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At the Cutting Edge

Neuroendocrinology 2012;95:267–276 Received: August 2, 2011
Accepted after revision: October 23, 2011
DOI: 10.1159/000334612
Published online: January 12, 2012

Diffuse Endocrine System,
Neuroendocrine Tumors and Immunity:
What’s New?
Pietro Ameri Diego Ferone
Department of Internal Medicine and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy

Key Words ing the mechanisms by which the immune system contrasts
Neuroendocrine tumors ⴢ Immunity ⴢ Neuropeptides ⴢ NET growth and spreading, ground-breaking clinical trials of
Somatostatin ⴢ Cortistatin dendritic cell vaccination as immunotherapy for metastatic
NETs have shown in principle that the immune reaction to
NETs can be exploited for treatment.
Abstract Copyright © 2012 S. Karger AG, Basel
During the last two decades, research into the modulation
of immunity by the neuroendocrine system has flourished,
unravelling significant effects of several neuropeptides, in- Introduction
cluding somatostatin (SRIH), and especially cortistatin (CST),
on immune cells. Scientists have learnt that the diffuse neu- The anatomical organization and the functions of the
roendocrine system can regulate the immune system at all diffuse (neuro)endocrine and immune systems are ex-
its levels: innate immunity, adaptive immunity, and mainte- ceedingly complicated, and the more we discover the
nance of immune tolerance. Compelling studies with animal more new questions arise. The diffuse endocrine system
models have demonstrated that some neuropeptides may (DES) is composed of neuroendocrine cells scattered
be effective in treating inflammatory disorders, such as sep- throughout the entire body, either isolated or grouped to
sis, and T helper 1-driven autoimmune diseases, like Crohn’s form discrete aggregates, such as the neuroepithelial bod-
disease and rheumatoid arthritis. Here, the latest findings ies in the bronchopulmonary tract or the islets of Lang-
concerning the neuroendocrine control of the immune sys- erhans in the pancreas [1]. While at least some of the DES
tem are discussed, with emphasis on SRIH and CST. The sec- cells in the gut are known to regulate secretion, absorp-
ond part of the review deals with the immune response to tion, motility, and mucosal proliferation [2], the physio-
neuroendocrine tumors (NETs). The anti-NET immune re- logical role of the neuroendocrine cells in most other or-
sponse has been described in the last years and it is still be- gans remains elusive.
ing characterized, similarly to what is happening for several The immune system includes two branches, i.e. innate
other types of cancer. In parallel with investigations address- immunity, which is evolutionarily older, and adaptive

© 2012 S. Karger AG, Basel Diego Ferone
0028–3835/12/0954–0267$38.00/0 Department of Internal Medicine and Center of Excellence for Biomedical Research
Fax +41 61 306 12 34 University of Genoa, Viale Benedetto XV, 6
E-Mail karger@karger.ch Accessible online at: IT–16132 Genoa (Italy)
www.karger.com www.karger.com/nen Tel. +39 010 353 7946, E-Mail ferone @ unige.it

biochemical language of autocrine. resting conditions. IHC = Im- munohistochemistry. and somatostatin receptors (SSTR) 1–5 in the im- mune system. Innate immu. 1. when induced to differentiate into macrophages or DCs gan to be characterized. and – most many neuropeptide receptors varies across different notably – short-term protection. non-pathogen-specific. [8]. studies on the interactions between the human monocytes do not transcribe any SSTR gene in DES and the immune system have been addressed to es. based on a phocytes are the cornerstone of the second. cortistatin (CST). neutrophils. Fig. The complement. 12]. As exemplified by somatostatin recep- DCs) are at the interface between the two.95:267–276 Ameri/Ferone . 11. and basophils are central to the first. and changes upon their differen- immunity’s defense is specific and lasts much longer (see tiation or activation status. macrophages and DCs [5. SSTR2A is present on the membrane of found in lymphoid organs and neuroendocrine media. making tissues physi- tors (biogenic amines. and phago. neuropeptides) and their receptors ologically or pathologically rich of SSTR2A detectable 268 Neuroendocrinology 2012. As shown by Lichtenauer-Kaligis et al. and endo- cytic cells (monocyte/macrophages and dendritic cells. paracrine. In contrast. ulation of immunity by neuropeptides [13]. suggesting the existence of a neuroen- eosinophils. Historically. when neuroendocrine cells were [7–9]. docrine modulation of immune functions. immunity [3]. and both SSTR1 and SSTR2A This research direction was taken as early as the DES be. the adaptive types of immune cells. lym. with lipopolysaccharide. For instance. mast cells. but express SSTR2A when activated tablish whether and how the first influences the latter. already a minimal activation of monocytes isolated from peripheral blood mononuclear cells (PBMCs) induces the expression of the SSTR2A mRNA. the expression profile of nity provides generic. in immune cells. further pointing to a fine reg- also the relevant paragraph). 1) [5–12]. Expression of somatostatin (SRIH). crine signals [4]. tors (SSTR) 1–5 (fig. In vivo.

we have been otherwise healthy organ. and inhibits in- flammation both locally and far from the site of release. SRIH a cation channel which binds several ligands. human diseases. such tide (CGRP). For instance. secondary to deficient release of SP into the pan- search work on neuropeptide-induced inflammation creatic islets of Langerhans by TRPV1-expressing senso- [14]. irrita- and their cognate receptors in immune cells has been tion of a deep organ. Moreover. detailed re. that initiate inflammation: in this way. a SRIH-mediated anti-inflammatory loop has been ry neurons [18]. 13]. potentially tis- The analysis of the expression profile of neuropeptides sue-damaging stimuli [14. such as substance P (SP) or calcitonin gene-related peptide (CGRP). and CGRP exocytosis. but also enters the circulation. innate inflammation. macrophages. but also to ␤-cell stress and autoimmune immunity response.Fig. which then drive local neurogen- ic inflammation. Capsaicin-sensitive. SP. In extreme cases. flammatory responses of neutrophils. can mediate neurogenic inflammation. However. the bladder. but essential. 15]. and CGRP exocy- transient receptor potential vanilloid 1 (TRPV1) protein. brain [16]. 2). Neuronally-derived SRIH acts in a paracrine/auto- myelinated or thinly myelinated fibers transmit electrical crine fashion.95:267–276 269 Neuroendocrine Tumors and Immunity . other neuropeptides tems. As a result. insulitis.g. SRIH binds to pre- (CNS) [14]. The nociceptive nerve terminals express the synaptic SSTRs and stops its own. as well as of non-immune cells like vascu- Diffuse Endocrine System. including from peptidergic nerve endings can inhibit the pro-in- capsaicin. may lead to ‘cross- paralleled by the study of animal models and. the same neuropeptides that drive neurogenic inflammation may be protective of tis- Regulation of Immunity by the DES sue homeostasis in other contexts. Neuroendocrinology 2012. Completing a previous. The somatostatinergic anti-inflam- matory loop. the same pep- tidergic nerve endings release also soma- tostatin (SRIH). Noxious stimuli cause sen- sory nerve fibers to release pro-inflamma- tory neuropeptides. to a far sensitization’ and neurogenic inflammation of another lesser extent. in type 1 diabetes mellitus-prone NOD mice. TRPV1-positive fibers contain Trigeminal and dorsal root ganglia contain the cell also SRIH and release it upon TRPV1 receptor activation bodies of capsaicin-sensitive sensory neurons. 2. 20]. whose un. inflammatory response against noxious. fully characterized in rodents in recent times (fig. a hypofunctional Innate Immunity mutant TRPV1 receptor leads to depressed neurogenic Inflammation is a stereotyped. tosis with negative feedback [14. phocytes [21]. such as neuroki- nin A [17]. Besides SP and CGRP. such as the colon. [19]. lym- tion of capsaicin-sensitive nerve endings triggers the re. TRPV1-dependent and -independent stimula. SP. In the same impulses coding for pain to the central nervous system body area where it has been released. e. as the routinely used 111In-pentetreotide (Octreoscan쏐) nociception is immediately coupled to a neurogenic [12. via reflexes able to partially understand the meaning of the biochem. which stops its own. through axon collaterals in the spinal cord and/or in the ical language connecting the endocrine and immune sys. Noteworthy. by SSTR scintigraphy with radiolabelled somatostatin lease of substance P (SP) and calcitonin gene-related pep- (SRIH) analogs having high affinity for SSTR2A.

CST ac. it has been hypothesized that in hu- sepsis. pos. Noteworthy. However. suggesting the existence of an autocrine CST-SSTR2 loop tinal epithelial cells [22]. and contact der. which have been reported to stimulate pro-inflammatory cytokines. and prostaglandin E2. CST. and binding protein considered a necessary and sufficient late partly also cancer pain in advanced neuroendocrine tu.lar endothelial cells. mediator of multiple organ failure in advanced sepsis mors (NETs). Interestingly. inflammation [38. on the effectors of inflammation is both local and sys. via the bloodstream. However. while a GHS-R antagonist concentrations of CgA. and intes. blood of patients with sepsis or undergoing surgery [37]. and its soluble receptors partially antagonized CST activity [28–30]. rath- be detected in human monocyte-macrophages. An. subacute pneumonia. 25]. obtained by inhibiting secretion of IL-10 [32. This inhibitory activity of SRIH (fig. flammation also in humans. Recently. but also the replication of the Cortistatin (CST) is a neuropeptide with strong ho. but not of CST. and rheumatoid arthritis [28–30]. and the Mas-related gene (Mrg) X2 receptor [26]. or even high affinity as SRIH. the latter being report of increased SRIH-like immunoreactivity in the interestingly highly expressed in dorsal root ganglia [27]. systemic inflammatory response to infectious agents. up to affecting or CST feedback may lead to increased susceptibility to circulating levels of these molecules and strikingly im. 39]. 24]. developing more severe inflammatory reactions. since it results merely from an excessive ed with capsaicin-sensitive nerve terminal stimulation. nitric oxide. In animals. In addition. because of their capability of inhibit- for SRIH anti-inflammatory effects in mice [24. blocked lipopolysaccharide-activated macrophages from Clinically. such as arthritis. SRIH can from endotoxemia. are expected to be the most animals have revealed that this SSTR subtype is crucial protective in sepsis. Eventually. CgA and only CST inhibited basal and IL-1␤-stimulated release of its breakdown products have been shown to protect prostaglandin E2 by primary rat microglia. and stimulate the secretion of the anti-in. and that lack of SRIH and/ flammatory cytokine interleukin (IL)-10. might be designed for therapy [36]. such as in- ry action appears to be stronger than that of SRIH. a DNA- controlling headache in patients with acromegaly. tients with chronic inflammatory disorders. CST anti-inflammato. Crohn’s disease. ing not only inflammation. and with lower affinity to type 1a better their analogs. but not SRIH. because increased Therefore. SRIH intestinal polypeptide (VIP) [28]. microorganisms against which inflammation is mount- mology to SRIH. which can bind to SSTRs with the same ed. elegant studies with SSTR4–/– tivities. flammatory bowel diseases [38]. in the latter case. SRIH expression at the inflammatory site in rats [23]. and bronchitis ically also to MrgX2). mans inflammation activates the DES. mRNA can of the DES or hyperactivity of the adrenal medulla. 2). and to stimulate the algesia is another effect of SRIH. Those neuropeptides which also have antimicrobial ac- matitis [19. prove survival and clinical outcomes in mouse models of More in general. chemokines. Both VIP and ghrelin also peripheral nerve firing and acting within the CNS [14]. er than a finalized feedback neuroendocrine response to regulated upon activation in parallel with SSTR2 mRNA. this category of neuropeptides. such as ghrelin [35]. smooth muscle cells [21]. cyclosomatostatin. [39]. rheumatoid arthritis sibly because of CST binding to GHS-R1a (and hypothet. and is up. CST has been shown to inhibit the production of pro. a population the endothelium from TNF-␣-induced inflammatory of CNS-resident macrophage-like cells [31]: thus. A significant anti-inflammatory effect of SRIH has Sepsis is probably the best scenario to pinpoint the been demonstrated in different animal models in which strength of the anti-inflammatory activity of neuroendo- the experimental induction of inflammation is associat. CST was synergic with vasoactive operate as an anti-inflammatory hormone (fig. [34]. In protecting mice exposed to lipopolysaccharide temic. Tumor necrosis factor-␣ (TNF-␣) might be the SSTR-antagonist. crine mediators. Neither implies the raise of CgA 270 Neuroendocrinology 2012. a [40]. growth hormone secretagogue receptor (GHS-R1a) and Despite the abundance of experimental data. TNF-␣.95:267–276 Ameri/Ferone . two different ligands can activate SSTRs to serum values of chromogranin A (CgA) are found in pa- dampen inflammation. since effect of SRIH. the increase in CgA in human tion on innate immunity cells might also be broader than inflammatory diseases may reflect reactive hyperplasia that of SRIH. SRIH analog-induced analgesia is effective in secreting high mobility group box 1 (HMBG1). fully blocked the anti-inflammatory main stimulus for neuroendocrine cell activation. 8]. 1) [7. there is yet no direct evidence that SRIH from capsaicin- inflammatory cytokines and nitric oxide by activated sensitive nerves or CST from other sources inhibit in- macrophages. free radicals. 33]. systemic lupus erythematosus [39]. are positively correlated [38. which has also been might also contribute to the anti-inflammatory action of shown to inhibit macrophage and microglia release of glucocorticoids. changes [42]. 41].

57]. Naïve T cells in the periphery can be converted into Adaptive Immunity Treg upon particular conditions. vival of self-tolerant and the death of autoreactive T cells. cause its ability to generate Treg has been proved in pri- bility complex (also known as human leukocyte antigen. especially affected by sarcoidosis [51]. 12. which instead occurs in the presence of intra. be- pathogen. respectively. cellular pathogens [32. including those mune tolerance to alloantigens (i. 30. respectively. In animal models of the latter two. pansion when they recognize peptides derived from a VIP is the most interesting molecule analyzed so far. For instance. and the apoptotic or mitogenic effects on thymocytes [6. over the allograft. Although not as thorough as DCs. some of these neuro- inhibited the release of Th1 cytokines by CD4+ lympho. 1). autoreactive effector cells [47]. Neuroendocrinology 2012. autoreactive T lymphocytes undergo negative tion factors in T cells. CD4+ T helper (Th) lym. such as sarcoidosis [13]. Ex. induced by tumor-associated anti- active T cells. 44]. analog octreotide.levels that other neuropeptides and/or amines are secret. mary human T cells [50]. When lymphocytes reactive against Immune Response to NETs: The Other Side of the self-tissues. evidence has been gained that other neuropep- immunity. the thymus. acterized Treg population expresses the surface marker ed and somehow involved in tuning the ongoing inflam. 55]. are Coin generated and/or not suppressed. typi. first-line innate immunity [3]. thymic epithelial cells. In a mouse model of skin trans- been demonstrated in mice that SRIH and VIP favor the plantation. Adaptive immunity is achieved through the activity of T cells against foreign or abnormal (non-self) cells which are to be destroyed. which viewed by Gonzalez-Rey and colleagues [36]. This modulation seems to be Immune self-tolerance is firstly produced in the thy- relevant in humans too. Growing attention is being given to the immune re- toimmunity is underlain by ineffective control of autore. 30]. and restore immune tolerance in autoimmune diseases. CD25 (in addition to CD4) and the transcription factor mation. non-self-antigens of brought on by neuropeptides [43]. it has been will then be attacked in a specific manner. and allergic sensitization [45]. selection and elimination [4]. and rheumatoid arthritis lymphocytes themselves [6. the system becomes po- tentially harmful to the host itself [32. The most extensively char- Diffuse Endocrine System. ensures a much higher level of protection than tides. have pro- cytes infiltrating the colon or joints. FoxP3 [48]. and sclerosis [46]. released by sympathetic and parasympathetic nerve toimmune processes. including CST. but not with the SRIH development and maintenance of a Th2 response. In general. can expand/generate Treg [29. treatment with CST. Crohn’s disease. such as SRIH and SP.e. through the stimulation of the recipient’s im- stimuli received during their activation. Treg are lymphocytes shown tumor biology and technical advances that have made to be crucial in sustaining self-tolerance and preventing cancer immunotherapy a feasible treatment perspective the development of autoimmune processes by inhibiting [56. Treg induction might be the conceptual basis for pre- phocytes orchestrate the adaptive immune response. As re- pand different subsets of T cells for every pathogen. without affecting the levels of the which makes them potentially involved in causing the sur- Th2 signature cytokine IL-4 [29. since in more than 300 children mus. referred to as adaptive for VIP. peptides. 54]. CST selectively species and in cell culture systems. tions of transforming growth factor (TGF)-␤ [49].95:267–276 271 Neuroendocrine Tumors and Immunity . properly presented with major histocompati. a function for which regulatory T cells gens (TAA). almost doubled the survival time of cally involved in helminthic infections and allergy. most notably. with a regulatory phenotype [53]. discovered recently that neuropeptides can induce Treg cific clones of T lymphocytes undergo activation and ex. DCs. the immune system is able to ex. and. expression of Th2 transcrip. This capability of adaptation. such as high concentra- In superior species. by venting the rejection of allogeneic transplants with neu- secreting different cytokine patterns according to the ropeptides. 32]. macrophages. which are to be ‘tolerated’ and preserved. and a subset of Treg is gen- ploiting the potential of some neuropeptides of determin. in patients HLA) molecules by antigen-presenting cells. sponse to neoplasms. the primary lymphoid organ where bone marrow- serum levels of SRIH and VIP have been associated with derived thymocytes maturate to T lymphocytes (fig. in the light of both a better understanding of (Treg) play a primary role. erated [47]. In circulating Th2 cytokines. Several neuropeptides are present in the thy- ing a Th2 bias might be of value to treat Th1-driven au. In different animal [32]. draining lymph nodes. it has the donor tissue) [52]. multiple fibers. mus. 47]. au. Antigen-spe. and increased CD4+ spleen lymphocytes a Th1 one.

response is hindered. 39 resected NET liver metastases. such as TGF-␤ and CCL22. A heavier tumor infiltration Carcinoid TAA-specific CD8+ T cells have been de. In humans. which makes it an attractive target for immuno. and there is a thresh.965 patients registered in the European Society for Im. CD4. while those who did not The number of circulating Treg was significantly show recognition of any CgA-derived epitope had either higher in 68 patients with midgut carcinoid tumors than very high or low plasma CgA levels. the authors of the study argue that a minimal tumor tients compared with 18 controls. In the absence of HLA class cies besides XHIGM. and it might be even higher.95:267–276 Ameri/Ferone . tumor-associated macrophages. with IFN-␣ [66]. 65]. tients with a low tumor burden. and in principle slows down or cules chiefly involved in T cell activation. NETs often elude immunosur- colleagues [60] recently reported a 7-year-old child who veillance regardless of the functionality of the immune died from a poorly-differentiated NEC. retrieved six fur. system: clinicians’ experience is that NETs will eventu- ther published cases of NECs in XHIGM. creted by cancer cells. since the introduction of interferon (IFN)-␣ biotherapy. IFN-␥ secretion by CD8+ lympho. cytes in response to TAA was significantly higher in pa. the pancreas being the Anti-tumor immune responses can be limited by Treg most common verified primary site [63].and T-cell functioning. which are therefore likely to pro- mors who were followed up for more than 5 years. Also non-tumor section [63]. which are Indirect evidence that a functional immune system re. direct cell lysis via tumor necrosis fac- hormone synthesis. and thus worse prognosis [69]. since the Euro. In the biggest case series analyzed so far.965. loss of ␤2-microglobulin being the pean database includes other primary immunodeficien. Based on this find. A subpopulation of DCs with natural killer properties which directly inhibits NET cell cycle progression and (CD56 positivity. and acti. tion of NETs. Erdos and As other cancer types. by Treg is associated with weaker anti-tumor immunity scribed in patients with midgut carcinoid tumors [64. can de. characterized by upregulation of costimulatory mole- acts to growing NETs. T cells and the development of a tumor-specific immune stantiated by the frequent finding of lymphocyte infiltra. TAA-derived peptides cannot be presented to That an immune response opposes to NETs is also sub. NET cells may escape the immune response in many munodeficiencies online database. precursors of these DC sub- ␣ [59]. CD3+ T blood precursors was completely abrogated if the latter cells were found to infiltrate 68% of 87 well-differentiated were incubated with cell-free supernatant from bronchial pancreatic NETs. and DCs. 6. comes also from the observation activity toward tumor cells upon stimulation with IFN-␣ that patients affected by X-linked hyperimmunoglobulin [67]. Significantly more CD14+/CD56+ monocytes have M syndrome (XHIGM). monary carcinoid tumor samples [68]. totoxic T lymphocyte-promoting cytokines IL-12p70 and 272 Neuroendocrinology 2012. may have similar or more potent effects than IFN. no CD1a and CD83-positive DCs were found in pul- improved recurrence-free survival following surgical re. In a subgroup of 25 pa- ing. therapy. respectively (fig. and found a ally progress and/or relapse in most immunocompetent total of 4 poorly-differentiated NECs in XHIGM out of patients. TAA then drive their expansion [69]. 3). subjects.4/100. if no therapy is given. Other IFN molecules. as assessed by immunohistochemistry for Immune cells can be inhibited by soluble factors se- CD3 (a general T lymphocyte marker). Treg are induced or re- The highest CD8+ T cell recognition was for the TAA cruited into the tumor by cytokines and chemokines se- CgA. serum levels of the cy- bulk is necessary to activate T cells. of 11 pancreatic NETs. Although an estimate ways [56]. and CD8 creted by NETs. most frequent alteration [61].000 can be extrapolated from the ra. reduces neoangiogenesis. being 15% of all monocytes in 3 cases [67]. like any immune response. Endocrinologists and oncologists have known that old of NET growth beyond which T cells are anergized or immunology may be a key to improve NET management deleted [65]. such as cells) can be generated in vitro by incubating monocytes IFN-␤. been demonstrated by immunohistochemistry in 10 out tio 4/6. an incidence of NECs in An altered expression of HLA class I molecules has XHIGM of 57. a primary immunodeficiency been reported in 4 NEC patients than in healthy control disorder with defective B. CD3+ duce molecules blocking DC differentiation. in 53 healthy blood donors [62]. carcinoid tumor cells. activation of T vates immune cells [58]. and cytolytic halts their progression. I antigens. velop neuroendocrine carcinoma (NEC) [60]. Interestingly. Consistent- T cell infiltration was a significant univariate predictor of ly. Generation of DCs from umbilical cord [61–63]. In patients with intermediate-grade tu. tor-related apoptosis-inducing ligand. type might be CD14+/CD56+ monocytes. CD3+ infiltration was also found in 97% of stromal cells may release immune inhibitory factors. cannot be equated with reality. As illustrated in figure 3.

including somatostatin analogs (SSA). anti-tumor im- mune response. 73]. for DC vaccination DCs perspectives. Even though Treg and no Treg within NETs have been reported too few patients. this really hap- cause of an anergized state caused by carcinoid-associat. see [44]). possibly be. A Although a clear. recruit/induce regulatory T cells (Treg). which is antagonized by several tumor-related factors. In NET liver me. The growth of a NET induces a specific. have received DC immunotherapy for than in primary carcinoid tumors [62]. loaded with TAA. the route and schedule of TAA-load- even though such an approach is not optimal to identify ed DC administration (for a review. in- fluence the anti-NET immune response is not known yet. Whether therapies. Tumor-as- sociated antigens (TAA). the way they are immunohistochemistry for single Treg markers [62. but to a variable extent. 63]. RT = radiotherapy. Research on animal models has shed light on the Even before most of the aforementioned data were physiological. the field is rapidly expanding and great hopes tastases (most from pancreatic NETs) it was significantly are pinned on it [74. Conclusions In Merkel cell carcinoma. dendritic cells (DCs). grown. After polyclonal activation. comprehensive picture of how the possible explanation is that mast cells may also stimulate DES and the immune system influence each other has immunosuppression. PRRT = peptide receptor ra- diotherapy. and concentrations of the and administered back to a patient. as VIP or CST.95:267–276 273 Neuroendocrine Tumors and Immunity . along with cy- tokines from NET cells. 3. a higher number of intratu- moral mast cells was a predictor of shorter survival. pens. tumor not yet been established. which inhibit the anti-tumor im- mune response as well. patients’ T cells cells.Fig. delivered into DCs. and has opened exciting therapy were published [71. and eventually induce an anti-tumor response re- proliferated less than those from controls. CT = Chemotherapy. significant modulation of immune func- available. ducing or arresting tumor outgrowth. Briefly. largely depending on tech- ed Treg [62]. NET-infiltrating Treg have been detected by nical issues as the choice of the TAA. Neuroendocrinology 2012. even though not TAA should cause the activation of tumor-specific T significantly. and extracellular matrix degradation [70]. IL-1␤ were significantly lower. denser in intermediate/high-grade than low-grade le- sions and correlated with a shorter overall survival in univariate analysis [63]. 75]. as depicted in the lower part of the figure. and tumor-associated macro- phages. which can inhibit exuberant and thus det- Diffuse Endocrine System. The immune response to neuroen- docrine tumors (NETs). our knowledge has remarkably proliferation. 72]. especially affected by medullary thyroid [61]. These mainly concern neuropeptides such are generated and/or purified ex vivo. pioneering reports about DC vaccination NETs tions by neuropeptides. along with angiogenesis. NETs so far. DCs pulsed with Treg cytokine TGF-␤ were increased. Treg infiltration tended to be heavier in metastases carcinoma [72.

Lamberts SW. kai L. tern of neuropeptides and their receptors. Lichtenauer-Kaligis EG. prognostic markers (e. Pivonello R. Nevertheless. its expression in human immune cells. Sasano H: Systemic distribution of 16 Ustinova EE. the pre- be resistant to experimental autoimmune encephalitis. P.g. 14 Pintér E. Burrell MA. because VIP exerts an unan. Lamberts SW. Colao functional role of somatostatin receptor sub. Mooy CM. in sarcoid granulomas. Am J mini E. van Hagen PM. Mikami Y. ceptor scintigraphy. Kwekkeboom DJ. Am J Physiol Renal Physi- localization of somatostatin receptor sst2A Talme T: Expression pattern of somatostatin ol 2007. Pozsgai G. Physiol Endocrinol Metab 2003. Guembe L. and so. to a direct comparison with the current best treatment In contrast to the wealth of information from basic and options for NETs. Tsui H. 13 Ameri P. Houtsmuller AB.44:399–406. Disclosure Statement if any. munohistochemical study of healthy sub. a liminary.112:440– NY Acad Sci 2004. Yantha J. 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