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Y Le Bouc

Publications and source records attributed to Y Le Bouc.

At least 37 records · Page 2Linked to original sources
PubMed2001

Loss of heterozygosity at the mannose 6-phosphate/insulin-like growth factor 2 receptor locus: a frequent but late event in adrenocortical tumorigenesis.

OBJECTIVE: Recent studies have pointed to the role of the IGF system in adrenocortical tumorigenesis. The IGF-II gene is overexpressed in malignant adrenocortical tumors and its proliferative effects are mediated by the type-1 IGF receptor (IGF1R). The mannose 6-phosphate/IGF2 receptor (M6P/IGF2R) plays a key role in regulating cell growth, by ensuring the clearance and inactivation of IGF-II and facilitating activation of the growth inhibitor, transforming growth factor beta (TGFbeta1). The M6P/IGF2R has been implicated as a tumor suppressor gene in various human tumors. METHODS: The purpose of this study was to determine if the M6P/IGF2R is involved in adrenal tumorigenesis. Two polymorphisms in the 3' untranslated region of M6P/IGF2R were used to screen a large series of 76 sporadic adrenocortical tumors for loss of heterozygosity (LOH) by PCR amplification of DNA. Tumors were classified into three groups based on pathological features: benign tumors (n=25), suspect tumors (n=22) and malignant tumors (n=29). RESULTS: LOH at the M6P/IGF2R locus was detected in 15 of 57 (26%) informative tumors and was more frequent in malignant tumors (58%) than in benign and suspect tumors (9 and 13% respectively). CONCLUSION: These findings provide evidence that LOH at the M6P/IGF2R locus is a frequent event in adrenocortical tumors and support the hypothesis that it may function as a tumor suppressor gene in adrenocortical tumorigenesis.

Adolescent↗
PubMed2001

Genotyping of Cre-lox mice and detection of tissue-specific recombination by multiplex PCR.

Conditional gene targeting, based on Cre-lox or other systems, requires frequent genotyping of transgenic mouse populations and monitoring of tissue-specific Cre recombinatory efficiency. This is currently achieved by Southern analysis from tail- and tissue-derived DNA. Multiplex PCR amplification of the floxed (flanked by loxP sites) genomic region, combined with the PCR detection of the Cre transgene, simplifies this task. Here, we show that complete genotyping of a floxed locus is possible with three appropriately placed primers and that this triplex PCR can be performed simultaneously with a universal PCR assay for the detection of Cre transgenes. Using this approach, we also determined the ratios of recombined versus non-recombined floxed genomic segments in genomic DNA samples. This allowed us to estimate the efficiency of in vivo conditional inactivation from biopsy material and tissue samples that were too small for Southern analysis. As many new conditional knockouts are spatiotemporally restricted, such assays will become increasingly useful. The proposed PCR strategy is flexible and may be adapted to the structural specificities of any target gene.

Alleles↗
PubMed2001

[Involvement of the IGF system in the pathogenesis of adrenocortical tumors].

Adrenocortical carcinoma remains a challenge for the therapeutist; prognosis is ominous. Various abnormalities playing a pathogenetic role have been recently described in adrenocortical tumors. Among them, dysregulation of the IGF system and imprinting mistakes at the 11p15 locus play a determining role in malignant transformation of adrenocortical cells. These markers of the malignant phenotype might markedly improve our diagnosis and prognosis abilities.

Adrenal Cortex Neoplasms↗
PubMed2000

Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue.

The secretion and the blood levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) decrease profoundly with age, and the question is posed whether administration of the steroid to compensate for the decline counteracts defects associated with aging. The commercial availability of DHEA outside the regular pharmaceutical-medical network in the United States creates a real public health problem that may be resolved only by appropriate long-term clinical trials in elderly men and women. Two hundred and eighty healthy individuals (women and men 60-79 years old) were given DHEA, 50 mg, or placebo, orally, daily for a year in a double-blind, placebo-controlled study. No potentially harmful accumulation of DHEAS and active steroids was recorded. Besides the reestablishment of a "young" concentration of DHEAS, a small increase of testosterone and estradiol was noted, particularly in women, and may be involved in the significantly demonstrated physiological-clinical manifestations here reported. Bone turnover improved selectively in women >70 years old, as assessed by the dual-energy x-ray absorptiometry (DEXA) technique and the decrease of osteoclastic activity. A significant increase in most libido parameters was also found in these older women. Improvement of the skin status was observed, particularly in women, in terms of hydration, epidermal thickness, sebum production, and pigmentation. A number of biological indices confirmed the lack of harmful consequences of this 50 mg/day DHEA administration over one year, also indicating that this kind of replacement therapy normalized some effects of aging, but does not create "supermen/women" (doping).

Absorptiometry, Photon↗
PubMed2000

Differences in the capacity of several biochemical bone markers to assess high bone turnover in early menopause and response to alendronate therapy.

We measured bone mineral density (BMD), four markers of bone formation [bone alkaline phosphatase (bAP), osteocalcin (Oc), N- and C-terminal propeptide of type I procollagen (PINP and PICP respectively)] and five markers of bone resorption [serum C-terminal telopeptide of type I collagen (CTx), urinary CTx, N-terminal cross-linked telopeptide (NTx), free and total deoxypyridinoline (fDpd and tDpd respectively)] in 28 healthy premenopausal women (45.7 +/- 3.0 years), 15 early (< 7 years) healthy menopausal women (53.8 +/- 3.1 years) and 20 osteoporotic women (65.3 +/- 8.2 years). Bone markers and BMD were also measured in the osteoporotic women 4.1 +/- 0.2 and 12.6 +/- 1.2 months after the beginning of alendronate therapy (Fosamax, 10 mg/day) respectively (BMD in 16/20). We calculated the intra-individual coefficient of variation (iCV) and the least significant change (LSC) for each bone marker from a subset of 9 healthy premenopausal women (32 +/- 5 years) who had a first and a second morning void urine collection (FMV and SMV respectively) and a blood sample on 4 nonconsecutive days (mean interval 14 +/- 3 days). None of the bone markers was correlated with BMD (except p = 0.043 between serum Oc and hip BMD). All markers, except fDpd, were increased significantly in early menopausal women when compared with the premenopausal group. Serum CTx presented the highest increase at menopause (+67.8%) and identified the highest rate (11/15) of early menopausal women with bone turnover above the premenopausal range. The iCVs for bone formation markers (7.2-14.4%) were lower than those for bone resorption markers (14.6-22.3%). The iCVs obtained on FMV and SMV were not different. The decrease after 4 months of alendronate was significant for each bone marker but variable from one marker to another. Serum CTx showed the largest decrease (70.8%) and identified the highest number of biologically responding patients (change > LSC; n = 17/20). A significant change in serum CTx after 4 months of alendronate was the best predictor of a significant gain in spine BMD (i.e., > or = 27 mg/cm2) after 1 year of therapy, allowing 15 of 16 patients (94%) to be classified correctly (one false-positive). Urinary NTx/Cr was the second best predictor. Despite a moderately high iCV (20.6%), serum CTx appeared the most effective of the markers tested and could be of interest for the detection of high bone turnover and the longitudinal monitoring of alendronate therapy in the individual patient. It must be stressed that serum PINP and urinary NTx and tDpd compared very similarly with serum CTx for monitoring alendronate therapy.

Adult↗
PubMed2000

Pathogenesis of adrenocortical incidentalomas and genetic syndromes associated with adrenocortical neoplasms.

The study of genetic syndromes associated with adrenocortical tumors (Beckwith-Wiedemann, Li-Fraumeni, McCune-Albright, Carney, and multiple endocrine neoplasia type 1) has shed light on the molecular basis of tumorigenesis. Abnormalities at the 11p15 locus appear as crucial and frequent events found specifically in malignant, sporadic tumors, leading to overexpression of a growth-promoting factor and loss of expression of tumor suppressor genes. In benign tumors, the cAMP pathway can be exacerbated in an ACTH-independent manner when various membrane receptors of the seven transmembrane superfamily are "illegitimately" expressed.

Adenoma↗
PubMed2000

Alterations of the 11p15 imprinted region and the IGFs system in a case of recurrent non-islet-cell tumour hypoglycaemia (NICTH).

BACKGROUND AND OBJECTIVE: Non-islet-cell tumour hypoglycaemia (NICTH) is a rare disorder and has been explained by oversecretion of non mature IGF-II and dysregulation of the IGFs sytem. The mechanisms responsible for tumoural IGF-II overexpression in NICTH have been rarely studied. We report an extensive study of IGF-II and IGFBPs as well as chromosome 11p15 gene expression regulation in a case of a pleural fibrosarcoma in a 63-year-old patient presenting with NICTH. METHODS AND RESULTS: Abnormal high molecular weight precusor forms of IGF-II were present in the patient's serum and were associated with dramatic alterations in the circulating levels of IGF-I, IGF-II and their binding proteins, as well as an inhibition of the somatotroph axis. These alterations returned to normal following complete surgical removal of the tumour. No structural change in chromosome 11p15 region was apparent in the tumour. However, dysregulation of this imprinted region was demonstrated, leading to the loss of imprinting of the IGF-II gene associated with high IGF-II expression, and by contrast decreased level of expression of H19 and p57KIP2 genes. Recurrence of the tumour four years latter was not associated with hypoglycaemia or changes in the levels of circulating IGFs or IGFBPs, despite IGF-II overexpression by the tumour. This suggests that a large tumour volume is required to reach high enough levels to cause changes in the levels of circulating IGFs and IGFBPs, and to cause hypoglycaemia. CONCLUSION: These results suggest that a dysregulation of gene expression and imprinting of chromosome 11p15 region is associated with tumour growth and IGF-II overexpression in non-islet-cell tumour hypoglycaemia.

Blotting, Southern↗
PubMed2000

Insulin-like growth factor-I (IGF-I), insulin-like growth factor binding proteins (IGFBP) and insulin-like growth factor type I receptor in children with various status of chronic renal failure.

Chronic renal failure in childhood causes severe growth retardation. The aim of the study was to identify whether changes in the IGF system could account for the growth retardation observed in children with chronic renal failure. Insulin-like growth factor (IGF-I) serum concentrations, insulin-like growth factor binding proteins (IGFBP) and/or IGF-I binding to erythrocyte type I receptor of IGF were analysed in 69 children (mean age 11.6 +/- 4.3 years) with chronic renal failure and growth retardation (mean height -2.6 +/- 1.8 SD). The study population was separated into three groups, according to their renal status, children on conservative treatment (CRF group: n = 30), on haemodialysis (ESRD group: n = 26) and those transplanted (RT group: n = 13). Nineteen of these children, some from each of the three groups, received recombinant growth hormone therapy (rhGH). Mean basal IGF-I serum concentrations were -0.7 +/- 1.2 SD in the CRF group, + 2.1 +/- 3 SD in the ESRD group and + 1.1 +/- 2 SD in the RT group. Under rhGH therapy, as height velocity improved, mean IGF-I concentrations increased up to + 3.1 +/- 0.6 SD in the CRF group, to + 6.9 +/- 2.8 SD in the ESRD group and to + 3.9 +/- 2 SD in the RT group. Basal IGFBP-3 levels, studied by Western Ligand Blot were low in the CRF group and high in the ESRD and normal in the RT groups, whereas IGFBP-2 and a 30-32 kDa IGFBP were always high in all cases. Western immunoblot analysis showed that this 30-32 kDa IGFBP was mostly composed of IGFBP-1 and IGFBP-6 in all three groups, but IGFBP-6 was particularly abundant in the ESRD group. IGFBP-6 concentrations assessed by RIA were moderately increased in CRF children (392 +/- 177 ng/mL) and very high in children on ESRD (2094 +/- 1525 ng/mL) when compared to normal values (131 +/- 42 ng/mL). Binding studies of IGF type I receptor showed that there was no particular difference in IGF-I binding between renal failure patients and normal children. In poorly growing children, especially in ESRD children and to a lesser extent in RT children, high concentrations of IGF-I and IGFBP-1, 2, 3 and 6, suggest a resistance mainly by a sequestration mechanism. Moreover, in the CRF group, especially in the younger children, low levels of IGF-I and IGFBP-3 are evocative of an associated resistance at the GH receptor level.

Adolescent↗
PubMed2000

Assessment of p57(KIP2) gene mutation in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder involving developmental anomalies, tissue and organ hyperplasia and an increased risk of embryonic tumours (most commonly Wilms' tumour). This multigenic disorder is caused by dysregulation of the expression of imprinted genes in the 11p15 chromosomal region. It may involve paternal uniparental disomy (UPD), loss of imprinting of the IGF2 gene, maternal inherited translocations and trisomy with paternal duplication. Recently, a small proportion of BWS patients has been shown to have a mutation in the paternal imprinted p57(KIP2) gene, which encodes a cyclin-dependent kinase inhibitor and negatively regulates cell proliferation. We screened for p57(KIP2) gene mutations in 21 BWS patients with no 11p15 UPD in leucocyte DNA. All patients had a phenotype typical of BWS. We analysed the entire coding sequence of p57(KIP2), including intron-exon boundaries, by direct sequencing of five PCR-amplified fragments. No mutation was found in the p57(KIP2) gene. Our results are consistent with those of previous studies showing that mutation of p57(KIP2) is infrequent in BWS. Thus, other mechanisms of p57(KIP2) silencing (imprinting errors) and/or other 11p15 genes are probably involved in the pathogenesis of BWS.

Beckwith-Wiedemann Syndrome↗
PubMed2000

A targeted partial invalidation of the insulin-like growth factor I receptor gene in mice causes a postnatal growth deficit.

The insulin-like growth factor (IGF) system is a major regulator of somatic growth in vertebrates. Both ligands (IGF-I and IGF-II) signal via the same IGF receptor (IGF-IR). Classical IGF-IR invalidation is lethal at birth, so that conditional models are needed to study the postnatal role of this receptor. To establish a genetically inducible invalidation of IGF-IR, we targeted the IGF-IR gene using a construct that introduced a neomycin resistance cassette into intron 2, leaving the rest of the gene intact. This neomycin resistance cassette interfered with the processing of the primary transcript, resulting in there being 12% fewer IGF-binding sites at the cell surface in heterozygous mice and 41% fewer in homozygous mice. Hetero- and homozygous offspring grew more slowly than their wild-type littermates. This difference was noticeable from 4 weeks after birth and was significant from 5 weeks after birth in males. In females, the effect on postnatal growth of insertion of the neo cassette was not significant. In males, IGF-I levels increased moderately (+26%) but significantly, indicating effective feedback regulation of the IGF system. IGF-binding protein-4 (IGFBP-4) levels, estimated by Western ligand blotting, were low in homozygotes (-38%), whereas IGFBP-1, -2, and -3 levels were unaffected. In females, IGF-I and IGFBP-1, -2, -3, and -4 levels did not differ significantly among heterozygous, homozygous, and wild-type animals. We investigated the molecular mechanism involved and characterized two RNA-splicing events that could account for the decrease in IGF-IR. The phenotype of these mice developed exclusively postnatally, and body proportions were maintained. IGF-IRneo mice constitute a new model for human postnatal growth deficiency.

Animals↗
PubMed2000

Fibroblast growth factor-2 inhibits the maturation of pro-insulin-like growth factor-II (Pro-IGF-II) and the expression of insulin-like growth factor binding protein-2 (IGFBP-2) in the human adrenocortical tumor cell line NCI-H295R.

The IGF system is thought to play a major role in adrenocortical tumorigenesis. In this study, we used the NCI H295R cell line as a model to investigate the effects of fibroblast growth factor-2 (FGF-2), a potent mitogen for normal adrenal cells, on the proliferation and on the expression of the IGF system in cultured adrenocortical tumor cells. Three immunoreactive FGF-2 isoforms of molecular masses 18, 22, and 24 kDa were detected in H295R cell extracts. Recombinant human FGF-2 stimulated the proliferation of adrenocortical tumor cells in a dose- and time-dependent manner, with a maximal effect at a concentration of about 1 ng/ml. Treatment of H295R cells with 10 ng/ml FGF-2 for 7 days had no significant effect on IGF-II messenger RNA levels. However, a marked increase in levels of intracellular IGF-II protein was detected by immunoblotting. In contrast, FGF-2 induced a marked decrease in the amount of IGF-II protein secreted, with the disappearance of mature IGF-II and secretion of higher molecular forms of the growth factor, suggesting modifications of IGF-II processing. Cell cultures in the presence of brefeldin A (1 microg/ml), a specific inhibitor of protein secretion, suggested that FGF-2 did not increase IGF-II synthesis but instead inhibited the secretion of pro-IGF-II from H295R cells, thereby impairing the final steps of IGF-II processing to the mature 7.5-kDa peptide. At the same concentrations, FGF-2 also decreased both IGFBP-2 messenger RNA and secreted protein, which might increase IGF-II bioavailability. No proteolysis of IGFBP-2 was detected in FGF-2-conditioned medium. Altogether, these results indicate that FGF-2 is mitogenic for NCI H295R tumor cells and regulates the expression of both IGF-II and IGFBP-2 in this tumor model. Moreover, this study shows a novel effect of FGF-2, by which this growth factor modulates the processing of pro-IGF-II.

Adrenal Cortex Neoplasms↗
PubMed2000

Establishment and characterization of a human adrenocortical carcinoma xenograft model.

Adrenocortical carcinomas are rare malignant tumors. They have a poor prognosis, as they are often diagnosed late and are usually resistant to chemotherapy. The lack of a suitable animal model for these tumors has been a major obstacle to the evaluation of new therapeutic agents. The aim of this study was to establish and characterize xenografts of the human adrenocortical carcinoma NCI H295R cell line as a model of adrenocortical carcinoma for future therapeutic trials. This cell line was sc injected (6 x 10(6) cells) into nude mice (n = 20). Solid tumors were locally measurable after 45 days at 90% of the inoculation sites. The xenografts were similar histologically to the original adrenocortical carcinoma from which the cell line was derived. The xenografts precisely reproduced the dysregulation of the insulin-like growth factor (IGF) system [overexpression of the IGF-II and IGF-binding protein-2 (IGFBP-2) genes] typical of adrenocortical carcinoma. Similarly to adrenocortical carcinomas, human IGFBP-2 (but not IGF-II) was secreted in mouse plasma. We analyzed steroid production (cortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, delta4-androstenedione, 11-deoxycortisol, corticosterone, and testosterone). Xenografts produced all three class of steroids, with the preferential production of androgens of the delta4 pathway. The H295R xenograft model is a good model of human adrenocortical carcinoma, as it mimics dysregulation of the IGF system usually found in these tumors. It also produces IGFBP-2 and steroids that can be used as tumor markers. This model may therefore be useful for evaluating therapeutic agents.

Adrenal Cortex Neoplasms↗
PubMed2000

High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors.

Maternal loss of heterozygosity (LOH) of the 11p15 region and overexpression of the insulin-like growth factor (IGF)-II gene are associated with the malignant phenotype in sporadic adrenocortical tumors. In the imprinted 11p15 region, the p57KIP2 gene is maternally expressed and encodes a cyclin-dependent kinase (CDK) inhibitor involved in G1/S phase of the cell cycle. We hypothesized that maternal LOH in malignant adrenocortical tumors could be responsible for loss of p57KIP2 gene expression and, thus, could favor progression through the cell cycle. We investigated 3 normal adrenals, 31 adrenocortical tumors [11 tumors with normal expression of the IGF-II gene (mainly benign) and 20 with IGF-II gene overexpression (mainly malignant)], and the human adrenocortical tumor cell line NCI H295R for expression of the p57KIP2 gene, G1 cyclins (cyclin D2 and E) and G1 CDK (CDK2, CDK3 and CDK4) protein contents and for kinase activity of G1 cyclin-CDK complexes. The expression of p57KIP2, G1 cyclins, and G1 CDKs in benign tumors was similar to that in normal adrenal tissues, as were kinase activities of G1 cyclin-CDK complexes. By contrast, abrogation of the p57KIP2 gene expression and increased expression of G1 cyclins (cyclin E) and G1 CDKs (CDK2 and CDK4) were associated with high activity of G1 cyclin-CDK complexes in malignant tumors and in the H295R cell line. These data suggest that the p57KIP2 gene might act as a tumor suppressor gene in adrenocortical tumors. Maternal LOH with duplication of the paternal allele or pathological functional imprinting of the 11p15 region are responsible for loss of expression of the p57KIP2 gene and increased expression of the IGF-II gene. Consequently, both events favor cell proliferation in malignant adrenocortical tumors.

Adolescent↗
PubMed1999

EMK protein kinase-null mice: dwarfism and hypofertility associated with alterations in the somatotrope and prolactin pathways.

Gene trapping was used in embryonic stem (ES) cells in an attempt to inactivate genes involved in development. The Emk (ELKL motif kinase) gene has been disrupted and a mutant mouse line derived. Previous work had shown that EMK kinases, called MARK in the rat, exert a major control on microtubule stability by phosphorylating microtubule-associated proteins and that genes homologous to Emk in yeast or Caenorhabditis elegans are essential for cell and embryonic polarity. Although we found the Emk gene to be active in the preimplantation mouse embryo and then to show a widespread expression, Emk-null mice had no embryonic defect and were viable. They show an overall proportionate dwarfism and a peculiar hypofertility: homozygotes are not fertile when intercrossed, but are fertile in other types of crosses. Insulin-like growth factor I (IGF I) and IGF-binding protein 3 (IGFBP3) were reduced in the plasma of homozygotes of both sexes. A direct implication of the EMK kinase in IGF I plasmatic production is unlikely because the Emk gene does not seem to be expressed in hepatocytes. Nevertheless, GH assayed at arbitrary times in plasma did not show differences between genotypes and GH concentrations in pituitary extracts were not found to be altered in homozygotes. Our results, though, do not exclude the possibility that in the mutants the overall quantity of GH secreted daily is reduced. Our observation of a smaller size of the pituitaries of the mutants is in favor of this hypothesis. The prolactin concentration in the pituitaries was much lowered in homozygous females, but it was normal in males. The possible involvement of EMK protein kinase in hormone secretion in the pituitary and/or the hypothalamus, via the microtubule network, is discussed.

Animals↗
PubMed1999

Functional hypothalamic amenorrhoea: a partial and reversible gonadotrophin deficiency of nutritional origin.

OBJECTIVE: Functional hypothalamic amenorrhoea (FHA) is a consequence of low dietary intake as observed in two major pathophysiological conditions, anorexia nervosa and/or intensive physical exercise. The aim of the present study was to assess in women with FHA and normal body mass index (BMI) and apparently normal daily activities, the degree of impairment of GnRH secretion, its nutritional origin and its reversibility. PATIENTS: Twelve women (22-35 years) with FHA not related with exercise and 12 age and BMI matched menstruating controls (NC) were studied. Six women with congenital hypothalamic hypogonadism (CHH), representative of complete gonadotrophin deficiency, were also enrolled for comparison. DESIGN: Plasma oestradiol (E2) and androstenedione (A) levels were measured and the pulsatile profile of LH was studied. A GnRH agonist test, using 100 micrograms S/C of DTrp6 GnRH (Triptorelin) was performed (sampling every 2 h for 24 h). Dietary intake, body composition and nutritional markers (FT3, ferritin, retinol binding protein (RBP), SHBG, IGF-1 and leptin) were measured. All the women with FHA were advised to normalize their diet during four months. The same studies were performed if nutritional markers and body composition were normalized. RESULTS: In FHA, mean plasma E2 and A levels were low. LH pulse frequency and amplitude were significantly reduced compared to NC (P < 0.005). FSH/LH ratio increased rapidly after triptorelin with a significant increase in plasma E2 levels between 18 and 24 h. In contrast, no response to triptorelin was observed in women with CHH. The fat body mass was lower and the lean body mass higher in FHA than in NC. Marked differences in nutritional intake were identified, with altered dietary composition. FHA consumed significantly less fat (P < 0.001) and less carbohydrate (P = NS) than the BMI-matched controls. Mean plasma levels of SHBG were increased whereas mean plasma levels of FT3, ferritin, RBP, IGF-1, and leptin were significantly decreased. Only three patients with FHA kept a balanced diet and improved their body composition after 4 months. LH pulsatile profile and response to triptorelin challenge were normalized in these patients. CONCLUSION: Mild dieting, close to normal but prolonged and characterized by an important fat restriction, is able to interfere with gonadotrophin secretion. Assessment of nutritional markers allows recognition of mild nutritional insufficiency as a common cause of FHAs. The gonadotrophin deficiency is partial and may be reversible after improvement of nutritional intake and body composition.

Adult↗
PubMed1999

Autocrine role of IGF-II in proliferation of human adrenocortical carcinoma NCI H295R cell line.

In adrenocortical tumors, the malignant phenotype is associated with rearrangements (paternal isodisomy) at the 11p15 locus and IGF-II gene overexpression, strongly suggesting that the IGF system is a major determinant of adrenocortical tumor progression. The aim of this study was to validate an in vitro model for investigating the involvement of the IGF system in adrenocortical tumorigenesis. We analyzed the production of IGF mRNA and proteins, IGF-binding proteins (IGFBPs) and IGF receptors by the NCI H295R cell line, which is derived from a human adult adrenocortical carcinoma. H295R cells were shown to proliferate for a long period (26 days) in the absence of serum or any added growth factor. Northern blot analyses showed high IGF-II mRNA contents in H295R cells. The cells secreted large amounts of IGF-II protein (14 ng/10(6) cells per 48 h) although no IGF-I protein was detected. Western ligand blot analyses of conditioned media detected the presence of large amounts of a 34 kDa protein, which was identified as IGFBP-2 by immunoblotting. The presence of high-affinity binding sites for IGF-I and IGF-II on H295R cells was shown by binding experiments using radiolabeled IGFs and confirmed by reverse transcription PCR analyses showing type 1 and type 2 IGF receptors. Proliferation of H295R cells was inhibited by anti-IGF-II antibody (45%) and by anti-type 1 IGF receptor antibody (53%) indicating that IGF-II is an autocrine growth factor for these cells and that its effects are, at least in part, mediated by the type 1 IGF receptor. These findings confirm the involvement of the IGF system in adrenocortical tumors and suggest that the H295R cell line is a suitable in vitro model for studying the molecular mechanisms of adrenocortical tumor proliferation.

Adrenal Cortex Neoplasms↗