Endocrine Phenotype Research Articles

Ghrelin and NUCB2/nesfatin-1 are expressed in the same gastric cell and differentially correlated with body mass index in obese subjects

The orexigenic peptide ghrelin and the anorexigenic peptide nesfatin-1 are expressed by the same endocrine cell of the rat stomach, the X/A-like cell. However, data in humans are lacking, especially under conditions of obesity. We collected gastric tissue of obese patients undergoing sleeve gastrectomy and investigated the expression of nesfatin-1 and ghrelin in the gastric oxyntic mucosa by immunofluorescence. Nesfatin-1 immunoreactivity was detected in the human oxyntic mucosa in cells with an endocrine phenotype. A major portion of nesfatin-1 immunoreactive cells (78%) co-localized with ghrelin indicating the occurrence in human X/A-like cells. In patients with very high body mass index (BMI 55-65kg/m(2)), the number of nesfatin-1 immunoreactive cells/low-power field was significantly higher than in obese patients with lower BMI (40-50kg/m(2), 118±10 vs. 82±11, p<0.05). On the other hand, the number of ghrelin immunoreactive cells was significantly reduced in obese patients with higher compared to lower BMI (96±12 vs. 204±21, p<0.01). Also the ghrelin-acylating enzyme ghrelin-O-acyltransferase decreased with increasing BMI. In conclusion, nesfatin-1 immunoreactivity is also co-localized with ghrelin in human gastric X/A-like cells giving rise to a dual role of this cell type with differential effects on stimulation and inhibition of appetite dependent on the peptide released. The expression of these two peptides is differentially regulated under obese conditions with an increase of nesfatin-1 and a decrease of ghrelin immunoreactivity with rising BMI pointing towards an adaptive change of expression that may counteract further body weight increase.

Dose-dependent effect of tamoxifen in tamoxifen-resistant breast cancer cells via stimulation by the ERK1/2 and AKT signaling pathways

The majority of breast cancers undergo progression from an initially endocrine responsive phenotype to an endocrine therapy-resistant phenotype, and acquired resistance to tamoxifen (Tam) is a major clinical problem. In the present study, we aimed to identify the function and mechanism of Tam at different concentrations in cells with acquired Tam resistance. Estrogen-dependent MCF-7 cells were cultured with Tam to generate Tam-resistant (TAM-R) breast cancer cells or in estrogen-free medium to mimic the effects of clinical treatment. In addition, we analyzed the effects of different concentrations of Tam on TAM-R cells by cell counting. Furthermore, the crosstalk between the stimulatory G protein α subunit (Gαs) and the activation of ERK1/2 and AKT in TAM-R cells was examined by small interfering RNA (siRNA) and immunoblotting methods. Low-dose Tam was found to act as an estrogen agonist via stimulation of the ERK1/2 signaling pathway, resulting in acquired resistance to Tam, whereas high-dose Tam inhibited TAM-R cell growth by blocking the activation of ERK1/2 and AKT. Moreover, Gαs was involved in Tam resistance in breast cancer cells. Taken together, our study demonstrated a dose-dependent growth response to Tam in TAM-R cells, which will promote the understanding of the importance of the appropriate use and dosage of Tam in the clinic.

Endocrine Evaluation of Children with and without Shwachman-Bodian-Diamond Syndrome Gene Mutations and Shwachman-Diamond Syndrome

To characterize the endocrine phenotype of patients with Shwachman-Diamond syndrome (SDS). Clinically indicated endocrine screening data from 43 patients with SDS or SDS-like presentation were analyzed according to sex, age, and genetic testing. In addition to 25 patients with biallelic Shwachman-Bodian-Diamond syndrome (SBDS) gene mutations, we evaluated 18 patients with cytopenias who were receiving pancreatic enzyme replacement but were without SBDS mutation. We performed a retrospective review of growth records and clinically indicated endocrine evaluations. Of patients with SBDS mutations, 2 had low stimulated growth hormone levels, 2 had mildly elevated thyrotropin levels, 5 had abnormal glucose levels, and 1 had an elevated follicle-stimulating hormone level (post transplantation). In contrast, 1 patient without SBDS mutations had postprandial hyperglycemia and 3 had mildly low free thyroxine levels without short stature. Endocrine abnormalities were identified in 19% of short patients and 26% of the whole group. Of patients with SBDS mutations, 56% had a height expressed in SD units from the mean for age and sex of <-1.8, in contrast to only 12% of patients without SBDS mutations (38% of the whole group). Body mass index z score was significantly greater in the group with SBDS mutations (P<.001). Although short stature was more common in patients with SBDS mutations, no consistent endocrine phenotype was observed in patients with SDS regardless of genetic testing.

PROP-1 gene mutations in a 63-year-old woman presenting with osteoporosis and hyperlipidaemia

PROP-1 gene mutations have been reported as a cause of combined pituitary hormone deficiency. Physical and hormonal phenotypes of affected individuals are variable. We report a 63-year-old female who presented with osteoporosis. She was short, did not enter puberty spontaneously and had primary amenorrhea. Biochemical evaluation revealed secondary hypothyroidism and mixed hyperlipidaemia, while dynamic testing of pituitary function was diagnostic of hypopituitarism. Bone density in the lumbar spine disclosed osteoporosis. DNA analysis showed that the patient was homozygote for the R73H mutation of the PROP-1 gene. The unfavourable long-term course of an untreated patient with PROP-1 gene mutation emphasizes the need for early aetiologic classification and proper management and follow-up of patients with short stature and/or disturbances of pubertal development.

Abstract P6-04-01: Global analysis of breast cancer metastasis suggests cellular reprogramming is central to the endocrine resistant phenotype.

Abstract The development of breast cancer resistance to endocrine therapy results from altered cellular plasticity leading to the emergence of a hormone independent tumour. We have previously shown that the endocrine resistant phenotype is poorly differentiated and has greater metastatic potential when compared with an endocrine sensitive phenotype. The underlying mechanism of how an ER positive, endocrine sensitive tumour can turn on these adaptive mechanisms remains unresolved. We hypothesise that cellular reprogramming can occur as a result of long-term exposure to endocrine treatment which manifests clinically as tumour recurrence. Our aim was to identify the mechanism of breast cancer cellular reprogramming in a clinical context. In this study we adopted a global approach to define transcriptional networks significantly elevated in the breast cancer metastatic setting. Using RNAseq we determined the gene expression profile of three ER positive patients who developed tumour recurrence on tamoxifen treatment. RNAseq was performed on primary tumours, axillary node metastases and subsequent distant metastases. Following bioinformatic analysis, we defined the genes that were significantly elevated in the metastatic tumours. In the metastases, genes clustered away from those in the primary and node, with 209 genes uniquely elevated in the metastatic context, suggesting altered gene expression in response to endocrine therapy. Pathway analysis of genes significantly elevated in the metastatic setting included developmental pathways (WNT signalling and TGFbeta), growth factor signalling pathways (MAPkinase), cell adhesion molecules, junction adherens and pathways in cancer. Further analysis provided a list of clinically relevant transcriptional networks which may facilitate tumour cell de-differentiation. Transcription factors including Myc, SMAD2, ESR, TCF3, CUX1 and CLOCK were identified which potentially drive reprogramming in response to endocrine treatment. We interrogated this data to identify downstream targets of this ‘de-differentiation’ network for new predictive markers of response to endocrine treatment. Bioinformatic analysis identified PAWR, an inhibitor of progenitor cell expansion as a potential SMAD2 target. In a xenograft model of endocrine resistance, PAWR expression was found to be reduced in metastatic tissue from lung, liver and bone compared with the primary tumour. In human breast cancer patients PAWR significantly associated with a good response to endocrine treatment and luminal A status (p = 0.0008), establishing PAWR as a predictor of good response to endocrine therapies. We have identified a transcriptional network which may drive a de-differentiated phenotype following endocrine treatment. Data presented here proposes a mechanism by which apparently less aggressive Luminal A type tumours may fail endocrine treatment and develop subsequent recurrence. This represents a fundamental shift in how we approach the development of resistance to endocrine therapy, establishing a number of biomarkers which will allow tracking of response to endocrine therapy or allow accurate early prediction of those who will respond to treatment. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-01.

Continuous Administration of a P450 Aromatase Inhibitor Induces Polycystic Ovary Syndrome with a Metabolic and Endocrine Phenotype in Female Rats at Adult Age

Studying the mechanisms for the complex pathogenesis of polycystic ovary syndrome (PCOS) requires animal models with endocrine, reproductive, and metabolic features of the syndrome. Hyperandrogenism seems to be a central factor in PCOS, leading to anovulation and insulin resistance. In female rats, continuous administration of letrozole, a nonsteroidal inhibitor of P450 aromatase, at 400 μg/d starting before puberty induces hyperandrogenemia and reproductive abnormalities similar to those in women with PCOS. However, despite high circulating testosterone levels, these rats do not develop metabolic abnormalities, perhaps because of their supraphysiological testosterone concentrations or because estrogen synthesis is completely blocked in insulin-sensitive tissues. To test the hypothesis that continuous administration of lower doses of letrozole starting before puberty would result in both metabolic and reproductive phenotypes of PCOS, we performed a 12-wk dose-response study. At 21 d of age, 46 female Wistar rats were divided into two letrozole groups (100 or 200 μg/d) and a control group (placebo). Both letrozole doses resulted in increased body weight, inguinal fat accumulation, anovulation, larger ovaries with follicular atresia and multiples cysts, endogenous hyperandrogemia, and lower estrogen levels. Moreover, rats that received 200 μg/d had insulin resistance and enlarged adipocytes in inguinal and mesenteric fat depots, increased circulating levels of LH, decreased levels of FSH, and increased ovarian expression of Cyp17a1 mRNA. Thus, continuous administration of letrozole, 200 μg/d, to female rats for 90 d starting before puberty results in a PCOS model with reproductive and metabolic features of the syndrome.

Caught between a disc and a tumour: lumbar radiculopathy secondary to disc herniation and filum paraganglioma

Dear Editor, Nerve root compression secondary to a combination of lumbosacral disc herniation and intrathecal space-occupying lesion is a rare co-incidence, particularly when histology reveals a paraganglioma. Cauda equina paraganglioma is a rare tumour that can be hypervascular and is associated with neuroendocrine disturbance during intraoperative tumour manipulation. Dual extraand intra-thecal pathology is unusual in the spine but can be addressed by a single operation to good effect. A 33-year-old gentleman was referred with a 12month history of persistent left leg sciatica associated with troublesome paraesthesiae in the left S1 dermatome. Neurological examination revealed 4+/5 left plantar flexion, an absent left ankle reflex and reduced pinprick sensation in the S1 dermatome. MR imaging of the lumbar spine revealed an avidly enhancing, intrathecal space-occupying lesion at the L5/S1 level (1.5×2 cm) as well as a large posterolateral L5/S1 disc protusion, resulting in S1 nerve root compression (Fig. 1). The patient underwent L5 and S1 laminectomies followed by intrathecal resection of a dark red, encapsulated lesion. Bipolar coagulation of the attached filum terminale arrested the tumour blood supply prior to manipulation. After dural closure, the left S1 root was retracted and a microdiscectomy was performed (Fig. 2). The patient was pain-free postoperatively with resolution of his antalgic gait, regaining the ability to walk on tiptoes. Histology revealed paraganglioma (WHO I) (Fig. 3). Followup imaging at 12 months did not reveal any evidence of recurrence, and the patient remained asymptomatic. Cauda equina paraganglioma (CEP) accounts for 3–4 % of all tumours in the region of the cauda equina [6]. There are no particular radiological features that reliably distinguish this entity from other more commonly encountered tumours at this site, such as ependymoma or nerve sheath tumour. The literature classifies CEP as a distinct sub-category of paraganglioma since its first description in 1970 by Miller and Torack [4]. CEP is thought to derive from primitive neural crest cells; however, whether the pathogenesis is due to aberrant migration of paraganglioma cells or the non-regression of paraganglioma cell nests is unclear [3]. The most common presenting symptoms of CEP are low back pain (51 %) and sciatica (19 %) [2]. CEP is found as commonly attached to the filum terminale as it is to nerve roots. Spinal paraganglioma has a characteristic vascular and endocrine phenotype. Typically, histopathology reveals small, rounded, polyhedral cells arranged in nests or ‘Zellballen’. Immunohistochemistry is positive for a variety of markers for both chief and sustenacular cells, including synaptophysin, chromogranins A and B, and S-100 protein [3]. CEP can demonstrate hormonal activity; however, in the largest review in the literature to date, this was found in only 3/174 cases (approximately 2 %) [2]. Intraoperative release of catecholaminergic hormones during tumour manipulation can result in haemodynamic instability, and we advise early vascular detachment. CEP can be highly vascular, and some authors advocate preoperative vascular imaging [1]. Gross R. Bhatia (*) : L. Zrinzo Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK e-mail: robbhatia@yahoo.com

Testosterone production, sexually dimorphic morphology, and digit ratio in the dark-eyed junco

The hormonal environment an individual experiences during development can have lasting effects on behavior, morphology, and physiology. However, measuring endogenous hormone exposure during early embryonic development and relating it to adult phenotype has proved to be challenging. The relative length of digit 2 to digit 4 (2D:4D) in adults is thought to reflect the relative concentration of androgens and estrogens during development and has been used as a morphological proxy of developmental hormone exposure, enabling the exploration of the relationships between individual differences in hormone exposure and phenotype. Here, we use this approach and ask whether 2D:4D relates to the responsiveness of the adult hypothalamicpituitary-gonadal axis and to sexually dimorphic structures (wing, tail, and tarsus length) in a common songbird, the dark-eyed junco (Junco hyemalis). Among males, we found a negative relationship between 2D:4D and the ability to elevate testosterone in response to a physiological challenge, an injection of gonadotropin-releasing hormone. We also found age- and sex-specific relationships between 2D:4D and wing, tail, and tarsus length. We found a positive relationship between 2D:4D and body size measures in females, and second-year and older males, but a negative relationship in first-year males. We conclude that individual variation in exposure to developmental hormones, as reflected by 2D:4D, is correlated with adult hormone production ability and sexually dimorphic morphology in adulthood, suggesting that endogenous variation in steroid hormone exposure may have long-term consequences similar to those seen in experimental manipulations. Key wor ds: digit ratio, gonadotropinreleasing hormone, junco, maternal hormones, testosterone, 2D:4D. [Behav Ecol]

The endocrine stress response is linked to one specific locus on chromosome 3 in a mouse model based on extremes in trait anxiety

BackgroundThe hypothalamic-pituitary-adrenal (HPA) axis is essential to control physiological stress responses in mammals. Its dysfunction is related to several mental disorders, including anxiety and depression. The aim of this study was to identify genetic loci underlying the endocrine regulation of the HPA axis.MethodHigh (HAB) and low (LAB) anxiety-related behaviour mice were established by selective inbreeding of outbred CD-1 mice to model extremes in trait anxiety. Additionally, HAB vs. LAB mice exhibit comorbid characteristics including a differential corticosterone response upon stress exposure. We crossbred HAB and LAB lines to create F1 and F2 offspring. To identify the contribution of the endocrine phenotypes to the total phenotypic variance, we examined multiple behavioural paradigms together with corticosterone secretion-based phenotypes in F2 mice by principal component analysis. Further, to pinpoint the genomic loci of the quantitative trait of the HPA axis stress response, we conducted genome-wide multipoint oligogenic linkage analyses based on Bayesian Markov chain Monte Carlo approach as well as parametric linkage in three-generation pedigrees, followed by a two-dimensional scan for epistasis and association analysis in freely segregating F2 mice using 267 single-nucleotide polymorphisms (SNPs), which were identified to consistently differ between HAB and LAB mice as genetic markers.ResultsHPA axis reactivity measurements and behavioural phenotypes were represented by independent principal components and demonstrated no correlation. Based on this finding, we identified one single quantitative trait locus (QTL) on chromosome 3 showing a very strong evidence for linkage (2ln (L-score) > 10, LOD > 23) and significant association (lowest Bonferroni adjusted p < 10-28) to the neuroendocrine stress response. The location of the linkage peak was estimated at 42.3 cM (95% confidence interval: 41.3 - 43.3 cM) and was shown to be in epistasis (p-adjusted < 0.004) with the locus at 35.3 cM on the same chromosome. The QTL harbours genes involved in steroid synthesis and cardiovascular effects.ConclusionThe very prominent effect on stress-induced corticosterone secretion of the genomic locus on chromosome 3 and its involvement in epistasis highlights the critical role of this specific locus in the regulation of the HPA axis.

Expression of Pancreatic Endocrine Markers by Mesenchymal Stem Cells From Human Adipose Tissue

Mesenchymal stem cells (MSCs) from human adipose tissue have a great potential for use in cell therapy due to their ease of isolation, expansion, and differentiation, besides the relative acceptance from the ethical point of view. Our intention was to isolate and promote in vitro expansion and differentiation of MSCs from human adipose tissue into cells with a pancreatic endocrine phenotype. Human adipose tissue obtained from patients undergoing abdominal dermolipectomy was digested with type I collagenase. MSCs isolated by plastic adherence and characterized by cytochemistry and FACS were expanded in vitro. MSC differentiation into an endocrine phenotype was induced over 2 to 4 months with high glucose (25 mmol/L) media containing nicotinamide, exendin-4, and 2-mercaptoethanol. Insulin and glucagon expressions were analyzed by immunofluorescence. Cells isolated from human adipose tissue and expanded in vitro expressed MSC markers as confirmed by FACS and cytochemistry. Insulin but not glucagon production by differentiated cells was demonstrated by immunofluorescence. MSCs isolated from human adipose tissue were induced to differentiate in vitro into an endocrine phenotype that expressed insulin.

Évaluation de la prise en charge de patients présentant un déficit en hormone de croissance (GHD) traité dans l’enfance, avant et après la période de la transition

Growth hormone deficiency (GHD) may result from a failure of hypothalamic GHRH production or release, from congenital disorders of pituitary development, or from central nervous system insults including tumors, surgery, trauma, radiation or infiltration from inflammatory diseases. Idiopathic, isolated GHD is the most common sporadic form of hypopituitarism. GHD may also occur in combination with other pituitary hormone deficiencies, and is often referred to as hypopituitarism, combined pituitary hormone deficiency (CPHD), multiple pituitary hormone deficiency (MPHD) or panhypopituitarism. Children without any identifiable cause of their GHD are commonly labeled as having idiopathic hypopituitarism.MRI imaging is the technique of choice in the diagnosis of children with hypopituitarism. Marked differences in MRI pituitary gland morphology suggest different etiologies of GHD and different prognoses. Pituitary stalk agenesis and ectopic posterior pituitary (EPP) are specific markers of permanent GHD, and patients with these MRI findings show a different clinical and endocrine outcome compared to those with normal pituitary anatomy or hypoplastic pituitary alone. Furthermore, the classic triad of ectopic posterior pituitary gland, pituitary stalk hypoplasia/agenesis, and anterior pituitary gland hypoplasia is generally associated with permanent GHD. T2 DRIVE images aid in the identification of pituitary stalk without the use of contrast medium administration. Future developments in imaging techniques will undoubtedly reveal additional insights. Mutations in a number of genes encoding transcription factors – such as HESX1, SOX2, SOX3, LHX3, LHX4, PROP1, POU1F1, PITX, GLI3, GLI2, OTX2, ARNT2, IGSF1, FGF8, FGFR1, PROKR2, PROK2, CHD7, WDR11, NFKB2, PAX6, TCF7L1, IFT72, GPR161 and CDON – have been associated with pituitary dysfunction and abnormal pituitary gland development; the correlation of genetic mutations to endocrine and MRI phenotypes has improved our knowledge of pituitary development and management of patients with hypopituitarism, both in terms of possible genetic counseling, and of early diagnosis of evolving anterior pituitary hormone deficiencies.

Early handling modulates outcome of neonatal dexamethasone exposure

Synthetic glucocorticoids such as dexamethasone (DEX) are used to prevent or treat respiratory disorders in prematurely born infants. Besides the short-term benefit on lung development, numerous human and animal studies have reported adverse neurodevelopmental side effects. In contrast, maternal care is known to exert a positive influence on neurodevelopmental outcome in rodents. The aim of the current study was therefore to investigate whether neonatal handling (days 1–21), known to induce maternal care, might serve as an intervention strategy modulating the adverse effects of DEX treatment (days 1–3). For this purpose we have measured the outcome of these early-life manipulations on development as well as adult endocrine and behavioral phenotype of male rats. Maternal care was observed during the first week of life and indeed enhanced in response to handling. Eye opening was accelerated and body weight reduced in DEX-treated animals. In adulthood, we report that handling ameliorated impaired spatial learning observed in DEX treated non-handled animals in the T-maze. Additionally, handling reduced susceptibility to the impact of DEX treatment in the water maze. Although DEX treatment and handling both resulted in enhanced negative feedback of the stress-induced corticosterone response and both reduced startle reactivity, the acquisition of fear was only reduced by handling, without effect of DEX. Interestingly, handling had a beneficial effect on pre-pulse inhibition, which was diminished after DEX treatment. In conclusion, these findings indicate that handling of the neonate enhances maternal care and attenuates specific DEX-induced alterations in the adult behavioral phenotype.

The interaction between ER and NFκB in resistance to endocrine therapy

Endocrine therapy is a commonly used treatment for estrogen receptor (ER)-positive breast cancer. Although endocrine therapy has a favorable outcome in many patients, development of resistance is common. Recent studies have shown that NFκB, a transcription factor regulating a wide variety of cellular processes, might play a role in the development of endocrine resistance. The precise interaction between ER and NFκB and how this contributes to the attenuated responsiveness of ER-positive breast cancer cells to hormonal treatment remains unclear. This review provides an overview of the mechanisms of action for both transcription factors and focuses on the current knowledge explaining how ER and NFκB affect each other's activity and how this cross-talk might contribute to the development of an endocrine resistance phenotype in breast cancer cells.

Impact of Clinical, Hormonal, Radiological, and Immunohistochemical Studies on the Diagnosis of Postmenopausal Hyperandrogenism

Postmenopausal biochemical hyperandrogenism occurs rarely. The presence of an underlying tumor in women with this condition may be missed without careful evaluation. Androgen excess in these women is the result of either tumoral or nontumoral causes. Factors that distinguish between tumoral and nontumoral etiology have not been identified. The primary goal of this retrospective study was to identify specific characteristics that could help differentiate between tumoral or nontumoral etiology among postmenopausal women suspected of having an androgen-secreting tumor. Participants were 22 postmenopausal women with biochemical hyperandrogenism referred to a medical center between 1995 and 2009. Clinical, biological, and morphological evaluations were performed in all women. Surgical resection of both ovaries was most often proposed for women without adrenal tumors, and immunocytochemical studies of the ovaries were performed. Among the 22 participants, 8 cases of ovarian tumors were identified based on ultrasound and/or magnetic resonance imaging. Two additional cases had an adrenal tumor diagnosed by computed tomography. The remaining 12 women had various nontumoral conditions. The clinical presentation in women with and without tumors was very similar. Some differences between the 2 groups, however, were found in the biological phenotype. Compared with women without tumors, women with tumors had significantly higher levels of testosterone [2.6 (2.7) vs 0.9 (0.9) ng/mL, P < 0.05] and lower levels of basal follicle-stimulating hormone [FSH; 26.5 (22.9) vs 66.5 (26.0) IU/L, P < 0.01] and luteinizing hormone [12.0 (8.6) vs 24.1 (8.9) IU/L, P < 0.05]. Based on the likelihood ratio, the risk of having a testosterone level of 1.4 ng/mL or greater or an FSH level of 35 IU/L or less in postmenopausal women with a tumor was 8.4 and 10.8 times higher, respectively. Immunochemistry using P450c17α antibody allowed identification of an elevated number of ovarian androgen-producing cells in 5 patients with tumors undetectable by conventional histology. These findings show no differences in clinical phenotype that can be used to discriminate between androgen-secreting tumors and other nontumoral causes of postmenopausal hyperandrogenism. The data suggest that 2 hormonal phenotypes, testosterone and basal FSH levels, may be discriminating markers.

Malignant Paraganglioma: A Case Diagnosed by Fine-Needle Aspiration

The prevalence of malignant paragangliomas is approximately 10% and is defined by the presence of metastases. Differential diagnosis includes hepatic tumors, alveolar soft part sarcoma, melanoma, glomus tumors, vascular neoplasms, and primary or metastatic carcinomas with endocrine or nonendocrine phenotype. Increasingly, fine-needle aspiration (FNA) is being used to evaluate primary and potential metastatic lesions. We describe a recent case …

Placental fatty acid transport in maternal obesity.

Pregestational obesity is a significant risk factor for adverse pregnancy outcomes. Maternal obesity is associated with a specific proinflammatory, endocrine and metabolic phenotype that may lead to higher supply of nutrients to the feto-placental unit and to excessive fetal fat accumulation. In particular, obesity may influence placental fatty acid (FA) transport in several ways, leading to increased diffusion driving force across the placenta, and to altered placental development, size and exchange surface area. Animal models show that maternal obesity is associated with increased expression of specific FA carriers and inflammatory signaling molecules in placental cotyledonary tissue, resulting in enhanced lipid transfer across the placenta, dislipidemia, fat accumulation and possibly altered development in fetuses. Cell culture experiments confirmed that inflammatory molecules, adipokines and FA, all significantly altered in obesity, are important regulators of placental lipid exchange. Expression studies in placentas of obese-diabetic women found a significant increase in FA binding protein-4 expression and in cellular triglyceride content, resulting in increased triglyceride cord blood concentrations. The expression and activity of carriers involved in placental lipid transport are influenced by the endocrine, inflammatory and metabolic milieu of obesity, and further studies are needed to elucidate the strong association between maternal obesity and fetal overgrowth.

Generation of Glucose-Responsive, Insulin-Producing Cells from Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells

We sought to assess the potential of human cord blood-derived mesenchymal stem cells (CB-MSCs) to derive insulin-producing, glucose-responsive cells. We show here that differentiation protocols based on stepwise culture conditions initially described for human embryonic stem cells (hESCs) lead to differentiation of cord blood-derived precursors towards a pancreatic endocrine phenotype, as assessed by marker expression and in vitro glucose-regulated insulin secretion. Transplantation of these cells in immune-deficient animals shows human C-peptide production in response to a glucose challenge. These data suggest that human cord blood may be a promising source for regenerative medicine approaches for the treatment of diabetes mellitus.

Exocrine and Endocrine Modulation in Common Gastric Carcinoma

Diagnostic and prognostic implications of endocrine differentiation were evaluated in 103 common gastric adenocarcinomas and undifferentiated carcinomas. Maturely differentiated exocrine and endocrine phenotypes were evaluated by using gastric exocrine and endocrine markers along with intestinal exocrine and endocrine markers. Immunohistochemical analysis revealed that 66 tumors (64%) were positive for generic endocrine markers such as chromogranin A and/or synaptophysin. The 14 patients with more than 20% tumor cells positive for at least 1 endocrine marker experienced a poorer prognosis than patients with no (n = 37) or 1% to 20% (n = 52) positivity. The 16 carcinomas expressing the maturely differentiated exocrine gastric phenotype significantly correlated with poorer outcome compared with carcinomas with mature exocrine intestinal (n = 22) or mixed/gastrointestinal (n = 64) phenotypes. Among tumors expressing chromogranin A and/or synaptophysin, the maturely differentiated endocrine gastric phenotype (n = 26) was a negative prognostic factor compared with mature endocrine intestinal (n = 21) and mixed/gastrointestinal (n = 5) phenotypes. Endocrine differentiation and maturely exocrine/endocrine gastric phenotypes are associated with an unfavorable prognosis and may identify subsets of patients for tailored therapy.

Performances de la TEP-TDM à la 6-Fluoro-[18F]-L-Dihydroxyphénylalanine (FDOPA) et de l’imagerie radiologique conventionnelle dans la prise en charge des patients avec maladie tumorale endocrine dont le primitif est inconnu

IntroductionDespite the extensive diagnostic work-up performed by conventional morphologic and functional imaging in patients with endocrine metastatic malignancies, the primary tumor remains often unknown. Knowledge of the primary tumor improves patients’ management in case of metastatic disease, and allows curative surgical debulking. At present, few studies have focused on the detection of the primary lesion. AimsTo retrospectively assess the FDOPA PET/CT accuracy in the detection of primary endocrine tumors and to evaluate the incremental value of FDOPA PET/CT over conventional imaging. Patients and methodsFourteen patients with biopsy-proven or clinically and biologically suspected endocrine tumors underwent FDOPA PET/CT. Results were compared with conventional imaging, and related to a pathologic or follow-up gold standard. ResultsFDOPA PET/CT detected the primary tumor in four out of 14 patients. Conventional imaging detected the primary tumor in three out of 14 patients. The association of FDOPA PET/CT and morphologic imaging allowed the identification of five out of 14 primary tumors. On an organ-based analysis, FDOPA PET/CT detected more metastasis than morphologic imaging (respective sensitivities of 92% and 58%). ConclusionIn our study, FDOPA PET/CT seemed more sensitive than conventional imaging for the detection of primary endocrine tumors and metastatic spread assessment. Physiological pancreatic uptake hampers FDOPA PET/CT accuracy for the detection of islet cell primary malignancies. Moreover, some pathologic characteristics of the endocrine phenotype, such as cellular differentiation, may influence FDOPA tumoral uptake.

Abstract 684: Identification of biomarker genes associated with endocrine therapy responsiveness in patients with estrogen receptor positive IBC and nIBC

Abstract Introduction: Endocrine therapy is a cornerstone in the treatment of patients with Estrogen Receptor (ER) positive (+) breast cancer. Nevertheless, resistance to endocrine treatment, either de novo or acquired, irreversably develops. In this study, we build upon the endocrine therapy resistant phenotype of patients with ER+ Inflammatory Breast Cancer (IBC) to identify and validate predictive biomarkers of endocrine therapy responsiveness. Materials and methods: Expression profiles of 21 ER+ IBC and 42 non-stage matched ER+ nIBC samples were compared using Prediction Analysis of Microarrays. The resulting gene signature was applied onto expression datasets from ER+ nIBC patients with documented intervals of relapse-free survival (RFS) for adjuvant endocrine treatment (GSE17705; N=298) or of progression-free survival (PFS) for first-line endocrine treatment (Jansen dataset (JCO, 2005), N=101). The gene signature classified samples as “IBC-like” or “nIBC-like” and Kaplan Meier and Cox regression analyses were performed. Robust biomarkers for endocrine resistance were selected using permutation analysis and validated using qRT-PCR on a series of samples from 225 ER+ nIBC patients with metastatic disease receiving first-line tamoxifen. Results: We identified a gene signature of 139 unique genes able to discriminate ER+ IBC from ER+ nIBC samples (sensitivity: 100%; specificity: 87.5%). Application of this signature onto data sets of patients with ER+ nIBC revealed significant associations with RFS (HR=1.87, P=0.001) and PFS (HR=2.04, P&amp;lt;0.001) under endocrine therapy. Permutation analysis selected 6 genes robustly discriminating ER+ IBC from ER+ nIBC samples: ABAT, ADAMDEC1, CLEC7A, ETS1, ITK1 and STC2. Expression analysis with qRT-PCR confirmed the predictive value of ADAMDEC1 (HR=1.127, P=0.020), ABAT (HR=0.779, P&amp;lt;0.001) and STC2 (HR=0.866, P&amp;lt;0.001) in 225 patients with ER+ breast cancer treated with Tamoxifen. Ingenuity Pathway Analysis revealed an intricate network linking each of the core genes with ER-, NFkB- and TGFβ-signalling. Conclusion: In this study we identified and validated a gene signature predictive of response to endocrine therapy in patients with breast cancer by comparing ER+ IBC samples to ER+ nIBC samples. Within this gene signature, ADAMDEC1, ABAT and STC2 were identified as robust markers for endocrine therapy responsiveness. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 684. doi:1538-7445.AM2012-684