https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)61375-1.pdf

Cushing's syndrome

The microRNA(miRNA)-34a is a key regulator of tumor suppression. It controls the expression of a plethora of target proteins involved in cell cycle, differentiation and apoptosis, and antagonizes processes that are necessary for basic cancer cell viability as well as cancer stemness, metastasis, and chemoresistance. In this review, we focus on the molecular mechanisms of miR-34a-mediated tumor suppression, giving emphasis on the main miR-34a targets, as well as on the principal regulators involved in the modulation of this miRNA. Moreover, we shed light on the miR-34a role in modulating responsiveness to chemotherapy and on the phytonutrients-mediated regulation of miR-34a expression and activity in cancer cells. Given the broad anti-oncogenic activity of miR-34a, we also discuss the substantial benefits of a new therapeutic concept based on nanotechnology delivery of miRNA mimics. In fact, the replacement of oncosuppressor miRNAs provides an effective strategy against tumor heterogeneity and the selective RNA-based delivery systems seems to be an excellent platform for a safe and effective targeting of the tumor.

Mir-34: A New Weapon Against Cancer?

Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.

The Treatment of Cushing's Disease

Detection of Atherosclerotic Inflammation by 68Ga-DOTATATE PET Compared to [18F]FDG PET Imaging

Somatostatin receptors: From signaling to clinical practice

Dopamine is known to play a role in the modulation of aldosterone and catecholamine secretion from the adrenal gland, where dopamine receptors (DR), in particular the DR type 2 (D(2)), have been found to be expressed. DR expression has also been demonstrated in some types of benign adrenal tumors. The aims of the current study were to evaluate DR expression and D(2) localization in the normal adrenal gland and in different types of benign and malignant adrenal tumors, as well as to evaluate the in vitro effects of the dopamine agonists bromocriptine and cabergoline on hormone secretion in nontumoral adrenal cells. Adrenal tissues from 25 patients, subjected to adrenal surgery for different diseases, were studied. These included three normal adrenals; five adrenal hyperplasias; four aldosterone-secreting, two cortisol-secreting, and two clinically nonfunctioning adrenal adenomas; two aldosterone-secreting, two cortisol-secreting, and two androgen-secreting adrenal carcinomas; and three pheochromocytomas. In all tissues, DR and D(2) isoform (D(2long) and D(2short)) expression was evaluated by RT-PCR. D(2) localization was also evaluated by immunohistochemistry using a specific polyclonal antibody, whereas D(2)-like receptor expression was evaluated by receptor-ligand binding study, using the radiolabeled D(2) analog (125)I-epidepride. The effects of bromocriptine and cabergoline on baseline and ACTH and/or angiotensin II-stimulated aldosterone, cortisol, and androstenedione secretion were evaluated in cell cultures derived from five different adrenal hyperplasia. At RT-PCR, both D(1)-like and D(2)-like receptors were expressed in all normal and hyperplastic adrenals. D(2) and D(4) were expressed in aldosterone- and cortisol-secreting adenomas, cortisol-secreting carcinomas, and clinically nonfunctioning adenomas, whereas no DR was expressed in aldosterone- and androgen-secreting carcinomas. D(2), D(4), and D(5) were expressed in pheochromocytomas. In all D(2)-positive tissues, both D(2) isoforms were expressed, with the exception of one case of aldosterone-secreting adenoma and the cortisol-secreting carcinomas, in which only the D(2long) isoform was expressed. D(2)-like receptor expression was confirmed at receptor-ligand binding study. At immunohistochemistry, D(2) was mainly localized in the zona glomerulosa and reticularis of the adrenal cortex and, to a lesser extent, in the zona fasciculata and medulla of normal and hyperplastic adrenal tissue. In the positive tumors, D(2) was localized in the tumoral cells. At the in vitro study, a significant inhibition of both baseline and ACTH-stimulated aldosterone secretion was found after high-dose cabergoline, but not bromocriptine, administration; and a significant inhibition of angiotensin-II-stimulated aldosterone secretion was found after both bromocriptine and cabergoline administration in the adrenal hyperplasias. In conclusion, the current study demonstrated that both D(1)-like and D(2)-like receptors are expressed in the normal adrenal gland and in a percentage of adrenal adenomas or carcinomas. Bromocriptine and cabergoline induce only a minor inhibition of the secretion of adrenal hormones in the nontumoral adrenal gland in vitro, not excluding, however, the possible effective use of dopamine agonists in vivo in the treatment of adrenal tumors.

/pdf/dopamine-receptor-expression-and-function-in-human-normal-wtxkp8fsar.pdf

Dopamine receptor expression and function in human normal adrenal gland and adrenal tumors.

Pancreatic adenocarcinoma is a highly aggressive malignancy.1 Surgery is the only curative therapy. Unfortunately, only 5% to 15% of patients are surgical candidates at the time of the diagnosis due to a lack of specific symptoms, limitations in diagnostic methods, and the biologically aggressive nature of this tumor.1 In this selected group of patients, adjuvant chemotherapy has a survival benefit but the 5-year survival of 21%, as described by the European Study Group for Pancreatic Cancer, remains poor.2 The role of chemoradiotherapy in the management of pancreatic adenocarcinoma is unclear.3 However, it has been recently described4 that interferon (IFN)-α in combination with adjuvant chemoradiotherapy improved 5-year survival to 55%.

In vitro and in vivo studies have demonstrated the efficacy of type I IFNs (eg, IFN-α, IFN-β, IFN-ω, IFN-κ, and IFN-τ), in the treatment of several tumors.5–9 Although the antitumor effects of IFN-α have been studied in detail, those of IFN-β are not well clarified. IFN-β is a multifunctional cytokine that binds the same receptor of IFN-α, but with higher affinity.10 It seems to be an essential mediator not only for the innate immune responses against microbial infections, but also for a host defense system against oncogenesis.6,11 Moreover, several studies showed that IFN-β has greater antitumor effects than IFN-α.10,12–16 On the basis of these observations, IFN-β represents a promising drug in the treatment of cancer.

Importantly, several chromosomal aberrations have been detected in pancreatic adenocarcinoma, including a frequent loss of chromosome arm 9p, observed in more than 80% of human pancreatic cancer.17 Together with the tumor-suppressor genes p16INK4a, p15INK4b, and p14ARF also the IFN-α and IFN-β genes are located on chromosome 9p.18 Therefore, in relation to the defensive role of IFNs against tumors,11 the absence of the expression of IFNs may have an important role in the pathogenesis and probably in the treatment of pancreatic adenocarcinoma.

To further explore the possibilities of new medical treatments in pancreatic cancer, we evaluated in the present study the antitumor activity of IFN-α and IFN-β in 3 human pancreatic adenocarcinoma cell lines (BxPC-3, MiaPaCa-2, and Panc-1), as well as the role of IFN receptors in the responsiveness to type I IFNs.

Type I interferons in the treatment of pancreatic cancer: Mechanisms of action and role of related Receptors

Background: Somatostatin (SS)-binding sites have been demonstrated in human lymphoid tissues and peripheral blood cells. However, not much is known with respect to the SS receptor subtype (sst) expression pattern and the expression of SS itself in the immune system. Objective: The aim of this study was to evaluate the mRNA expression of the five known sst (sst 1‐5 )i n peripheral blood mononuclear cell (sub)populations. Moreover, the expression of the mRNAs encoding SS and the SS-like peptide cortistatin (CST) in immune cell subsets was studied. Methods: RT-PCR and quantitative PCR were performed to evaluate sst, SS and CST mRNA expression in cells in the basal or activated state. Fluorescence-activated cell sorter (FACS) analysis using fluorescent SS was performed to visualize sst protein on cell membranes. Results: B- and T-lymphocytes selectively expressed sst3 mRNA. sst3 expression in B-lymphocytes was significantly lower compared with T-lymphocytes. Unstimulated, freshly isolated monocytes did not express any sst mRNA. Upon activation, monocytes selectively expressed sst2 mRNA, whereas T-lymphocyte activation upregulated sst3 expression. sst2 mRNA expression on monocytes was confirmed by FACS analysis. B- and T-lymphocytes did not express SS mRNA, while both cell types expressed CST mRNA. CST mRNA expression was downregulated following T-lymphocyte activation. Conclusion: We demonstrate for the first time unequivocally that human peripheral blood B- and T-lymphocytes selectively express sst3, whereas monocytes do not express sst. However, upon activation, monocytes are induced to express sst2A. No expression of SS mRNA was detected in any cell type, whereas all cell types expressed CST mRNA. The differential expression of sst and CST mRNA in lymphocytes and monocytes suggests a functional significance for the CST ‐ sst interaction in immune cells, but further studies should be performed to evaluate the significance of sst and CST in these cells.

/pdf/differential-expression-of-somatostatin-receptor-subtypes-in-2xok8721z9.pdf

Differential expression of somatostatin receptor subtypes in human peripheral blood mononuclear cell subsets.

The novel somatostatin analog SOM230 has a broad spectrum of inhibitory action on hormone release by human somatotroph, corticotroph and PRL-secreting pituitary adenomas in vitro

Diana M. Mooij

Papers

Dopamine receptor expression and function in human normal adrenal gland and adrenal tumors.

Type I interferons in the treatment of pancreatic cancer: Mechanisms of action and role of related Receptors

Differential expression of somatostatin receptor subtypes in human peripheral blood mononuclear cell subsets.

The novel somatostatin analog SOM230 has a broad spectrum of inhibitory action on hormone release by human somatotroph, corticotroph and PRL-secreting pituitary adenomas in vitro