ReviewCholecystokinin and gastrin receptors targeting in gastrointestinal cancer
Introduction
Gastrointestinal/gut hormones are chemical messengers that exist in multiple molecular forms and bind to multiple cell-surface receptors which are coupled to one of the several possible signal transduction systems. Thus activation of these receptors by their cognitive ligand leads diverse biologic responses and regulates a broad range of physiologic functions. Although these are primarily expressed within the tissues of gut, these peptide hormones are widely distributed throughout the body and act on multiple target tissues [1]. These also regulate gastrointestinal homeostasis by affecting cell proliferation, differentiation, apoptosis and gene expression. The aberrant control of these biological processes is thought to play an important role in the establishment of gastrointestinal neoplasia [2].
Since gut peptides receptors are (over)expressed on cancer cells, these represent the basis for receptor-targeted tumour imaging in nuclear medicine with radiolabeled peptides as well as growth factor and growth factor receptor alterations may provide new potential targets for the cancer therapy [3], [4]. For e.g., cholectstokinin type-B receptor/gastrin receptor (CCK2R/GR) ligands allow for a sensitive and reliable staging of patients with metastatic medullary thyroid cancer (MTC) and thus adding in diagnosis and therapy of these tumours expressing CCK2R/GR [5]. As a consequence several radiolabeled cholecystokinin (CCK) or gastrin (Gs) analogues/derivatives have been formulated and use of these analogues for diagnostic imaging and possible therapy of cancers that overexpress these receptors in patients using in vivo CCK receptor scintigraphy are being explored proving the feasibility of targeting CCK receptors in human tumours [6], [7], [8], [9]. Thus knowing the exact contribution and type of these receptor in carcinogenesis will allow the development of noncytotoxic modalities therapy with hormones, antihormones or hormone ablation [10], [11].
Section snippets
CCK, Gs hormone and its receptor
CCK and Gs both belong to one classical family of gastrointestinal peptides that regulate a variety of functions in the gastrointestinal tract and central nervous system. Both the peptides share a common C-terminal pentapeptide sequence (Gly-Trp-Met-Asp-PheNH2) (Fig. 1) but have different biological roles. Gs is produced by G cell; endocrine cells located in the gastric antrum. It is the major stimulant of gastric acid secretion and has a growth stimulatory effect on the stomach, exocrine
CCK Gs, its receptor and cancer
Gs or CCK showed growth stimulatory effect on cancer cell lines originating from the biliary tract [19]. CCK enhanced carcinogens mediated induction of acinar tumours in the pancreas. Gs is a central growth factor encouraging malignancies of the gastrointestinal tract, MTC, small cell lung cancer as well as tumours of the central and peripheral nervous systems [20], [21], [22]. It stimulates the survival or proliferation of normal cells along with gastric, colorectal or pancreatic cancer cells
CCK, Gs and its receptor in gallbladder cancer (GBC)
CCK is the chief humoural modulator of gallbladder that interacts with CCK1R and elicits the contraction of gallbladder by activating post-membrane signalling passage in smooth muscle [64]. In humans, the release of CCK is correlated intimately with contraction of the gallbladder [65] and CCK1R were demonstrated on smooth muscle cells of gallbladder [66]. Abnormality in the CCK-gallbladder relationship in comparison with normal subjects [67], [68] and reduced or delayed postprandial gallbladder
CCK, Gs and its receptor in stomach carcinoma (Sc)
Knockouts studies for Gs gene or CCK2R/GR gene has confirmed that Gs is well known growth factor for enterochromaffin-like cells (ECL) in the stomach determining the fate of ECL cells [36], [81], [82], [83]. Long-standing condition of hypergastrenemia were associated with ECL cell hyperplasia and ultimately to malignant carcinoids transformation [84], [85], [86], [87]. It is also regarded as an important biomarker for gastric inflammation [88]. Gs and CCK2R/GR was also found to play an
CCK, Gs and its receptor in pancreatic carcinoma
CCK and Gs was found to increase pancreatic DNA, RNA and protein content [13], [14], [106], [107], [108] resulting in increased pancreatic size and weight [109]. Experimental hypercholecystokininemia stimulate pancreatic growth and induced pancreatic hypertrophy, hyperplasia, and dysplasia thus enhancing normal, preneoplastic and malignant pancreatic growth [110] and this effect was mediated by CCK1R [111].
CCK is the most potent peptide influencing growth of human pancreatic cancers [112], [113]
CCK, Gs and its receptor in esophageal carcinoma
Endogenous hypergastrenemia was found to promote chemically induced esophageal carcinogenesis [144]. CCK2R/GR has been also identified in both lower and mid esophageal mucosa [145] and in human esophageal adenocarcinoma (OAC). Gs binding to these receptors increases proliferation of cells in a dose-dependent way and this effect are abolished by CCK2R/GR specific antagonist [146]. However, there was no effect on those lacking CCK2R/GR. Thus CCK2R/GR seems to be involved in the development of OAC
CCK, Gs and its receptor in colon carcinoma
The role of CCK, Gs and their receptors in the pathogenesis of colon cancer has been discussed for many years but it still remains a disputable issue. Both in vivo and in vitro studies have asserted Gs as a growth stimulus for normal colonic mucosa as well as colon carcinoma in a receptor-mediated fashion. The first evidence for autocrine growth stimulatory role of Gs/CCK-like peptide in cultured colon tumour cells was provided by Hoosein et al., (1990) [58], though some studies have reported
Peptide-receptor targeting in cancer
In law, cell surface receptors overexpressed on tumour cells are of raising clinical importance, as it furnishes targets for anticancer drugs linked to receptor ligands [177]. Moreover, during the past decade, the specific receptor binding property of the ligand/peptide have been tapped by labelling the ligand with a radionuclide and using these radiolabeled receptor-binding ligand as a vehicle to guide the radioactivity to the tissues expressing a particular receptor, in vivo. These
Targeting Cck1r and Cck2r in gastrointestinal cancer
Cholecystokinin receptor is a novel and promising candidate in the field of receptor-targeted tumour imaging and a means of delivering CCK-receptor-mediated cytotoxic agents for anticancer drugs therapy [6]. Over the past few years the increased concern: (1) to potential therapeutic denotations of the tumour growth effect of gastrin and CCK, (2) possibility of using the CCK2R and CCK1R over/expression for tumour imaging or therapy has pipelined several body for the search of CCK/Gs receptor
Clinical trials
Compounds directed at the CCK2R/GR have shown promising results in clinical trials in humans. Initial randomized, controlled study using proglumide, the GR/CCK2R antagonist, as therapy in patients with gastric carcinoma failed to show an overall effect on survival. Since porglumide has relatively low affinity with the CCK2R/GR and also has partial agonist activity, further clinical trials of more specific and potent GR antagonists is required which may have a greater effect on survival to
Conclusion
CCK1R expression was found in bulk of GBC, esophageal and pancreatic cancer while CCK2R/GR was found in majority of SC, pancreatic and colon carcinoma. These affirms that Gs and CCK wield a trophic effect on normal gut mucosa and can also act in autocrine, endocrine or paracrine mode to regulate growth of some cancers of the GI tract and pancreas through cell specific receptor [207]. The availability of an adequately specific, sensitive and high affinity radioligand fulfils the successful
Funding
This study was supported by the grant from Indian Council of Medical Research (ICMR Project Ref No. 3/2/2/187/2009/NCD-III).
Conflict of interest statement
The authors declare that there are no conflict of interests.
Authorship statement
Guarantor of the integrity of the study: Hari S. Shukla.
Study concepts: Hari S. Shukla.
Study design: Rajani Rai.
Definition of intellectual content: Hari S. Shukla, Mallika Tewari, Rajani Rai.
Literature research: Rajani Rai, Vishal Chandra, Mallika Tewari, Mohan Kumar.
Data acquisition: Rajani Rai, Vishal Chandra.
Data analysis: Rajani Rai, Mallika Tewari.
Manuscript preparation: Mallika Tewari, Rajani Rai, Vishal Chandra.
Manuscript editing: Rajani Rai, Mallika Tewari, Hari S. Shukla.
Manuscript
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2019, PeptidesCitation Excerpt :Impaired release of CCK or mutations of the CCK receptors may contribute to pancreatic pathologies (e.g. acute/chronic pancreatitis), impairment of gastrointestinal motility (e.g. irritable bowel syndrome) and hypergastrinemia-related disorders (e.g. hyperplasia, carcinoid) [8]. CCK promotes development of gastrointestinal malignancies, acting via CCK1 and CCK2 receptors expressed by the tumor cells and via an autocrine/paracrine loop [4,7–10]. CCK receptors belong to the family with seven transmembrane segments.
Immunogenicity and safety of a novel tetanus toxoid-conjugated anti-gastrin vaccine in BALB/c mice
2018, VaccineCitation Excerpt :The signal transduction pathways posited for the promotion of tumours by gastrin-17 and progastrin are both numerous and complex [14–16], but targeting them has become an investigative strategy for the treatment of related GI tumours by anti-gastrin therapies, which specifically include endocrine-secretion inhibitors, receptor antagonism, and anti-gastrin antibody methods. Endocrine-secretion inhibition (e.g., by somatostatin [17] and antisense oligonucleotides [18]) and receptor antagonism (e.g., by cholecystokinin receptor antagonists [19–21]) are methods that have often had low anti-gastrin specificity, weak anti-tumour effects, and necessarily large dosages, with a significant number of toxic side effects. Anti-gastrin antibody methods include both passive and active immunizations.
Gastrin and Gastric Cancer
2017, Cellular and Molecular Gastroenterology and HepatologyCitation Excerpt :Because gastrin has been shown to stimulate growth of gastric cancer and other gastrointestinal malignancies, researchers have been studying means to block the ligand:receptor interaction in an attempt to slow or arrest tumor growth. Numerous investigations have been conducted in cell culture and animal models of gastric cancer using small-molecule CCK-B receptor antagonists,91,92 and their use in human trials has been reviewed.76,93,94 Clinical trials in human subjects with agents directed to the gastrin:CCK-B–receptor pathway are rare and most studies have investigated agents in other gastrointestinal cancers rather than in gastric cancer, such as gastrazole in pancreatic cancer95 or netazepide96 in gastric neuroendocrine tumors.
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