Neuropeptides in the Development of Colon Cancer

Sergio Britto Garcia¹, Stefania Bovo Minto¹, Vinicius Kannen² and Enio Chaves Oliveira^3*

¹Department of Pathology and Legal Medicine, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo, Ribeirão Preto, Brazil

²Department of Toxicology, Bromatology, and Clinical Analysis, University of Sao Paulo, Ribeirão Preto, Brazil

³Department of Surgery, School of Medicine, Federal University of Goiás, Brazil

Corresponding Author:

Oliveira EC
Department of Surgery, School of Medicine
Federal University of Goiás, Brazil
E-mail: eco1.br@gmail.com

Received: April 05, 2016 Accepted: April 30, 2016 Published:May 06, 2016

Citation:Garcia SB, Minto SB, Kannen V, Oliveira EC (2016) Neuropeptides in the Development of Colon Cancer. Can Surg 1:104.

Copyright: © 2016 Garcia SB, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Visit for more related articles at Cancer Surgery

Abstract

Neuropeptides modulate a broad range of physiologic processes as paracrine and endocrine factors in peripheral systems. These complex neuronal activities are only possible because neurons can release one or more neuropeptides together, which can signal as neuromodulators. Given that a large number of neuropeptides has been reported, it would be almost impossible to describe such complexity herein. Therefore, we will focus only on those molecules with more known pronounced activity throughout the development of colon cancer. Given that the intestinal neuro-immune axis plays a significant role in regulating the severity of inflammation, it possibly has a pivotal role in the colon cancer development. Nevertheless, the precise role and the real impact of neuropeptides in the development of colon cancer, remains to be fully elucidated.

Keywords

Neuropeptides; Colon cancer; Growth factors; Peptide hormones; Neurotransmitters

Introduction

A class of small protein-like molecules synthesized from short amino acid chains were coined ‘neuropeptides’ by David de Wied in the early 1970's. These hormones were originally thought to modulate brain-related events only [1,2]. Burbach et al. [1] has recently proposed that chemokines, growth factors, and hormones should be considered neuropeptides, although such idea remains debatable [2]. Scientific research engaged in clarifying the functions of neuropeptides still is mostly carried out in the brain tissue under either physiological or pathological conditions. In the last 20 years, neuroscience has revealed that these molecules play a vital role in several physiological functions from virtually all peripheral tissues. Neuropeptides modulate a broad range of physiologic processes as paracrine and endocrine factors in peripheral systems. These complex neuronal activities are only possible because neurons can release one or more neuropeptides together, which can signal as neuromodulators. These molecules have been mainly reported to act through several G protein-coupled receptors [1]. Given that a large number of neuropeptides has been reported, it would be almost impossible to describe such complexity herein. Therefore, we will focus only on those molecules with more known pronounced activity throughout the development of colon cancer (Table 1).

Table 1: Reported effects of neuropeptides on experimental models of colonic cancer *↑ stimulatory effect; ↓ inhibitory effect.

‘The Second Brain’ Activity in Inflammation and Colon Cancer

The American neuro-gastroenterologist Gershon [3] has precisely nicknamed the intestines as ‘The second brain’, taking into account the size and complexity of the enteric nervous system (ENS). Enterochromaffin cells (EC) are functionally connected with the ENS and can also synthesize neuropeptides to control intestinal functions [4]. Novel evidence has shown that EC indeed differentiates from the intestinal cryptal stem cell niche [5,6]. Besides, mammalian bombesinlike peptides, cholecystokinin (CCK), gastrin, and neurotensin are gastrointestinal neuropeptides that impact on the body development, inflammation, tissue regeneration, and neoplastic transformation [7].

These molecules signal through their receptors that are highly expressed in the human colon but have, however, a differentiated pattern of expression for each one of them, which might illustrate their specific physiological roles. Hence, GRP receptors, Y2 receptors, PACAP type1-receptors, cholecystokinin-A receptors, neurotensin1 and somatostatin st2 receptors were abundantly expressed in the myenteric plexus, whereas VIP/PACAP and sst2 receptors were found in lymphoid follicles, and Y2, VIP type1 and sst2 receptors were present in the colonic mucosa [8]. Specific binding sites for VIP, have been characterized in isolated human colonic epithelial cells in the early 80s [9,10]. Given that the intestinal neuro-immune axis plays a significant role in regulating the severity of inflammation, it possibly has a pivotal role in the colon cancer development. For instance, neuropeptides might have either anti-inflammatory (VIP and galanin) or pro-inflammatory effects (NPY, substance P, serotonin, and neurotensin). The activation of specific immune signaling pathways might be the key to understanding the complex and controversial effects of these neuropeptides, from which inflammatory signals increase in a cascade of events [11]. Corticotropin-releasing factor (CRF), which is a stress peptide, has been shown to control the colonic IL-6 release and neuronal activation, a fact that helps to clarify the effects of stressful conditions on the development of colonic inflammation [12].

Whether colitis increases the expression of neuropeptide Y (NPY) in the enteric nervous system, NPY knockout mice showed reduced intestinal inflammation [11]. Pharmacological inhibition of vasoactive intestinal peptide (VIP), which is a neurotransmitter and vasodilator, protected experimental models from colitis [13]. VIP-deficient mice, authors have also found reduced inflammation in trinitrobenzene sulfonic acid-induced colitis [14]. Then, glucagon-like peptide 2 (GLP-2), which is an enteroendocrine hormone trophic for intestinal mucosa, has been shown to increase enteric neuronal expression of VIP [15]. Sigalet et al. [15] suggested that GLP-2 acts on enteric neurons and glial cells via a PI3Kγ/Akt pathway, stimulating neuronal differentiation via mTOR and ERK pathways, as well as the expression of receptors and ligands for IGF-I and ErbB pathways. Conversely, the anti-inflammatory and blood flow effects of GLP-2 are related to VIP and nitric oxide synthesizes and release from submucosal enteric neurons [16].

Although GLP-2 is a hormone with multiple beneficial intestinal effects, as regeneration of the mucosal surface area through increased crypt cell proliferation, and promotion of nutrient digestion and absorption, we have discussed its potential pro-malignant effects in colon cancer through the PI3Kγ/Akt pathway [16]. Another study has shown that GLP-2 not only modulated intestinal stem cell behaviour but also promoted colon carcinogenesis in experimental models [17].

Substance P (SP) also seems to modulate intestinal inflammation, and recovery process of chemically-induced colitis [18,19]. This peptide inhibits apoptosis activating the Akt signaling through NK-1R, which promotes the tissue recovery during colitis [20]. SP is yet recognized by the neurokinin receptor NK-1R in stromal colonic cells enhancing angiogenesis in the chronic phase of colitis [21]. In intestinal bowel diseases (IBD), expression of SP and vanilloid-type ion channel receptor transient receptor potential vanilloid type 1 (TRPv1) was observed to be increased in enteric nervous fibers, which grown in density near to mesenteric blood vessels instead of those submucosal units [22]. Yet, TRPV-1 has been suggested to inhibit the neuroinflammation in IBD, because its activation induces the release of somatostatin and SP [23]. Such control on the neuroinflammatory processes by TRPV-1 has been hypothesized to decrease the initiation and progression of colon cancer [24].

Tutton et al. [25] developed an elegant study that revealed that colonic cell proliferation, but not the tumour proliferative activity, was controlled by the autonomic nervous system. We have also explored the relationship between the myenteric neuronal activity and colon carcinogenesis for two decades now and found that reduced myenteric neuronal density impairs the development chemical-induced colonic pre-neoplastic lesions [26,27]. It helped to clarify the old empirical idea that Brazilian physicians had that ‘carcinoma of the colon does not occur in cases of acquired chagasic megacolon’. Indeed, our latest report has shown that DNA damage in epithelial cells is decreased in patients and experimental murine models with reduced enteric neuronal density [28].

Although these reports seem controversial at first, we should consider that pre-neoplastic cells are not malignant cells yet, from which we might hypothesize that enteric neurons and intestinal neuropeptides possibly have different activities according to each phase of colon carcinogenesis. In a chemically-induced colon cancer model, the relative density of substance P- and VIP-IR nerve fibres was increased in the muscularis propria [29]. In colon cancer samples, the density of VIP, PACAP, and NPY-positive neurons and neural fibres have been, however, found decreased in sub-mucousal and enteric plexuses [30]. Neuropeptides and their receptors have been also found expressed by either neuroendocrine or non-neuroendocrine tumour cells [31]. Indeed, colon carcinomas containing NE populations, even if small, have been reported to behave worse than their counterparts without these NE cells [32]. In adenomas, argyrophilic cells were detected in such large number, and so intricately blended with other cell types, that they were regarded as an intrinsic part of the tumor. An immunocytochemistry analysis then revealed that these tumor cells expressed glucagon, pancreatic polypeptide, somatostatin, and serotonin in close resemblance to their expression pattern in the normal colorectal mucosa [33,34]. However, novel evidence has shown that serum levels of SP and TNF receptor 1 were higher in colon cancer patients than in healthy subjects [35].

Understanding the Effects of Main Neuropeptides in the Development of Colon Carcinogenesis

Davis et al. [36] were the first to report that enkephalin levels in colon adenocarcinomas were significantly higher than in normal controls. Then, Taniguchi and colleagues observed that enkephalin also enhanced experimental and chemically induced colon carcinogenesis [37]. A recent report has discussed that tachykinins, neuropeptide Y, and β-adrenergic receptors might enhance the progression of gastrointestinal tumours through the immune system [38].

In ulcerative colitis patients, who have increased risk of colon cancer, VIP neural fibres were found in higher density in comparison with normal colon samples, although those positive fibres for SP and neurotensin were reduced [39]. VIP is known to act through specific receptors in the plasma membrane of human colonic adenocarcinomas [40-43]. Recently, VIP has been reported to bind to some receptors, named as VIP/pituitary adenylate cyclase-activating peptide receptors (VPACs), which are overexpressed in poor differentiated colon adenocarcinomas [44]. Experimentally, VIP also enhanced the development of azoxymethane-induced colonic tumours [45].

Galanin (GAL) is a neuropeptide expressed by neurons, and with complex physiological functions. In colon cancer patients, GAL expression by myenteric neurons was increased in comparison with healthy subjects [46]. According to the colon cancer size and stage, GAL serum levels were significantly increased [47]. A worsen prognosis was related to high-GAL serum levels in colon cancer patients at the stage II [48]. Iishi et al. [49] had, however, reported that this neuropeptide might suppress the development of colon tumors. Notably, cell culture experiments have clarified that GAL receptor type I (GALr1) has anti-proliferative effects, whereas its receptor type II could induce either anti- or pro-proliferative according to the stimuli intensity. Hence, GAL and its receptors might be powerful biomarkers in colon cancer diagnosis [50].

The physiological functions of gastrin and cholecystokinin (CCK) are well-known in the nervous and gastrointestinal systems. However, pro-gastrin, a gastrin precursor has been reported to promote colonic epithelial proliferation and cancer, as well as to inhibit the acquisition of an M2-phenotype by tumour-associated macrophages [51,52]. Notably, long-term treatment with the proton pump inhibitor (PPI), which increases gastrin levels, did not increase the risk of colon cancer. Authors reported that PPI-induced anti-inflammatory, anti-oxidative, and anti-mutagenic effects, reducing the risk of colon cancer [53]. Furthermore, pro-gastrin inhibited the acquisition of a M2-phenotype by tumour-associated macrophages [51]. These facts illustrate the complex activity of neuropeptides in colon carcinogenesis.

Neurotensin, which is another intestinal neuropeptide, has been reported to modulate pro-inflammatory and tissue repair signalling pathways by activating the insulin-like growth factor-1 receptor (IGF-1R) that induces Akt phosphorylation and NF-κB activation after this neuropeptide is coupled to its receptor (NTr1) in colonic epithelial cells [54]. Notably, NTr1 expression was found increased in colon cancer but not in normal epithelial cells. Authors suggested that that cancer outgrowth induced by mutations in the Wnt/APC signalling pathway further enhanced the NTr1 expression [55]. Another recent report has shown that neurotensin induces proliferation and differentiation of colon cancer cells through calcium signalling [56], which has its intracellular levels modulated by this neuropeptide in an inositol triphosphate-dependent manner [57]. In azoxymethaneexposed rats, the neurotensin treatment increased colon tumours in size and numbers, as well as their development into adenocarcinomas [58]. In the HT29 cells, NT stimulated MAP kinase phosphorylation through its receptors promoting cell growth aside from the epidermal growth factor (EGF) signalling [59].

Dougherty et al. [60] have recently suggested that EGF acts through its receptor (EGFr) promoting tumorigenesis in azoxymethane/dextran sulphate sodium-exposed mice. In another carcinogen-induced colon cancer murine model has been revealed that bombesin stimulates cell proliferation, a fact later confirmed in human colon carcinoma cells [61,62]. In Caco-2 colon cancer cells, this neuropeptide was also reported to induce gene and protein expression of cyclooxygenase-2 expression, which promoted cell growth, invasiveness, and tumour progression [63].

Given that somatostatin (SST) has anti proliferative and proapoptotic effects in cancer cells, and is usually decreased in tumours, its reduced expression was suggested to release cancer cells toward proliferation. Such reduced expression of SST was revealed to related to a gene silencing via hyper methylation of its promoter region, which is a central event in the pathogenesis of several types of cancer [64,65]. Another example of the neuropeptide complex activity in cancer is illustrated by comparing the calcitonin to its precursor pro-calcitonin. Whereas hypermethylating the promoter gene region of calcitonin enhance cancer cell survival [66], high-pro-calcitonin serum levels were observed to promote distant metastases in colon cancer patients [67]. Increased expression levels of adrenomedullin (ADM) have been also observed in colon cancer samples, which was then hypothesized to determine the cancer stage and the clinical survival rate [68,69]. Notably, tumour hypoxia was suggested to upregulate this neuropeptide expression that increased Bcl-2 activity, but down regulated those Bax and Bid proapototic factors [70].

Angiotensin is a peptide with stimulatory effects on colon carcinogenesis, since it has been observed that angiotensin-converting enzyme inhibitor strongly suppress chemically-induced colon carcinogenesis by attenuating chronic inflammation and reducing oxidative stress in obese mice [71]. Diabetic patients with primary colon cancer patients have been reported to have high serum levels of angiotensin-II (A-II), which seemed to increase the number of liver metastasis in comparison with nondiabetic subjects. In cell culture experiments these findings were confirmed, since A-II treatment promoted growth, invasion, and anti-apoptotic signals [72]. Another neuropeptide close related to metabolic events is the melaninconcentrating hormone (MCH), which modulates appetite and energy balance in the hypothalamus. In APCmin mice, knocking out strategies against MCH has been reported to reduce the number of intestinal tumours, which were smaller and less dysplastic tumours than those from the wild-type group [73]. Interestingly, reduced expression of corticotrophin-Releasing-Hormone receptors (CRHr) enhanced the risk of distant metastases and poor clinical prognosis [74].

Finally, it must be mentioned the hypothesis of existence of links between psychosocial factors and colon cancer development. If such relationship eventually will be demonstrated, certainly neuropeptides will play a major role on it. Studying the β-endorphin activity, which is an opioid peptide enrolled in controlling the central nervous stress axis, has been applied to understand how nervous, endocrine, and immune systems can impact on cancer growth and metastasis. For instance, high-β-endorphin hypothalamic levels have been found to suppress sympathetic neuronal functions, improving the killing activity of cancer cells by the immune system that reduced tumour incidence in prostate and breast cancer models [75]. On the other hand, the tachykinins family of neuropeptides, such as substance P, neurokinin A and B, hemokinin-1 and endokinins, can act in different steps of carcinogenesis [76,77]. Indeed, they seem to promote proliferation and survival of cancer cells and facilitate tumor metastases by infiltrating in the bone marrow [78]. Regardless of tumour histology, tachykinins might favour cancer incidence and metastases promoting immunosuppression together with improved malignant neovascularization in tumours [79].

Conclusions

We have mentioned here various reports on effects of isolated given neuropeptides in colon cancer development, as summarized on Table 1. Nevertheless, it must be taken into account that: (1) concomitant effects of various neuropeptides in cancer have not been evaluated so far and (2) the huge complexity and the vast number of variables involved in the modulation of colonic carcinogenesis by neuropeptides defy our current capacity of analysis. Thus, the precise role and the real impact of neuropeptides in the development of colon cancer, remains a major scientific challenge.

References

1. Burbach JP, Meijer OC (1992) The structure of neuropeptide receptors. Eur J Pharmacol. 227:1-18.
2. Burbach JP (2010) Neuropeptides from concept to online database. Eur J Pharmacol 626:27-48.
3. Gershon MD (1995) The enteric nervous system: a second brain. HospPract 34:31.
4. Heredia DJ, Gershon MD, Koh SD, Corrigan RD, Okamoto T, et al. (2013) Important role of mucosal serotonin in colonic propulsion and peristaltic reflexes: in vitro analyses in mice lacking tryptophan hydroxylase 1. J Physiol591:5939-5957.
5. Yan KS, Chia LA, Li X, Ootani A, Su J, et al. (2012) The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. ProcNatlAcadSci USA 109:466-471.
6. Sei Y, Lu X, Liou A, Zhao X, Wank SA (2011) A stem cell marker expressing subset of enteroendocrine cells resides at the crypt base in the small intestine. Am J PhysiolGastrointest Liver Physiol 300:G345-56.
7. Rozengurt E, Guha S, Sinnett-Smith J (2002) Gastrointestinal peptide signalling in health and disease. . Eur J Surg587:23-38.
8. Rettenbacher M, Reubi JC(2001) Localization and characterization of neuropeptide receptors in human colon. NaunynSchmiedebergs Arch Pharmacol 364:291-304.
9. Broyart JP, Dupont C, Laburthe M, Rosselin G(1981) Characterization of vasoactive intestinal peptide receptors in human colonic epithelial cells. J ClinEndocrinolMetab 52:715-721.
10. Muller JM, Luis J, Fantini J, Abadie B, Giannellini F, et al. (1985) Covalent cross-linking of vasoactive intestinal peptide (VIP) to its receptor in intact colonic adenocarcinoma cells in culture (HT 29). Eur J Biochem 151:411-417.
11. Chandrasekharan B, Jeppsson S, Pienkowski S, Belsham DD, Sitaraman SV, et al. (2013) Tumour necrosis factor neuropeptide Y cross talk regulates inflammation epithelial barrier functions, and colonic motility. Inflamm Bowel Dis 19: 2535-2546.
12. O'Malley D, Cryan JF, Dinan TG(2013) Crosstalk between interleukin-6 and corticotropin-releasing factor modulate submucosal plexus activity and colonic secretion. Brain BehavImmun30:115-24.
13. Vu JP, Million M, Larauche M, Luong L, Norris J, et al. (2014) Inhibition of vasoactive intestinal polypeptide (VIP) induces resistance to dextran sodium sulphate (DSS) induced colitis in mice. J MolNeurosci 52:37-47.
14. Abad C, Cheung Lau G,CoûtéMonvoisin AC, Waschek JA (2015) Vasoactive intestinal peptide deficient mice exhibit reduced pathology in tri nitrobenzene sulfonic acid induced colitis. . Neuroimmunomodulation 22:203-212.
15. de Heuvel E, Wallace L, Sharkey KA, Sigalet DL(2012) Glucagon like peptide 2 induces vasoactive intestinal polypeptide expression in enteric neurons via phophatidylinositol 3 kinase γ signaling. Am J PhysiolEndocrinolMetab 303:E994-1005.
16. Kannen V, Garcia SB, Stopper H, Waaga Gasser AM(2013) Glucagon like peptide 2 in colon carcinogenesis: Possible target for anti cancer therapy? PharmacolTher139:87-94.
17. Rowland KJ, Brubaker PL(2011) The cryptic mechanism of action of glucagon-like peptide 2. Am J PhysiolGastrointest Liver Physiol 301:G1-8.
18. El Aidy S, Kunze W, Bienenstock J, Kleerebezem MT (2012) The microbiota and the gut brain axis: insights from the temporal and spatial mucosal alterations during colonisation of the germfree mouse intestine. Benef Microbes 3:251-259.
19. Zhao P, Dong L, Luo JY, Guan HT, Ma H, et al. (2013) Possible role of mast cells and neuropeptides in the recovery process of dextran sulphate sodium-induced colitis in rats. Chin Med Sci J 28:28-33.
20. Koon HW, Zhao D, Zhan Y, Moyer MP, Pothoulakis C (2007) Substance P mediates antiapoptotic responses in human colonocytes by Akt activation. ProcNatlAcadSci USA104: 2013-2018.
21. Koon HW, Zhao D, Xu H, Bowe C, Moss A, et al. (2008) Substance P mediated expression of the pro angiogenic factor CCN1 modulates the course of colitis. Am J Pathol 173:400-10.
22. de Fontgalland D, Brookes SJ,Gibbins I, Sia TC, Wattchow DA(2014) The neurochemical changes in the innervation of human colonic mesenteric and submucosal blood vessels in ulcerative colitis and Crohn's disease. NeurogastroenterolMotil 26:731-44.
23. Keszthelyi D, Troost FJ, Jonkers DM, Helyes Z, Hamer HM, et al. (2013) Alterations in mucosal neuropeptides in patients with irritable bowel syndrome and ulcerative colitis in remission: a role in pain symptom generation? Eur J Pain 1:1299-1306.
24. Vinuesa AG, Sancho R, GarcíaLimones C, Behrens A, ten Dijke P, et al. (2012) Vanilloid receptor 1 regulates neurogenic inflammation in colon and protects mice from colon cancer. Cancer Res 72:1705-1716.
25. Tutton PJ, Barkla DH (1977) The influence of adrenoceptor activity on cell proliferation in colonic crypt ipithelium and in colonic adenocarcinomata. Virchows Arch B Cell Pathol 24:139-146.
26. Oliveira EC, Lette MS, Ostermayer AL, Almeida AC, Moreira H(1997) Chagasicmegacolon associated with colon cancer. Am J Trop Med Hyg 56:596-608.
27. Garcia SBO JS, Pinto LZ, Muccillo G, Zucoloto S(1996) The relationship between megacolon and carcinoma of the colon: an experimental approach. Carcinogenesis17: 1777-1779.
28. Kannen V, de Oliveira EC, Motta BZ, Chaguri AJ, Brunaldi MO, et al. (2015) Trypanosomiasis induced megacolon illustrates how myenteric neurons modulate the risk for colon cancer in rats and humans. PLoS neglected tropical diseases 9:e0003744.
29. Sitohy B, El Salhy M (2002) Changes in the colonic enteric nervous system in rats with chemically induced colon dysplasia and carcinoma. ActaOncol 41:543-549.
30. GodlewskiJ, Lakomy IM (2010) Changes in vasoactive intestinal peptide pituitary adenylate cyclase activating polypeptide and neuropeptide Y ergic structures of the enteric nervous system in the carcinoma of the human large intestine. Folia HistochemCytobiol48: 208-16.
31. Burbach JP (2011) What are neuropeptides? Methods MolBiol789:1-36.
32. Jansson D, Gould VE, Gooch GT, Rittenhouse HG, Shin SS, et al. (1988) Immunohistochemical analysis of colon carcinomas applying exocrine and neuroendocrine markers. APMIS 96:1129-1139.
33. Van den Ingh HF, Van den Broek LJ, Verhofstad AA, Bosman FT (1986) Neuroendocrine cells in colorectal adenomas. J Pathol 48:231-237.
34. Sarvi S, Mackinnon AC, Avlonitis N, Bradley M, Rintoul RC, et al. (2014) CD133+ cancer stem like cells in small cell lung cancer are highly tumorigenic and chemoresistant but sensitive to a novel neuropeptide antagonis. Cancer Res 74:1554-65.
35. Johansson M, Jönsson M, Norrgård O, Forsgren S (2008) New aspects concerning ulcerative colitis and colonic carcinoma: analysis of levels of neuropeptides neurotrophins and TNFalpha/TNF receptor in plasma and mucosa in parallel with histological evaluation of the intestine. Inflamm Bowel Dis 14:1331-1340.
36. Davis WG, Tormey WP, Delaney PV(1979) Enkephalins in large bowel malignancy and in acute appendicitis. Gut 20:865-867.
37. Iishi H, Tatsuta M, Baba M, Okuda S, Taniguchi H (1991) Enhancement by methionine enkephalin of colon carcinogenesis induced by azoxymethane. Cancer Res 51:785-788.
38. Xu XT, Xu B, Song QB, Zeng H(2013) The role of neural related factors in the metastasis of the gastrointestinal cancer. J Cancer Res TherS123-128.
39. Tomita R, Tanjoh K, Fujisaki S, Fukuzawa M(2000) Peptidergic nerves in the colon of patients with ulcerative colitis. Hepatogastroenterology 47:400-404.
40. Laburthe M, Rousset M, Boissard C, Chevalier G, Zweibaum A, et al. (1978) Vasoactive intestinal peptide: a potent stimulator of adenosine 3':5' cyclic monophosphate accumulation in gut carcinoma cell lines in culture. ProcNatlAcadSci USA 75:2772-2775.
41. Dupont C, Amiranoff B, Laburthe M, Rosselin G (1978) Receptors for vasoactic intestinal peptide (VIP) in human colonic adenocarcinoma membranes: specific binding and stimulation of adenylate cyclase. C R AcadSciHebdSeancesAcadSci D 286:209-212.
42. Laburthe M, Rousset M, Chevalier G, Boissard C, Dupont C, et al. (1980) Vasoactive intestinal peptide control of cyclic adenosine 3':5' monophosphate levels in seven human colorectal adenocarcinoma cell lines in culture. Cancer Res 40:2529-2533.
43. Rousset M, Laburthe M, Chevalier G, Boissard C, Rosselin G, et al. (1981) Vasoactive intestinal peptide (VIP) control of glycogenolysis in the human colon carcinoma cell line HT 29 in culture. FEBS Lett1 26:38-40.
44. Liu S, Zeng Y, Li Y, Guo W, Liu J, et al. (2014) VPAC1 overexpression is associated with poor differentiation in colon cancer. Tumour Biol 35:6397-6404.
45. Iishi H, Tatsuta M, Baba M, Okuda S, Taniguchi H (1987) Enhancement by vasoactive intestinal peptide of experimental carcinogenesis induced by azoxymethane in rat colon. Cancer Res 47:4890-4893.
46. Godlewski J, Pidsudko Z(2012) Characteristic of galaninergic components of the enteric nervous system in the cancer invasion of human large intestine. Ann Anat 194:368-372.
47. Kim KY, Kee MK, Chong SA, Nam MJ (2007) Galanin is up regulated in colon adenocarcinoma. Cancer Epidemiol Biomarkers Prev 16:2373-2378.
48. Nagayoshi K, Ueki T, Tashiro K, Mizuuchi Y, Manabe T, et al. (2015) Galanin plays an important role in cancer invasiveness and is associated with poor prognosis in stage II colorectal cancer. Oncology Rep 33:539-546.
49. Iishi H, Tatsuta M, Baba M, Uehara H, Yano H, et al. (1995) Chemoprevention by galanin against colon carcinogenesis induced by azoxymethane in Wistar rats. Int J Cancer 61:861-863.
50. Rauch I, Kofler B(2010) The galanin system in cancer. EXS 102:223-241.
51. Hernández C, Barrachina MD, Cosín-Roger J, Ortiz-Masiá D, Álvarez Á, et al. (2014) Progastrin represses the alternative activation of human macrophages and modulates their influence on colon cancer epithelial cells. PLoS One 9:e98458.
52. Dimaline R, Varro A (2014) Novel roles of gastrin. J Physiol 592:2951-2958.
53. Han YM, Hahm KB, Park JM, Hong SP, Kim EH (2014) Paradoxically augmented anti tumorigenic action of proton pump inhibitor and GastrininAPCMin/+ intestinal polyposis model. Neoplasia 16:73-83.
54. Zhao D, Bakirtzi K, Zhan Y, Zeng H, Koon HW, et al. (2011) Insulin like growth factor 1 receptor transactivation modulates the inflammatory and proliferative responses of neurotensin in human colonic epithelial cells. JBiolChem 286:6092-6099.
55. Souazé F, ViardotFoucault V, Roullet N, Toy MiouLeong M, Gompel A, et al. (2006) Neurotensin receptor 1 gene activation by the Tcf/beta-catenin pathway is an early event in human colonic adenomas. Carcinogenesis 27:708-716.
56. Chowdhury MA, Peters AA, Roberts Thomson SJ, Monteith GR (2013) Effects of differentiation on purinergic and neurotensinmediated calcium signalling in human HT 29 colon cancer cells. BiochemBiophys Res Commun 439:35-39.
57. Amar S, Kitabgi P, Vincent JP (1986) Activation of phosphatidylinositol turnover by neurotensin receptors in the human colonic adenocarcinoma cell line HT29. FEBS Lett 201:31-36.
58. TasutaM, Iishi H, Baba M, Taniguchi H(1990) Enhancement by neurotensin of experimental carcinogenesis induced in rat colon by azoxymethane. Br J Cancer 62:368-371.
59. Massa F, Tormo A, Béraud-Dufour S, Coppola T, Mazella J (2011) Neurotensininduced Erk1/2 phosphorylation and growth of human colonic cancer cells are independent from growth factors receptors activation. BiochemBiophys Res Commun 414:118-122.
60. Dougherty U, Mustafi R, Sadiq F, Almoghrabi A, Mustafi D, et al. (2014) The renin angiotensin system mediates EGF receptor vitamin d receptor cross-talk in colitis-associated colon cancer. Clin Cancer Res 20:5848-5859.
61. Ide A, Yoshinaga K, Iwama T, Mishima Y(1994) Bombesin enhances experimental carcinogenesis induced in rat colon by 1,2 dimethylhydrazine. Carcinogenesis 15:2095-2098.
62. Saurin JC, Némoz-Gaillard E, Sordat B, Cuber JC, Coy DH, Abello J, et al. (1999) Bombesin stimulates adhesion, spreading, lamellipodia formation, and proliferation in the human colon carcinoma isreco1 cell line. Cancer Res 59:962-967.
63. Corral RS, Iñiguez MA, Duque J, López Pérez R, Fresno M(2007) Bombesin induces cyclooxygenase 2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco2 colon carcinoma cells. Oncogene 26:958-969.
64. Mori Y, Cai K, Cheng Y, Wang S, Paun B, et al. (2006) A genome wide search identifies epigenetic silencing of somatostatin, tachykinin 1 and 5 other genes in colon cancer. Gastroenterology 131:797-808.
65. Leiszter K, Sipos F, Galamb O, Krenács T, Veres G, et al. (2015) Promoter hypermethylationrelated reduced somatostatin production promotes uncontrolled cell proliferation in colorectal cancer. PLoS One 10:e0118332.
66. Silverman AL, Park JG, Hamilton SR, Gazdar AF, Luk GD, et al. (1989) Abnormal methylation of the calcitonin gene in human colonic neoplasms. Cancer Res 49:3468-3473.
67. Keramidaris D, Koronakis N, Lagoudianakis EE, Pappas A, Koukoutsis I, et al. (2013) Procalcitonin in patients with colorectal cancer. J BUON 18:623-628.
68. Kim JY, Park WD, Lee S, JHP (2012) Adrenomedullin is involved in the progression of colonic adenocarcinoma. Mol Med Rep 6:1030-1034.
69. Zudaire E, Martínez A, Cuttitta F(2003) Adrenomedullin and cancer. RegulPept 112:175-183.
70. Martínez A, Vos M, Guédez L, Kaur G, Chen Z, et al. (2002) The effects of adrenomedullin overexpression in breast tumour cells. J Natl Cancer Inst 94:1226-1237.
71. Kubota M, Shimizu M, Sakai H, Yasuda Y, Ohno T, et al. (2011) Renin angiotensin system inhibitors suppress azoxymethaneinduced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. BiochemBiophys Res Commun 410:108-113.
72. Shimomoto T, Ohmori H, Luo Y, Chihara Y, Denda A, et al. (2012) Diabetes associated angiotensin activation enhances liver metastasis of colon cancer. ClinExp Metastasis 29:915-925.
73. Nagel JM, Geiger BM, Karagiannis AK, Gras-Miralles B, Horst D, et al. (2012) Reduced intestinal tumorigenesis in APCmin mice lacking melanin concentrating hormone. PLoS One 7:e41914.
74. Rodriguez JA, Huerta Yepez S, Law IK, BaayGuzman GJ, TiradoRodriguez B, et al. (2015) Diminished expression of CRHR2 in human colon cancer promotes tumor growth and EMT via persistent IL 6/Stat3 signalling. Cell MolGastroenterolHepatol 1:610-630.
75. Sarkar DK, Murugan S, Zhang C, Boyadjieva N (2012) Regulation of cancer progression by β endorphin neuron. Cancer Res 72:836-840.
76. Muñoz M, Rosso M, González A, Saenz J, Coveñas R(2010) The broad spectrum anti-tumour action of cyclosporin A is due to its tachykinin receptor antagonist pharmacological profile. Peptides 31:1643-1648.
77. Jaggi M, Prasad S, Singh AT, Praveen R, Dutt S, et al. (2008) Anticancer activity of a peptide combination in gastrointestinal cancers targeting multiple neuropeptide receptors. Invest New Drugs 26:489-504.
78. Prasad S, Mathur A,Jaggi M, Singh AT, Mukherjee R(2007) Substance P analogs containing alphaalphadialkylated amino acids with potent anticancer activity. J PeptSci 13:544-548.
79. Palma C(2006) Tachykinins and their receptors in human malignancies. Curr Drug Targets 7:1043-1052.