source] Testicular carcinoma in situ in subfertile Danish menINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 4 2007Inge A. Olesen Summary Carcinoma in situ (CIS) testis is the precursor stage for the majority of testicular germ cell tumours (TGCT). Infertility is one of the conditions known to predispose to TGCT, but based on scarce existing data, the prevalence of CIS in this risk group was estimated at only approximately 1%. To establish more objective data, we investigated retrospectively the prevalence of CIS based on testicular biopsies performed in a well-defined group of subfertile males. We included 453 patients who had testicular biopsies performed for infertility reasons during 1995,2005 at the Copenhagen University Hospital (Rigshospitalet). Biopsies were evaluated by two experienced observers independently. CIS was detected in 10 individuals, of whom three had bilateral CIS, corresponding to a prevalence of 2.2% (95% CI 1.1,4.0%). This is greater than the estimated risk of 0.45% for the age- and birth cohort-matched general Danish population. All patients with CIS testis had severe oligozoospermia (,2.06 million/mL). We confirmed that a thorough examination of men suffering from subfertility/infertility can identify those with an increased risk for testicular neoplasia and recommend performing bilateral biopsies, especially in the subpopulation of men with atrophic testicles, severe oligozoospermia and/or irregular ultrasonic pattern of their testicles. [source] Aurora B expression in post-puberal testicular germ cell tumours,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2009Francesco Esposito Aurora/Ipl1-related kinases are a conserved family of proteins that are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumours and have been implicated in mechanisms leading to mitotic spindle aberrations, aneuploidy, and genomic instability. Previous studies of our group have shown that Aurora B expression is restricted to specific germinal cells. In this study, we have evaluated by immunohistochemical analysis Aurora B expression in post-puberal testicular germ cell tumours (22 seminomas, 2 teratomas, 15 embryonal carcinomas, 5 mixed germinal tumours with a prominent yolk sac tumour component and 1 choriocarcinoma). The Aurora B protein expression was detected in all intratubular germ cell tumours, seminomas and embryonal carcinomas analysed but not in teratomas and yolk sac carcinomas. The immunohistochemical data were further confirmed by Western blot analysis. In addition, the kinase Aurora B was vigorously expressed in GC-1 cells line derived from murine spermatogonia. The block of Aurora B function induced by a pharmacological inhibitor significantly reduced the growth of GC-1 cells suggesting that Aurora B is a potential therapeutic target. J. Cell. Physiol. 221: 435,439, 2009. © 2009 Wiley-Liss, Inc. [source] Increased expression and nuclear localization of the centrosomal kinase Nek2 in human testicular seminomas,THE JOURNAL OF PATHOLOGY, Issue 3 2009Federica Barbagallo Abstract Protein kinases that regulate the centrosome cycle are often aberrantly controlled in neoplastic cells. Changes in their expression or activity can lead to perturbations in centrosome duplication, potentially leading to chromosome segregation errors and aneuploidy. Testicular germ cell tumours (TGCTs) are characterized by amplification of centrosomes through unknown mechanisms. Herein, we report that Nek2, a centrosomal kinase required for centrosome disjunction and formation of the mitotic spindle, is up-regulated in human testicular seminomas as compared to control testes or other types of testicular germ cell tumours. In addition, Nek2 activity is also increased in human seminomas, as demonstrated by immunokinase assays. Analysis by immunohistochemistry indicated that Nek2 is prevalently localized in the nucleus of neoplastic cells of primary human seminomas. Such nuclear localization and the up-regulation of Nek2 protein were also observed in the Tcam-2 seminoma cell line. We demonstrate that nuclear localization of Nek2 is a feature of the more undifferentiated germ cells of mouse testis and correlates with expression of the stemness markers OCT4 and PLZF. These studies suggest that up-regulation of Nek2 is a frequent event in human seminomas and that this may participate in the onset or progression of neoplastic transformation through deregulation of centrosome duplication and/or nuclear events in germ cells. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents,THE JOURNAL OF PATHOLOGY, Issue 1 2009DC Gilbert Abstract Interaction between the chemokine CXCL12 (SDF1) and the G-protein coupled receptor CXCR4 is responsible for the maintenance of adult stem cell niches and is known to play an important role in utero in the migration of primordial germ cells. We demonstrate expression of CXCL12 by Sertoli cells and confirm CXCR4 expression by the germ cell population of the adult human testes. CXCR4 is also known to mediate organ-specific patterns of metastases in a range of common cancers. We identify consistent expression of CXCR4 mRNA and protein in testicular germ cell tumours (TGCT) that accounts for their patterns of relapse in sites of known CXCL12 expression. Extragonadal primary germ cell tumours express CXCR4 and their sites of occurrence are coincident with areas of known CXCL12 expression in utero. We show that CXCL12 stimulates the invasive migration of a TGCT cell line in vitro in a CXCR4-dependent fashion and activates ERK. Furthermore, we demonstrate that expression of CXCL12 in stage I non-seminomas is significantly associated with organ-confined disease post-orchidectomy and reduced risk of relapse (p = 0.003). This may be through the loss of CXCL12 gradients that might otherwise attract cells away from the primary tumour. We propose CXCL12 expression as a potential predictor of subsequent relapse that could lead to avoiding unnecessary treatment and associated late toxicities. Our observations support a role for CXCL12/CXCR4 in the adult germ cell population and demonstrate pathological function in germ cell tumour development and metastasis that may have clinical utility. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Deregulation of Aurora kinase gene expression in human testicular germ cell tumoursANDROLOGIA, Issue 4 2010E. Baldini Summary The Aurora kinases regulate chromosome segregation and cytokinesis, and alterations in their expression associate with cell malignant transformation. In this study, we demonstrated by qRT-PCR analysis of 14 seminomas that Aurora-A mRNA was, with respect to control tissues, augmented in five of 14 tumour tissues by 2.17 ± 0.30 fold (P < 0.05) and reduced in 9 to 0.38 ± 0.10 (P < 0.01). Aurora-B mRNA was increased in 11 tumour tissues by 4.33 ± 0.82 fold (P < 0.01) and reduced in 3 to 0.41 ± 0.11 fold. Aurora-C mRNA was reduced to 0.20 ± 0.32 fold (P < 0.01) in 13 seminomas and up-regulated in one case. Western blot experiments, performed on protein extracts of nine seminomas and six normal testes, showed an up-regulation of Aurora-B protein by 10.14 ± 3.51 fold (P < 0.05), while Aurora-A protein was found increased in four seminomas by 2.16 ± 0.43 (P < 0.05), unchanged in three and reduced in two tumour tissues. Aurora-C protein was increased by 9.2 ± 2.90 fold (P < 0.05), suggesting that post-transcriptional mechanisms modulate its expression. In conclusion, we demonstrated that expression of Aurora kinases is deregulated in seminomas, suggesting that they may play a role in the progression of testicular cancers. [source] Testicular adenomatoid tumours: clinical and ultrasonographic characteristicsBJU INTERNATIONAL, Issue 3 2000A. Kassis Objective,To determine if benign testicular tumours can be identified clinically and ultrasonographically before surgery. Patients and methods,The clinical and ultrasonographic findings of six patients with testicular adenomatoid tumours and 16 with testicular germ cell tumours were assessed retrospectively and compared. Results,All adenomatoid tumours were characterized on physical examination by a well-defined, painful and unfixed nodule, contrasting with the painless and ill-defined malignant lesions. On ultrasonography, of the six adenomatoid tumours, two appeared hypoechoic, one hyperechoic, two isoechoic and one was normal, whereas none of the 16 tumours appeared normal or isoechoic. Conclusions,While isoechogenicity was not apparent in the group of testicular malignancies, the two groups had hypo- and hyperechoic patterns. Small, superficial, painful and unfixed testicular tumours that appear isoechoic on ultrasonography should be biopsied through an inguinal approach, with frozen sections assessed, instead of the patients undergoing immediate radical orchidectomy. [source] | ||||||||||||||||||||||