Alteration in the serum concentrations of FGF19, FGFR4 and ßKlotho in patients with thyroid cancer.

INTRODUCTION: ßKlotho (ßKL) is known to act as co-receptor for fibroblast growth factor receptor 4 (FGFR4) which is the main cognate receptor for fibroblast growth factor 19 (FGF19). Dysregulation of this FGF19/FGFR4/ßKL signaling axis has been implicated in the pathogenesis of several cancers. However, its role in the pathogenesis of thyroid cancer has not been determined. MATERIALS AND METHODS: The aim of this study was to assess FGF19, FGFR4 and ßKL concentrations in a group of 36 patients with papillary thyroid cancer (PTC), 11 patients with follicular thyroid cancer (FTC), 9 patients with anaplastic thyroid cancer (ATC) and a group of 19 subjects with multinodular nontoxic goiter (MNG). The control group consisted of 20 healthy volunteers. Serum FGF19, FGFR4 and ßKL concentrations were measured using specific ELISA methods. RESULTS: Significantly lower concentrations of ßKL and higher concentrations of FGF19 were found in patients with PTC, FTC and ATC as compared with MNG group and controls. An elevation of FGFR4 serum concentration was observed in all thyroid cancer groups in comparison to MNG group and controls; however, in FTC group it was statistically insignificant. A positive correlation was found between ßKL and FGFR4 concentrations in PTC patients. The levels of ßKL, FGF19 and FGFR4 did not differ significantly between MNG group and healthy controls. CONCLUSIONS: Our results indicate that a disrupted FGF19/FGFR4/ßKL signaling pathway may play a role in the development of thyroid cancers. However, further studies are needed to elucidate the molecular mechanism of the neoplastic transition of thyroid epithelial cells.

Estimation of vitamin D status in patients with secondary and primary hypothyroidism of different etiology.

BACKGROUND: Though vitamin D deficiency is a global problem with wide spectrum of severe public health consequences, inadequate vitamin D status still remains one of the most common and untreated medical conditions. Thyroid diseases, including hypothyroidism, also represent the most frequent endocrinopathies in general population. OBJECTIVES: To determine the vitamin D status in hypothyroid patients and to ascertain the status of thyroid hormone replacement. METHODS: The 25(OH)D concentrations (ECLIA) in 71 hypothyroid patients recruited in the Outpatient Clinic of Endocrinology or Department of Clinical Endocrinology were assessed. The examined group was composed of 59 subjects diagnosed with primary hypothyroidism of different etiology and 12 patients with secondary hypothyroidism. The control group included 16 healthy individuals. RESULTS: Mean serum 25(OH)D concentration in healthy volunteers was significantly lower than in hypothyroid subjects (13.09±1.63 vs. 19.92±1.37 ng/mL). Patients with a history of thyroidectomy presented with significantly higher mean 25(OH)D concentration than controls (23.25±2.75 vs. 13.09±1.63 ng/mL). Mean serum 25(OH)D concentration in effectively treated hypothyroidism was significantly higher than in controls (21.90±1.47 vs. 13.09±1.63 ng/mL) or undertreated hypothyroidism (21.90±1.47 vs. 13.52±3.39 ng/mL). Hypothyroid patients aged under 60 years presented with significantly lower mean 25(OH)D concentration than elders (16.46±1.54 vs. 24.39±1.18 ng/mL). The major 25(OH)D deficient (≤10 ng/mL) or deficient (≤20 ng/mL) hypothyroid patients were significantly younger than those with 25(OH)D concentrations exceeding 10 ng/mL or 20 ng/mL respectively. CONCLUSIONS: These findings confirm the necessity for vitamin D status improvement in the general population and more effective healthcare of hypothyroid patients.

Somatostatin Analogs and Tumor Localization Do Not Influence Vitamin D Concentration in Patients with Neuroendocrine Tumors.

Patients with neuroendocrine tumors (NETs), malignancies of rare but still rising incidence, may be a group at higher risk of vitamin D insufficiency. The gastrointestinal tumor prevalence and somatostatin analog (SSA) therapy may cause vitamin D malabsorption. The aim of this study was to evaluate the serum level of vitamin D in NET patients. A total of 36 NET patients were enrolled into the experimental group and 16 individuals were enrolled into the control group. All patients were further classified into subgroups according to primary tumor localization (gastropancreatic, lung, and other NETs) or therapy (with or without SSA treatment). The concentrations of total 25(OH)D were assayed with Electrochemiluminescence immunoassay (ECLIA). Serum concentration of 25(OH)D in NET patients did not differ significantly from that of the control group. However, the average level of 25(OH)D in both groups met the criteria of vitamin D deficiency. Importantly, SSA therapy did not aggravate vitamin D deficiency. Moreover, the concentration of 25(OH)D in the studied group was not significantly influenced by primary tumor localization, patient age, or season. Vitamin D deficiency is a widespread disorder affecting both NET patients and individuals without other health problems, and SSA and gastrointestinal tumor localization do not exacerbate this condition.

Decreased serum level of IL-7 in patients with active Graves' disease.

BACKGROUND: Graves' disease (GD) is a common autoimmune disease which is one of the major causes of hyperthyroidism. Interleukin 7 (IL-7) has been recently reported to play an important role in various autoimmune diseases, but its role in the pathogenesis of GD has not been assessed. The aim of this study was to evaluate the levels of IL-7 and the soluble form of its receptor (sIL-7R) in the serum of GD patients, and to identify their association with disease activity. METHODS: A total of 37 GD patients were enrolled into the experimental group and 16 individuals into the control group. All patients were further classified into three subgroups: a GD-active group (hyperthyroidism and TRAb (thyroid stimulating hormone receptor antibody) >7.5 U/L) (N=15), a GD-inactive group (euthyreosis and TRAb<1 U/L) (N=8), and other GD patients (euthyreosis and TRAb>1 U/L) (N=14). Concentrations of IL-7 and sIL-7R were assayed with ELISA. Additionally, the relationship between IL-7 and sIL-7R serum concentrations with disease activity (free triiodothyronine [FT3], free thyroxine [FT4], thyroid stimulating hormone [TSH] and TRAb) was also analyzed. RESULTS: The serum concentrations of IL-7 in GD-active patients were significantly lower than those of the control group as well as the GD-inactive and GD-other groups. The serum level of IL-7 in GD patients negatively correlated with FT4 and TRAb concentrations. Moreover, no significant difference was observed in the serum level of sIL-7R in GD patients compared to the control group. CONCLUSIONS: These observations suggest that IL-7 may play a role in the pathogenesis of GD and may be associated with its clinical activity. To this end, the serum level of IL-7 could be an additional diagnostic biomarker predictive of the disease and could be particularly valuable for TRAb-negative GD patients.

Current Prospects for Adrenocortical Carcinoma Pharmacotherapy.

Adrenocortical carcinoma (ACC) is a rare but very aggressive malignancy of the endocrine system with specific biology characterized frequently by hormonal activity and high aggressiveness, resulting usually in locally-invasive or metastatic disease at the time of initial diagnosis. Despite an intense multidirectional search for novel strategies, there has been no satisfactory improvement in the effectiveness of standard therapy currently used in the clinic. ACC diagnosis usually means poor prognosis. Thus, the necessity to identify and implement novel and more effective treatment of ACC in clinical management remains constantly an ambitious challenge. The review briefly summarizes the current management of adrenocortical carcinoma and focuses mainly on novel prospects for ACC pharmacotherapy, including targeted therapies, immunotherapy and checkpoint inhibitors, theranostics, and at last, the individualized molecular approach based on the exact identification of specific genetic profile of ACC cells using next-generation sequencing methods as the next-generation perspective for precisely personalized therapy.

The involvement of angiotensin type 1 and type 2 receptors in estrogen-induced cell proliferation and vascular endothelial growth factor expression in the rat anterior pituitary.

The aim of our study was to examine the involvement of renin-angiotensin system (RAS) in estrogen-induced lactotropes proliferation and vascular endothelial growth factor (VEGF) expression in rat pituitary. The study was performed on Fisher 344 rats underwent 8-day treatment with diethylstilboestrol (DES). The proliferation index (PCNA) and VEGF expression in pituitary sections were estimated using immunohistochemical methods. Treatment with DES increased the number of PCNA-positive cells, VEGF-positive cells, and VEGF-positive blood vessels in pituitary. Stimulatory effect of estrogen on cell proliferation and VEGF expression in blood vessels was attenuated by losartan, PD123319, and captopril. VEGF immunoreactivity in pituitary cells of DES-treated rats was decreased by AT1 antagonist and not changed by AT2 blocker and ACE inhibitor. Our findings suggest the involvement of RAS in DES-induced cell proliferation and VEGF expression in pituitary. Both the AT1 and AT2 receptors appear to mediate the estrogen-dependent mitogenic and proangiogenic effects in rat pituitary.

Angiotensins inhibit cell growth in GH3 lactosomatotroph pituitary tumor cell culture: a possible involvement of the p44/42 and p38 MAPK pathways.

The local renin-angiotensin system is present in the pituitary. We investigated the effects of angiotensins on GH3 lactosomatotroph cells proliferation in vitro and the involvement of p44/42 and p38 MAPK inhibitors in the growth-regulatory effects of angiotensins. Materials and Methods. Cell viability using the Mosmann method and proliferation by the measurement of BrdU incorporation during DNA synthesis were estimated. Results. Ang II and ang IV decreased the viability and proliferation of GH3 cells. Inhibitor of p44/42 MAPK attenuated the effects of ang II on cell viability and proliferation but did not affect the ang 5-8-dependent actions. Inhibitor of p38 MAPK prevented the decrease in the number of GH3 cells in ang-II- and ang-IV-treated groups. Conclusions. The growth-inhibitory effect of ang II is possibly mediated by the p44/42 MAPK. The p38 MAPK appears to mediate the inhibitory effects of both ang II and ang 5-8 upon cell survival.

Elevated peripheral blood plasma concentrations of tie-2 and angiopoietin 2 in patients with neuroendocrine tumors.

BACKGROUND: Gastro-entero-pancreatic/neuroendocrine (NET) tumors are highly vascularized neoplasms. However, our knowledge concerning circulating levels of the angiogenic factors in NET patients still remains insufficient. METHODS: The aim of this study was to measure plasma concentrations of VEGF, angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), soluble Tie-2, endostatin, osteopontin (OPN) and chromogranin A (CgA) in 36 NET patients and 16 controls. RESULTS: Only the plasma concentrations of Tie-2 and CgA were higher in NET patients as compared to controls. These levels were within the reference range in controls; however one control demonstrated slightly elevated Tie-2 and 4 elevated CgA. Similarly, in the subgroup of patients with carcinoid syndrome, only Tie-2 and CgA concentrations were higher than those in patients with non-functioning NETs. In turn, in the subgroup of metastatic patients, only Ang-2 levels were higher than in those with localized disease. A positive correlation was found between Ang-2 and Tie-2 levels in metastatic patients and between Ang-1 and Tie-2 in localized NETs. CONCLUSIONS: The plasma concentration of Tie-2 is proposed as an additional marker for NET patients and seems to be similarly effective as the currently used CgA level. Moreover, higher plasma levels of Ang-2 together with the positive correlation between Ang-2 and Tie-2 levels in metastatic subjects, implies that cases with a Tie-2 level above the upper limits, together with higher level of Ang-2 seem to be highly predictive of metastases.

Anti-neoplastic effect of protein kinase CK2 inhibitor, 2-dimethylamino-4,5,6,7-tetrabromobenzimidazole (DMAT), on growth and hormonal activity of human adrenocortical carcinoma cell line (H295R) in vitro.

Several studies indicate the involvement of protein kinases in the progression of various malignancies. Kinase inhibitors are therefore becoming important anticancer drugs. CK2 kinase (casein kinase-2) has been suggested to be a constituent of a neoplastic milleu, and its inhibition might represent a new approach to cancer therapy. Adrenocortical carcinomas (ACCs) are highly malignant neoplasms with poor overall prognosis. We have examined the effects of 2-dimethylamino-4,5,6,7-tetrabromobenzimidazole (DMAT), a potent CK2 inhibitor, on the H295R human adrenocortical cancer cell line. Treatment with DMAT decreases the secretion of aldosterone, dehydroepiandrosterone sulfate, and androstendione and results in an accumulation of 17-OH-progesterone. Cell growth as measured by the MTT and 5-bromo-2'-deoxyuridine incorporation assays is inhibited, and cell cycle analysis has revealed a slight induction of apoptosis. Thus, CK2 kinase activity is probably involved in human ACC endocrine activity and growth.

Growth hormone-releasing hormone stimulates the secretion of interleukin 17 from human peripheral blood mononuclear cells in vitro.

OBJECTIVES: Growth hormone-releasing hormone (GHRH) plays a crucial role in the secretion of GH from the pituitary, acts as a growth factor in variety of cancer cells and possesses immunomodulatory activity. Interleukin(IL)-17 apart from its pro-inflammatory role has been also shown to play a role in carcinogenesis. The effect of GHRH on the IL-17 has not been studied so far. AIM: To evaluate the effect of GHRH on the secretion of IL-17 from human peripheral blood mononuclear cells (PBMC) in vitro. MATERIALS AND METHODS: The concentrations of IL-17 in supernatants from PBMC cultured for 24 hrs were assessed using ELISA kit. RESULTS: We show for the first time that GHRH can stimulate the secretion of IL-17 from human PBMC in 24 hrs culture, and that GHRH antagonist counteracts this effect. CONCLUSION: Our study further elucidates the immunomodulatory role of GHRH.

IGF1R and MAPK15 Emerge as Potential Targets of Pentabromobenzylisothioureas in Lung Neuroendocrine Neoplasms.

Pentabromobenzylisothioureas are antitumor agents with diverse properties, including the inhibition of MAPK15, IGF1R and PKD1 kinases. Their dysregulation has been implicated in the pathogenesis of several cancers, including bronchopulmonary neuroendocrine neoplasms (BP-NEN). The present study assesses the antitumor potential of ZKKs, a series of pentabromobenzylisothioureas, on the growth of the lung carcinoid H727 cell line. It also evaluates the expression of MAPK15, IGF1R and PKD1 kinases in different BP-NENs. The viability of the H727 cell line was assessed by colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) and its proliferation by BrdU (5-bromo-2'-deoxyuridine) assay. Tissue kinase expression was measured using TaqMan-based RT-PCR and immunohistochemistry. ZKKs (10-4 to 10-5 M) strongly inhibited H727 cell viability and proliferation and their antineoplastic effects correlated with their concentrations (p < 0.001). IGF1R and MAPK15 were expressed at high levels in all subtypes of BP-NENs. In addition, the SCLC (small cell lung carcinoma) patients demonstrated higher mRNA levels of IGF1R (p = 0.010) and MAPK15 (p = 0.040) than the other BP-NEN groups. BP-NENs were characterized by low PKD1 expression, and lung neuroendocrine cancers demonstrated lower PKD1 mRNA levels than carcinoids (p = 0.003). ZKKs may suppress BP-NEN growth by inhibiting protein kinase activity. Our results suggest also a possible link between high IGF1R and MAPK15 expression and the aggressive phenotype of BP-NEN tumors.

Elevated serum concentrations of IGF-1 and IGF-1R in patients with thyroid cancers.

BACKGROUND: The rising incidence of thyroid cancer observed in the last few decades requires an improvement in diagnostic tools and management techniques for patients with thyroid nodules. AIMS: The aim of this study was to assess serum concentrations of IGF-1 and IGF-1R in patients diagnosed with thyroid cancers. METHODS: 36 patients diagnosed with papillary thyroid cancer (PTC), 11 subjects with follicular thyroid cancer (FTC), 9 patients with anaplastic thyroid cancer (ATC) and 19 subjects with multinodular nontoxic goiter (MNG) were enrolled to the study. The control group (CG) consisted of 20 healthy volunteers. Blood samples were collected one day before surgery. Serum IGF-1 and IGF-1R concentrations were measured using specific ELISA methods. RESULTS: Significantly higher concentrations of IGF-1 were found in patients with PTC as compared with controls but not that obtained from subjects diagnosed with MNG. The concentration of IGF-1R was significantly elevated in subjects with PTC and ATC as compared with healthy volunteers. Similarly, patients diagnosed with PTC or ATC presented significantly higher serum concentration of IGF-1R in comparison to the MNG group. CONCLUSIONS: Our results show that the IGF-1 - IGF-1R axis plays a significant role in the development of PTC and ATC and imply that serum concentrations of both cytokines may be considered as additional markers for the differentiation of malignancies during the preoperative diagnosis of patients with thyroid gland tumors. These results indicate that IGF-1R serum concentrations allow us to differentiate between MNG and PTC or ATC. Moreover IGF-1R serum values appear to be better predictor of PTC and ATC than IGF-1 concentrations.

Angiotensin receptors in hormone-independent prostate cancer cell line DU145: presence of two variants of angiotensin type 1 receptor.

BACKGROUND: Recently, the involvement of the renin-angiotensin system in the proliferation of prostate cancer has been suggested. There is increasing evidence that angiotensin II receptor type 1 (AT1) is expressed in a variety of cancer cells and tissues and may have a role in tumor growth, angiogenesis, and invasive activity of malignant lesions in vivo. The implications of data referring to an angiotensin receptor in hormone-independent human prostate cancer DU145 cells are unclear. Angiotensin II has been shown to inhibit the proliferation of DU145 cell lines. However, it is known that AT1 stimulates cell proliferation and that angiotensin II receptor type 2 (AT2) induces apoptosis and inhibits cell proliferation. MATERIAL/METHODS: The aim of our study was to investigate, by means of immunohistochemical and reverse transcriptase polymerase chain reaction assays, the type of angiotensin II receptor that is present in DU145 cells. RESULTS: In DU145-derived complementary deoxyribonucleic acid (cDNA), a polymerase chain reaction assay revealed 2 AT1-specific PCR products (93 bp and 126 bp). DU145-derived cDNA did not reveal AT2 expression at a level sufficient for detection by PCR. In cultured cells, immunohistochemical testing revealed a positive reaction in cultures immunostained with anti-AT1 antibody but not in those immunostained with AT2 antibody. CONCLUSIONS: The inhibitory effect of angiotensin II on the proliferation of DU145 cells is exerted via AT1. It is possible that presence of 2 variants of AT1 in that cancer cell line is essential to produce the biological effects of angiotensin.

Luzindole but not 4-phenyl-2- propionamidotetralin (4P-PDOT) diminishes the inhibitory effect of melatonin on murine Colon 38 cancer growth in vitro.

OBJECTIVE: Our earlier studies have shown that MLT exerts the inhibitory effect on murine cancer via membrane and nuclear receptors. We have found that the antagonist of MT1 receptors does not diminish the antiproliferative effect of MLT on Colon 38 cells, and the contribution of MT2 receptors has been suggested to be responsible. Therefore, in the present study we have examined the influence of the 4-phenyl-2-propionamidotetralin (4P-PDOT), which is a selective antagonist of MT2 membrane receptor, and luzindole - an antagonist of both membrane receptors, on an oncostatic action of MLT. MATERIALS AND METHODS: The murine cancer cell line Colon 38 was used in the experiments. In 48 hrs cell culture the effects of MLT, 4P-PDOT and luzindole administered alone and MLT applied jointly with either 4P-PDOT or luzindole were examined. The growth of cancer cells was assessed using the modified colorimetric Mosmann method. RESULTS: Melatonin at both examined concentrations (10-7, 10-9 M) significantly decreased the viability of cancer cells. The selective antagonist of MT2 membrane receptor, namely 4P-PDOT and luzindole applied separately did not have an effect on the growth of Colon 38 cells. The addition of 4P-PDOT to MLT did not change the inhibitory effect of MLT, whereas luzindole given together with MLT diminished, but failed to block totally, the oncostatic properties of MLT. CONCLUSIONS: The obtained data and our previous studies conducted on Colon 38 cancer indicate that membrane melatonin receptors are not indispensable to the oncostatic action of melatonin and thus other pathways such as nuclear signaling and receptor-independent mechanism may be also involved.

Effects of rosiglitazone--peroxisome proliferators-activated receptor gamma (PPARgamma) agonist on cell viability of human pituitary adenomas in vitro.

OBJECTIVES: Rosiglitazone (RGZ) belongs to thiazolidinediones - new class of antidiabetic drugs which are PPARgamma agonists. It was shown that tumoral tissue, including the pituitary adenomas, posses PPARgamma receptors. The activation of PPARgamma receptors inhibits tumour growth in rodents and induces the oncostatic effect on human cancer cell lines. The aim of the present study was to examine the anti-tumour effect of RGZ on human pituitary adenomas in vitro. MATERIALS AND METHODS: Cells of eight pituitary adenomas removed neurosurgically were used to our experiment. Before the operation, the hormonal secretion of the tumour was estimated. After the surgery, the histological diagnosis and immunohistochemical detection of pituitary hormones and PPARgamma receptors were performed. The cells of pituitary tumours were exposed in the primary culture to RGZ at the concentrations of 10(-9)-10(-4) M for 24 hours. To measure the cell growth the modified colorimetric Mossman method detecting the cells viability was applied. RESULTS: On the basis of the pre-operative diagnosis the 6 clinically non-functioning adenomas (CNFPA), one case of acromegaly and one case of Cushing's disease were recognized. In 5 out of 6 CNFPA the immunopositive reaction for different pituitary hormones such as: LH, HGH, PRL, FSH and alpha-subunit was detected. Expression of PPARgamma was found in all examined tumours. Rosiglitazone decreased the cell viability of all CNFPA and corticotropinoma for 20% or more. In somatotropinoma inhibition of the cell growth was about 13%. There is no correlation between PPARgamma expression and efficacy of rosiglitazone. THE MAIN FINDING: The obtained results indicate that RZG exerts a suppressive effect on the cell viability in non-functioning pituitary adenomas. The lack of correlation between PPARgamma expression and anti-tumoral effect of RZG suggests that the above-mentioned action of this compound is independent on PPARgamma expression. CONCLUSION: Our data suggest that rosiglitazone may be useful in the treatment of non-functioning pituitary adenomas, but its efficacy in Cushing's disease and acromegaly requires further study.

Peripheral blood concentrations of vascular endothelial growth factor and its soluble receptors (R1 and R2) in patients with adrenal cortex tumours treated by surgery.

INTRODUCTION: Neoangiogenesis appears to be an important event in tumour invasion and in the formation of metastases in many endocrine-related human cancers. Vascular endothelial growth factor (VEGF) is a glycoprotein with potent angiogenic, mitogenic and vascular permeability-enhancing activities specific for endothelial cells and acts through VEGF receptors. The aim of the study was to evaluate the plasma blood concentrations of VEGF, sVEGFR1, and sVEGFR2 in patients with benign and malignant adrenal tumours treated by surgery. MATERIAL AND METHODS: We studied the blood before surgery of 41 patients with adrenal cortex tumours and 10 normal subjects without hormonal or CT/USG pathology of the adrenal glands (controls). We studied the blood after adrenalectomy of 16 patients with tumours of the adrenal cortex. RESULTS: Concentrations of VEGF, sVEGFR1 and sVEGFR2 in blood plasma before as well as 30 days after surgery were evaluated by ELISA. VEGF blood concentrations before surgery did not differ in the patients with the cortical tumours as compared to the controls. After surgery VEGF concentrations decreased among the patients, taken in total, with adrenal cortex tumours and cortical adenomas. Before surgery sVEGFR1 blood concentrations were increased in the patients with Conn's syndrome only in comparison with the controls. After surgery, sVEGFR1 concentrations decreased significantly in the group with cortical adenomas only. Before and after surgery sVEGFR2 blood concentrations did not differ between the groups of patients studied and the controls. CONCLUSIONS: Peripheral blood concentrations of VEGF and its receptors cannot be clinically valuable markers that discriminate between benign and malignant adrenocortical tumours before and after adrenalectomy.

Dysregulation in IGF-1R, FGFR4 and ßKlotho signaling in patients with medullary thyroid cancer.

BACKGROUND: Medullary thyroid cancer (MTC) is a relatively rare thyroid neoplasm derived from neuroendocrine C cells which secrete calcitonin. αKlotho (αKL) and ßKlotho (ßKL) are transmembrane proteins which modulate different signaling systems, such as endocrine FGFs and IGF1 pathways. Dysregulation of the FGF19/FGFR4/ßKL and IGF-1/IGF-1R/αKL signaling axes has been implicated in the pathogenesis of several cancers. However, their role in the pathogenesis of MTC has not been determined. METHODS: The aim of this study was to assess αKL, ßKL, FGF19, IGF-1, FGFR4, and IGF-1R concentrations in a group of 11 patients with medullary thyroid cancer (MTC). The control group consisted of 20 healthy volunteers. Serum concentrations of these factors were measured using specific ELISA methods. RESULTS: Significantly lower concentrations of ßKL and higher concentrations of FGFR4 and IGF-1R were found in patients with MTC as compared to controls. CONCLUSIONS: Our results indicate that a disrupted signaling pathway for ßKL, FGFR4 and IGF-1R may play a role in the development of medullary thyroid cancers. However, further studies are required to confirm these findings and to use this knowledge in clinical practice.

Inhibition of proliferation, VEGF secretion of human neuroendocrine tumor cell line NCI-H727 by an antagonist of growth hormone-releasing hormone (GH-RH) in vitro.

Growth hormone-releasing hormone (GH-RH) can stimulate not only growth hormone (GH) secretion by anterior pituitary gland but also proliferation of many cancer cell lines in vitro and in xenografts tumor models in vivo. Several antagonists of GH-RH have been shown to inhibit several cancer growths, but the role of GH-RH antagonists in the regulation of neuroendocrine cancers cell proliferation and tumor progression remains obscure. The aim of the study was to evaluate the influence of JV-1-36 (synthetic GH-RH antagonist) on proliferation and VEGF secretion by human neuroendocrine lung non-small cell carcinoma (NCI-H727) using cell culture model. The in vitro effect of JV-1-36 on the proliferation of NCI-H727 cells was assessed by the measurement of BrdU incorporation by colorimetric immunoassay. The presence of VEGF and membrane GH-RH receptors on the surface of H727 cells were visualized by immunocytochemistry using specific anti-GH-RH receptor antibody directed to the carboxy-terminal region. VEGF secretion to the cell cultures supernatants was assessed by ELISA methods. Immunoreactive cell membrane GH-RH receptors and VEGF-immunopositive cytoplasmatic granules were clearly confined on the surface of nearly all cancer cells. JV-1-36 at the concentration of 10(-6)-10(-10)M significantly inhibited growth of H727 cells, compared with untreated controls. In H727 cells, the antiproliferative JV-1-36 effect was associated with a dose-dependent reduction of VEGF secretion. In conclusion, our findings demonstrate the strong evidence for the antiproliferative action of GH-RH antagonist JV-1-36 for the NCI-H727 cells. In addition the suppression of VEGF secretion by H727 cells might contribute, at least in part, to the antitumor action of GH-RH antagonists.

Effects of somatostatin on vascular endothelial growth factor (VEGF) secretion from non-functioning pituitary tumoral cells incubated in vitro.

OBJECTIVES: The aim of the study was to examine the effect of somatostatin (SST) on vascular endothelial growth factor (VEGF) secretion from clinically non-functioning pituitary tumors incubated in vitro. MATERIAL AND METHODS: Eight pituitary tumors surgically removed were investigated. All of the tumors were diagnosed before surgery as non-functioning. Seven of them were diagnosed after surgery as pituitary adenomas and expressed either gonadotropins or their subunits as detected by immunohistochemistry. Two tumors additionally expressed prolactin and growth hormone. One tumor was immunonegative for pituitary hormones and was diagnosed as haemangiopericytoma. All tumors but one were investigated immunohistochemically to detect the somatostatin receptors and expressed at least 3 of 5 subtypes of somatostatin receptors. The cells isolated from the examined tumors were exposed in vitro to native SST-14. The concentration of VEGF in the culture media was performed by means of ELISA method. RESULTS: It was found that the exposure on SST-14 resulted in the divergent changes (increase in 4 cases and decrease in 3 cases) in VEGF concentrations in the medium. It seems that the inhibition of VEGF secretion is related to the expression of somatostatin receptor subtypes sst1 and sst2. CONCLUSIONS: The response of VEGF secretion from pituitary tumoral cells to SST seems to depend on the spectrum of expressed somatostatin receptor subtypes. However, this presumption needs further studies on the larger material.

[Anti-cytokine and anti-lymphocyte monoclonal antibodies in the treatment of thyroid associated ophthalmopathy]. / Zastosowanie przeciwcial monoklonalnych przeciwcytokinowych i przeciwlimfocytarnych w leczeniu orbitopatii tarczycowej.

Graves' ophthalmopathy or thyroid associated ophthalmopathy (TAO) is an autoimmune disease of the orbit involving both the retroorbital connective tissue and the extraocular muscles, but its pathogenesis is still incompletely understood. Examination of retroorbital tissues in the initial inflammatory phase of TAO reveals an accumulation of hydrophilic glycosaminoglycans, increased fat volume, marked T and B lymphocytic infiltration, and presence of many pro-inflammatory cytokines and growth factors. Peripheral blood levels of pro-inflammatory cytokines released from T and B lymphocytes (IFN-gamma, IL-1beta, IL-2, slL-2R TNF-alpha, IL-6, IL-6R) and antibodies of TSH receptor (TRAb) secreted from B lymphocytes are markers of the immune system activity. Updated the efficacy of the new anti-cytokine and anti-lymphocyte treatment of the Graves' ophthalmopathy has been revived. We described the first positive results of anti-B lymphocyte (anti-CD20; rituximab) and anti-TNF-alpha monoclonal antibodies (infliximab; etanercept) administration as new therapeutic options in the treatment of patients with active TAO. A randomized prospective study are needed to determine whether rituximab, infliximab or etanercept prove sufficiently effective in reducing the inflammatory symptoms of TAO, and whether they can be administered safely for a prolonged period without side effects.