scholarly journals Ectopic FGF23 production induces mineral changes, osteogenic transdifferentiation, and cancer associated microcalcifications

2020 ◽  
Author(s):  
Ida Marie Boisen ◽  
John Erik Nielsen ◽  
Ireen Kooij ◽  
Jovana Kaludjerovic ◽  
Peter J. O’Shaughnessy ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Germ Cell ◽  
Phosphatase Activity ◽  
Sertoli Cell ◽  
Germ Cells ◽  
Alkaline Phosphatase Activity ◽  
Cell Cancer ◽  
Seminiferous Tubules ◽  
Testicular Germ Cell ◽  
Increased Risk

AbstractTesticular microcalcifications consist of hydroxyapatite and their demonstration by ultrasound has been associated with increased risk of testicular germ cell cancer (TGCT). Here, we show that fibroblast growth factor 23 (FGF23), a bone-specific regulator of phosphate homeostasis, is expressed in testicular germ cell neoplasia in situ (GCNIS), embryonal carcinoma (EC), and human embryonic stem cells. FGF23 is not glycosylated in TGCTs and thus rapidly cleaved into a C-terminal fragment that serves as a competitive antagonist for full-length FGF23. High levels of C-terminal FGF23 occupy the receptor formed by Klotho and FGF receptor 1 (FGFR1) in the germ cells facilitating a shift in the expression of phosphate transport proteins from SLC34A2 to SLC34A1 in seminiferous tubules adjacent to GCNIS. Fgf23 knockout mice have a marked epididymal deposition of hydroxyapatite, while the testicular phenotype is milder with spermatogenic arrest and focal germ-cell-specific expression of the bone-like markers runt-related transcription factor 2 (RUNX2) and bone gamma-carboxyglutamic acid-containing protein (BGLAP). In accordance, mice with no functional androgen receptor and lack of circulating gonadotropins develop microcalcifications in 94% of cases and have lower Slc34a2, and higher Slc34a1 and Bglap expression. In accordance, human testicular specimens with microcalcifications also have lower SLC34A2, and focally germ cells express SLC34A1, BGLAP, and RUNX2. Importantly, calcium or phosphate induced osteogenic transdifferentiation of a spermatogonial cell line in vitro demonstrated by induction of alkaline phosphatase activity and deposition of hydroxyapatite, which could be fully rescued by pyrophosphate (PPi). Severe microcalcifications were also found in a mouse model with Sertoli-cell ablation particularly when Sertoli-ablation was conducted prepubertally where the germ cells retain stem cell potential. In conclusion, cancer-related microcalcifications may arise secondary to gonadal mineral alterations, which in combination with impaired Sertoli cell function and reduced PPi due to high alkaline phosphatase activity in GCNIS and TGCTs, facilitates osteogenic transdifferentiation of testicular germ cells and deposition of hydroxyapatite.

Positive Oct -3/4 and D2–40 Immunohistochemical Expression in Germ Cells and Suspected Histology Pattern of Intratubular Germ Cell Neoplasia in Boys with Cryptorchidism Vanish after the Age of 2 Years

2016 ◽  
Vol 27 (04) ◽  
pp. 313-318 ◽  
Author(s):  
Erik Clasen-Linde ◽  
Dina Cortes ◽  
Jorgen Thorup
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Cell Cancer ◽  
Germ Cell Cancer ◽  
Repeat Biopsy ◽  
Seminiferous Tubules ◽  
Histological Pattern ◽  
Immunohistochemical Markers ◽  
Increased Risk ◽  
Intratubular Germ Cell Neoplasia

Introduction Intratubular germ cell neoplasia (ITGCN) is a precursor to testicular germ cell cancer. Adult germ cell cancer immunohistochemical markers may fail to detect ITGCN in prepubertal boys with congenital cryptorchidism, because positive immunohistochemistry is commonly seen in boys younger than the age of 2 years, where most orchiopexies are performed. The aim of the study was to evaluate the diagnostic challenge to differentiate between a histological pattern of ITGCN and a histological pattern with some atypical germ cells and all positive cancer immunohistochemical markers, but no increased risk of malignancy. Materials and Methods Histology sections from 373 testicular biopsies from 289 boys aged 1 month to 2 years operated for cryptorchidism were incubated with primary antibodies including anti-placental-like-alkaline phosphatase, antiOct-3/4, anti-C-kit, anti-D2–40, and in case of repeat biopsy with anti-stem cell factor (SCF) receptor. Results The prevalence of Oct-3/4 and D2–40-positive staining of germ cells in testicular biopsies were in age groups less than 6 months, 100% and 50%; 6–12 months, 60% and 17%; and 1–2 years, 12% and 4%. A 1 year, 1-month-old boy with Prader–Willi syndrome treated with growth hormone had ITGCN in both cryptorchid testes. In another three bilateral nonsyndromic cases, 8 months, 8 months and 1-year-old, a histological pattern in accordance with ITGCN was found. These three boys had a repeat biopsy from both testes performed at the age of 3 years, 4 months, 3.5 years, and 3 years, 10months, respectively. In all cases, the Oct-3/4 and D2–40 positive germ cells turned negative and the histological pattern normalized completely. The primary biopsies had SCF negative germ cells. Conclusion This study is valuable in identifying the age-related change in Oct-3/4 or D2–40 immunopositive germ cells in seminiferous tubules. An ITGCN-like histological pattern in nonsyndromic cryptorchidism will vanish after the age of 3 years. Even when immunohistochemistry is applied, prepubertal ITGCN is so rarely demonstrated in cryptorchid testes, that it is not plausible that ITGCN generally originates during fetal development in cryptorchidism.

scholarly journals Induction of germ-cell alkaline phosphatase by butyrate and cyclic AMP in BeWo choriocarcinoma cells

1993 ◽  
Vol 296 (1) ◽  
pp. 59-65 ◽  
Author(s):  
J F Telfer ◽  
C D Green
Keyword(s):  
Alkaline Phosphatase ◽  
Enzyme Activity ◽  
Cyclic Amp ◽  
Germ Cell ◽  
Cholera Toxin ◽  
Phosphatase Activity ◽  
Alkaline Phosphatase Activity ◽  
Sodium Butyrate ◽  
Dibutyryl Camp ◽  
Choriocarcinoma Cells

BeWo choriocarcinoma cells synthesize two alkaline phosphatase isoenzymes: germ-cell alkaline phosphatase and tissue-unspecific alkaline phosphatase. We have made use of the differential heat-stabilities of these two isoenzymes to study the induction of germ-cell alkaline phosphatase by sodium butyrate and cyclic AMP (cAMP). Sodium butyrate causes a large induction of germ-cell alkaline phosphatase activity (approx. 35-fold after 96 h) after an initial lag period of 12-24 h. We showed that butyrate increases germ-cell alkaline phosphatase mRNA. Dibutyryl cAMP also induces germ cell alkaline phosphatase (approx. 2.5-fold after 96 h). When optimal concentrations of butyrate and dibutyryl cAMP were added simultaneously to cells, they caused a synergistic induction of activity. This suggested that these compounds use separate mechanisms to induce germ-cell alkaline phosphatase activity and that it is the cAMP moiety of dibutyryl cAMP that induces enzyme activity. This was confirmed by the use of two additional cAMP analogues, 8-(4-chlorophenylthio) cAMP and 8-bromo cAMP, and of two compounds, 3-methyl-1-isobutylxanthine and cholera toxin, which raise the endogenous concentration of cAMP. All four compounds caused a 2-fold increase in enzyme activity. Treatment of cells with 8-(4-chlorophenylthio) cAMP, 8-bromo cAMP and cholera toxin increased germ-cell alkaline phosphatase mRNA between 2- and 7-fold. These data suggest that this alkaline phosphatase isoenzyme is regulated at the level of its mRNA by cAMP, in a manner distinct from that of butyrate.

scholarly journals ISOLATION OF GERM CELL GOLGI APPARATUS FROM SEMINIFEROUS TUBULES OF RAT TESTES

1971 ◽  
Vol 51 (1) ◽  
pp. 273-285 ◽  
Author(s):  
W. P. Cunningham ◽  
H. H. Mollenhauer ◽  
S. E. Nyquist
Keyword(s):  
Golgi Apparatus ◽  
Germ Cell ◽  
Sertoli Cell ◽  
Germ Cells ◽  
Sucrose Gradient ◽  
Cellular Component ◽  
Seminiferous Tubules ◽  
Early Spermatid ◽  
Gradient Technique ◽  
Biochemical Analyses

Intact Golgi apparatus have been isolated with good purity from rat testis by a simplified sucrose gradient technique. The procedure is inherently selective in that most of the Golgi apparatus in the isolate are from germ cells in late spermatocyte or early spermatid development. No Sertoli cell Golgi apparatus are present in the fraction. Biochemical analyses showed that the enzyme N-acetylglucosamine galactosyltransferase is enhanced in the band containing Golgi apparatus. Because they are easy to isolate, and because they are involved with the formation of a specific internal cellular component (the acrosome), these Golgi apparatus will be useful objects for comparison with other kinds of Golgi apparatus and for other studies leading to a better understanding of the basic functioning of Golgi apparatus.

Prevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms.

1996 ◽  
Vol 14 (12) ◽  
pp. 3126-3132 ◽  
Author(s):  
K P Dieckmann ◽  
V Loy
Keyword(s):  
Germ Cell ◽  
Cell Cancer ◽  
Testicular Tumor ◽  
Intraepithelial Neoplasia ◽  
Testicular Atrophy ◽  
Testicular Tumors ◽  
Testicular Germ Cell ◽  
Testicular Intraepithelial Neoplasia ◽  
Increased Risk ◽  
Testicular Germ Cell Neoplasms

PURPOSE Testicular intraepithelial neoplasia ([TIN], so-called carcinoma in situ of the testis) is hypothesized to be the precursor of testicular germ cell neoplasms. According to previous studies, it can be detected by testicular biopsy. Since patients with a unilateral testicular tumor are at high risk of a second testicular tumor, it seemed feasible to examine the prevalence of contralateral TIN in patients with testicular germ cell cancer and correlate it with the known prevalence of bilateral testicular tumors. The aim was to provide more evidence for the role of TIN as the preinvasive stage of testicular cancer. PATIENTS AND METHODS Nineteen hundred fifty-four consecutive patients with a unilateral testicular germ cell tumor underwent contralateral biopsy. All specimens were examined immunohistologically. RESULTS TIN was observed in 4.9% (95% confidence interval [CI], 3.95% to 5.91%). Testicular atrophy and a history of undescended testis were more frequently observed in patients with contralateral TIN, but only atrophy was shown to be independently associated by multivariate analysis. Patients with testicular atrophy have a 4.3-fold increased risk of having contralateral TIN. Sixty-four percent of TIN cases were found in normal testes. Patients with TIN were significantly younger than those without (P < .0017). Three patients developed a second testicular tumor despite a negative biopsy for TIN. CONCLUSION The prevalence of contralateral TIN corresponds well to the known prevalence of bilateral testicular tumors. Testicular atrophy is a strong indicator for the presence of TIN, but approximately 60% of TIN cases occur without atrophy. The present data are in accordance with the theory that TIN is an early step in the histogenesis of testicular germ cell neoplasms.

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