J Physiol 2014 Dimaline Jphysiol.2014.272435

Novel Roles of Gastrin Rod Dimaline and Andrea Varro
Department of Cellular and molecular Physiology, Institute of Translational Medicine, Uni ersity of !i erpool, Cro"n #treet, !i erpool !$% &'(, U) *mail+r,dimaline-li ,ac,u.
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Abstract
The e0istence of the hormone gastrin in the distal stomach 1antrum2 has 3een .no"n for almost 114 years, and the physiological function of this amidated peptide in regulating gastric acid secretion ia the CC)/ receptor is no" "ell esta3lished, In this 3rief re ie" "e consider important additional roles of gastrin including regulation of genes encoding proteins such as plasminogen acti ator inhi3itors and matri0 metalloproteinases that ha e important actions on e0tracellular matri0 remodelling, These actions are, at least in part, effected 3y paracrine signalling path"ays and ma.e important contri3utions to maintaining functional integrity of the gastric epithelium, Recent studies also pro ide support for the idea that gastrin, in concert "ith other hormones, could potentially contri3ute a post5 prandial incretin effect, 6e also re ie" recent de elopments in the 3iology of other gastrin gene products, including the precursor progastrin, "hich causes proliferation of the colonic epithelium and in certain circumstances may induce cancer formation, 7lycine5e0tended 3iosynthetic processing intermediates also ha e proliferati e effects in colonic mucosa and in some oesophageal cancer cell lines, 6hether or not these additional gene products e0ert their effects through the CC)/ receptor or a separate entity is currently a matter of de3ate,
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Introduction. It is o er 144 years since *d.ins, inspired 3y the "or. of 'ayliss and #tarling, proposed the e0istence of gastrin as a humoral mediator of gastric acid secretion 1*d.ins, 1%482, 9o"e er, the status of gastrin remained contro ersial for many years, and although physiological proof of an acid5stimulating hormone from gastric antrum "as presented in 1%:; 17rossman et al., 1%:;2, it "as not until 1%$: that gastrin "as isolated and its structure determined 17regory < Tracy, 1%$:2, The su3se=uent a aila3ility to in estigators of pure gastrin allo"ed detailed =uantitati e studies on its primary physiological function, It also ga e rise to many reports of actions in addition to that of stimulating acid secretion 17regory, 1%>:2 and although these no el actions "ere often elicited 3y ery high
concentrations, some ? nota3ly stimulation of gastric mucosal gro"th ? are no" "ell esta3lished, More recently it has also 3ecome clear that the nomenclature @gastrinsA rather than @gastrinA is more appropriate, "ith the realiBation that the gastrin precursor, progastrin, as "ell as intermediate processing products such as the glycine5e0tended gastrins, ha e their o"n distincti e 3iological acti ities, particularly in the colon 1Doc.ray et al., /4412, This 3rief re ie" "ill address no el actions of 3oth the classical 1i,e, amidated2 gastrins as "ell as the non5classical forms, Co el actions of these peptides ha e 3een re ie"ed pre iously 1Doc.ray et al., /441D Doc.ray et al., /448D Eerrand < 6ang, /44$D Dimaline < Varro, /44>2, and "e "ill therefore focus "hene er possi3le on more recent de elopments, Classical gastrins. The classical or amidated gastrins e0ist, in humans, mainly as peptides of 1> or &: amino acid residues 171>, 7&:2, "hose car3o0yterminus is amidated, and they may 3e sulphated on their solitary tyrosine residue 1Eig12, The sulphated and unsulphated forms of arious chain length ha e 3roadly similar 3iological acti ities at the CC)/ 1gastrin2 receptor, although their circulating half5li es ary, In human stomach the CC)/ receptor is located primarily on enterochromaffin5li.e 1*C!2 cells and parietal cells, although e0pression has 3een reported in other cell types such as mucous nec. cells and stromal cells,
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Insight into the ne" 3iology of gastrin has come from studies on genetically modified mice that ha e deficient or e0aggerated gastrin e0pression, on patients "ith hypergastrinaemic conditions, and functional genomics approaches, Eor e0ample, DCA array53ased studies on cancer cell lines treated "ith gastrin 1Varro et al., /44/D EFeld3o et al., /41/D Misund et al., /41&2, or on animals or patients undergoing gastric acid inhi3ition 1and therefore "ith secondary hypergastrinaemiaD Corsett et al., /448D Corsett et al., /44;2 ha e unco ered a num3er of hitherto unrecogniBed targets of gastrin, Co el targets ha e also 3een identified using DCA microarray 1Gain < #amuelson, /44>2, or mRCA differential display 1)han et al., /44&D Pagliocca et al., /44;2 of gastric tissue from gastrin deficient mice, Gastric targets of gastrin. The most "ell studied target of gastrin as a gro"th factor is the *C! cell of the acid secreting 1corpus2 mucosa, "hich in response to circulating concentrations of gastrin in the physiological range, secretes histamine that in turn stimulates the parietal cell to secrete 9Cl 1Eig/2, If circulating concentrations of gastrin are ele ated, the *C! cells undergo hyperplasia and "ith prolonged profound hypergastrinaemia 1e,g, in chronic atrophic gastritis2, *C! cell tumours 1carcinoids2 may de elop, Although these generally remain 3enign, larger tumours can e entually @escapeA from regulation 3y gastrin and ac=uire the capacity to metastasiBe, Clinical management of *C! cell tumours has included conser ati e o3ser ation, the use of somatostatin analogues to suppress gastrin release, surgical remo al of the source of gastrin 1antrectomy2 or total gastrectomy, The therapeutic use of CC)/ receptor antagonists to reduce *C! cell tumours has in the past 3een hampered 3y their percei ed lac. of potency, specificity or oral 3ioa aila3ility, 9o"e er, t"o recent reports 1Eossmar. et al., /41/D Moore et al., /41&2 sho"ed that the potent, highly selecti e and orally acti e CC)/ receptor antagonist, netaBepide 1HE:>$2, "as effecti e in reducing *C! cell tumours, 'iomar.ers of hypergastrinaemia such as plasma chromogranin A, and corpus mRCAs encoding chromogranin A and histidine decar3o0ylase "ere also reduced, suggesting a promising ne" non5in asi e approach to managing such tumours, In addition to its "ell documented proliferati e effects, gastrin has 3een sho"n to stimulate cell migration, in asion, apoptosis and tu3ulogenesis 1Dimaline < Varro, /44>2, The rationale for these effects is emerging as pre iously unrecogniBed targets of gastrin continue
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to 3e identified and their regulation e0plored, Eor e0ample, gastrin is no" recogniBed to regulate e0pression of a num3er of molecules that e0ert important effects on e0tracellular matri0 remodelling, including plasminogen acti ator inhi3itors 1PAID Almeida5Vega et al., /44%D Corsett et al., /4112, matri0 metalloproteinases 1MMPD Varro et al., /44>D Hin et al., /4142 and tissue inhi3itors of metalloproteinases 1TIMPD 'odger et al., /44;2 1Eig /2, The fact that gastrin may upregulate e0pression of molecules "ith apparently opposing effects on matri0 remodelling such as MMPs and TIMPs indicates that the mechanisms in ol ed are li.ely to 3e comple0, in ol ing precise spatial and temporal organiBation and dependent, at least in part, on paracrine cascades 1see 3elo"2, #eemingly antagonistic effects of gastrin ha e also 3een reported in the conte0t of cell sur i al, "here3y it may for e0ample upregulate 3oth pro5apoptotic PAI5/ 1Almeida5Vega et al., /44%D IJ9ara et al., /41&2 and the pro5sur i al factor clusterin 1EFeld3o et al., /41/2, Paracrine cascades The primary physiological function of gastrin is no" considered to 3e effected 3y paracrine release from *C! cells of histamine, "hich then acts on acid5secreting parietal cells, and there is e idence to suggest that a num3er of its no el actions may also 3e indirect, Eor e0ample, PAI5/, "hich is found in cells that e0press the CC)/ receptor 1e,g, *C! cells2 and cells that do not 1e,g, mucous cells2 1Varro et al., /44:2 may 3e acti ated directly 3y gastrin ia the CC)/ receptor, or 3y secondarily released paracrine agents such as prostaglandin */ and I!5; 1Almeida5Vega et al., /44%2 1Eig /2, Moreo er, the direct and paracrine routes to upregulate e0pression of PAI5/ employ distinctly different transcriptional acti ators 1Almeida5Vega et al., /44%D IJ9ara et al., /41&2, 7astrin has also 3een sho"n to regulate e0pression of the protecti e gastric Trefoil factors 1TEE2 in mouse stomach and in human gastric cancer cell lines 1)han et al., /44&D Eranic et al., /448D Tu et al., /44>2, and in the case of TEE1, paracrine mechanisms "ere demonstrated 1)han et al., /44&2, Although gastrin does not normally directly stimulate acid secretion from parietal cells, these cells do e0press functional CC)/ receptors, 7astrin acti ation of parietal cell CC)/ receptors may lead to increased gene e0pression e,g, eBrin 1Pagliocca et al., /44;2, 9'*7E 1#inclair et al., /44:2, PAI51 1Corsett et al., /4112, and release of paracrine signalling molecules 1MiyaBa.i et al., 1%%%2,
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Gastrin and gastric cancer In addition to the proliferati e effects of gastrin, se eral other actions ha e dra"n attention to its potential in ol ement in the de elopment or progression of gastric cancers, These include effects on epithelial remodelling 1Dimaline < Varro, /44>2, on epithelial5 mesenchymal signalling or transition 1Varro et al., /44>D Hin et al., /4142, and the fact that gastrin shares many targets and signalling path"ays "ith the carcinogenic 3acterium Helicobacter pylori 1Dimaline < Varro, /44>2, Moreo er, e0pression of 3oth gastrin and the CC)/ receptor in human gastric adenocarcinomas has 3een reported 17oetBe et al,, /41&2, In one mouse transgenic model 1IC#57A#2, ele ated circulating gastrin concentrations "ere sho"n to act synergistically "ith Helicobacter infection in the de elopment of gastric carcinoma 16ang et al., /4442, 9o"e er, aside from *C! carcinoid tumours, it presently remains uncertain to "hat e0tent, if any, amidated gastrin may contri3ute to the de elopment of gastric cancers in humans 1'ur.itt et al., /44%2, Gastrin as an incretin. *arly studies on gastrin in the 1%$4s and 1%>4s identified it as a potential incretin 1Unger et al., 1%$>D Rehfeld < #tadil, 1%>&2, although high concentrations "ere re=uired to elicit insulin secretion or induce 3eta cell proliferation, Interest in gastrin as an incretin "as re.indled some"hat 3y the o3ser ation that it is transiently e0pressed in foetal rat pancreas during a time of K cell proliferation 1!arsson et al., 1%>$D 'rand < Euller, 1%;;2, 3ut transgenic o ere0pression of gastrin alone in mouse pancreas did not increase K cell mass, and co5e0pression of T7EL "as re=uired 16ang et al., 1%%&2, #imilarly, although gastrin 1or glucagon5li.e peptide51, 7!P512 infusion alone failed to impro e glycaemia in non5o3ese dia3etic mice, com3inatorial therapy restored normoglycaemia 1#uareB5PinBon et al., /44;2, More recently, it "as sho"n that the gastrin and 7!P51 dual agonist MP&4// impro ed glycaemic control in a dia3etic mouse model more successfully than pure 7!P51 agonists alone 1Eosgerau et al., /41&2, again raising the possi3ility that gastrin may after all contri3ute an incretin effect in com3ination "ith other hormones, 6hether the findings from mouse studies can 3e e0trapolated to patients "ith dia3etes mellitus and could e entually form a 3asis for therapy remains to 3e esta3lished,
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Although su3stantially supraphysiological circulating concentrations of gastrin alone are re=uired to demonstrate e0perimentally an incretin effect 1#adry < Druc.er, /41&2, such concentrations are no" fairly commonly encountered "ith the "idespread clinical use of proton pump inhi3itors 1PPI2 to 3loc. gastric acid secretion, Initial trials to determine "hether hypergastrinaemia secondary to PPI therapy might impro e 3eta cell function or glycaemic control ha e so far pro ided conflicting data 1#ingh et al., /41/D 9o e et al., /41&2 and more e0tensi e trials "ill 3e needed to determine if PPIs might offer a 3enefit,
Non-classical gastrins. 9istorically, the term @non classical gastrinsA has 3een used to descri3e the gastrin precursor, progastrin, and the incompletely processed, glycine 17ly25e0tended gastrins, These peptides are found in all cells that e0press the gastrin gene and process the products of translation to the amidated gastrins, nota3ly 7 cells of the gastric antrum and duodenum 1Eig12, In addition, they may also 3e found in cell lines and cancers such those of the colon, oesophagus, and lung that e0press the gastrin gene 3ut are una3le to process translation products to the classical amidated peptides, e0cept for negligi3le amounts 1Doc.ray et al., /441D )oh et al., /44:D Doc.ray et al., /448D Du3ey.o s.iy et al., /44;D Huan et al., /44;2 , 9o"e er, e en colon cancers are ery aria3le 3oth in their progastrin e0pression profiles and in the plasma progastrin concentrations that result,
Progastrin and Gly-gastrins 9uman preprogastrin contains 141 amino acid residues 114: in rat2, *ndopeptidase clea age at pairs of 3asic residues 1follo"ed 3y car3o0ypeptidase trimming of C5terminal Arg or !ys residues2 generates the e0treme C terminal flan.ing peptide 1CEP2 together "ith 7&:57ly or 71>57ly, as "ell as 7&:5CEP or 71>5CEP 1Doc.ray et al., /441D Doc.ray et al., /4482 1Eig12, All of these peptides, together "ith intact progastrin, may 3e found in cells lac.ing the regulated secretory path"ay, It "as esta3lished pre iously, that proteolytic clea age at Arg5 Arg in positions %: and %8, is partially regulated 3y phosphorylation of #er5%$ 1'ishop et al.,
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1%%;2, Recently it "as proposed that in addition, ferric ions can inhi3it proteolytic processing of progastrin 3y inhi3iting prohormone con ertase 1 1'ramante et al., /4112,
Biological actions of progastrin. The colonic epithelium has 3een relati ely "ell studied as a target for progastrin, In transgenic mice that o er5e0press the precursor there is increased colonic proliferation and, in the presence of p8& mutations, cancer formation 1Ramanathan et al., /41/2, In addition, progastrin and CEP ha e 3een reported to 3e anti5apoptotic 1Umar et al., /44;D Patel et al., /4142, These actions can 3e the result of crosstal. 3et"een the CE5', K5catenin through 6nt ligands and Cotch signalling path"ays 1Panne=uin et al., /44%D Umar et al., /44%2, In this conte0t it is "orth noting, that in contrast, CEP has also 3een found to stimulate gastric apoptosis 1Marshall et al., /41&2, Moreo er, progastrin e0pression 3y CCD1&&N human primary colorectal cancer cells "as ital for tumour gro"th 1Eerrand et al., /44%2 and o ere0pression of progastrin induced the metastatic potential of em3ryonic epithelial cells 1#ar.ar et al., /41/a2, Interestingly, progastrin also induced colonic epithelial proliferation through a paracrine mechanism 3y stimulating secretion of I7E5/ from colonic myofi3ro3lasts 1Duc."orth et al., /41&2D similar mechanisms e0ist in the gastric corpus and may 3e acti ated 3y amidated gastrin 1Varro et al., /44>2, Progastrin receptor. #e eral putati e receptors for progastrin ha e 3een proposed o er the years 1Doc.ray et al., /41/2 3ut despite considera3le efforts, there is at present no "ell characterised receptor for progastrin 3ased on rigorous identification and gene cloning, In mice that o ere0press progastrin 1h7A#2, deletion of the receptor for amidated gastrin, CC)/R, inhi3ited progastrin5dependent colonic crypt fission, and progastrin increased colonic progenitor cell num3ers ia the CC)/R, suggesti e of a common receptor for all progastrin deri ed peptides 1Gin et al., /44%D Gin et al., /41&2, 9o"e er, most recently, a cell surface associated anne0in, C#5AC(A/, "as proposed as a non5con entional receptor that acts through 3inding and internaliBation of progastrin ia chlathrin coated pits 1#ar.ar et al., /41/32, Biological actions of Gly gastrins.
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Iriginally, the gro"th stimulating effect of 71>57ly "as descri3ed in the pancreatic cell line, AR:/G 1#e a et al., 1%%:2, #ince then, the proliferating effects of 7ly gastrins ha e 3een descri3ed on the colonic mucosa in mice o ere0pressing 7ly gastrins 1MTI57gly mice, Eerrand et al., /4142, Moreo er, the 3iological acti ity of the 7ly5e0tended gastrins, as for progastrin, ha e 3een reported to 3e dependent on ferric ions since the chelating agent desferrio0amine significantly reduced colonic proliferation 1Eerrand et al., /4142, This effect might 3e lin.ed to increased angiogenesis since 71>57ly upregulated V*7E e0pression ia the PI&) path"ay 1'ertrand et al., /4142 and induced tu3ule formation in ascular
endothelial cells 1Clar.e et al., /44$2, It also stimulated proliferation in oesophageal cancer cell lines 1I*1% and I*&&2 ia CI(5/ e0pression 1 Igun"o3i < 'eales, /44;2, In addition, 75 7ly1> inhi3ited apoptosis in 3oth 'arrettJs oesophageal cells 1Oh*RT2 and oesophageal adenocarcinoma 1I*&&2 deri ed cell lines ia GA)/ and #TAT& path"ays independently of CI(5/ 1'eales < Igun"o3i, /44%2, Amidated gastrin acting ia the CC)/ receptor has pre iously 3een reported to induce proliferation in 'arrettPs metaplasia 19aigh et al,, /44&2, 3ut "hether there is any synergy "ith 757ly has not 3een in estigated, Most recently it "as postulated that 757ly acts synergistically "ith amidated gastrin to stimulate somatostatin release from canine D5cells suggesting a role for 757ly in regulating D cell function 1'eales, /41&2, Gly-gastrin receptor. As in the case of progastrin, a specific receptor for 7ly5e0tended gastrins has not 3een cloned, #e eral groups ha e argued for 1Doc.ray et al., /41/2 and against 1Igun"o3i < 'eales, /44;D Doc.ray et al., /41/2 the CC)/ receptor 3eing the receptor for 7ly5e0tended gastrins, Recently it "as suggested that the E15ATPase at the cell surface of colonic epithelial cells may constitute a receptor for 7ly5gastrin 1)o"als.i5Chau el et al,, /41/2, 3ut at the time of "riting a final erdict on this =uestion remains elusi e,
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Conclusion #tudies on the "ider 3iology of gastrin 3ecame feasi3le "ith the a aila3ility of the pure peptide in the 1%$4s, Ce" functions ascri3ed to gastrin at the time included stimulation of gastric mucosal gro"th and an incretin effect, #e eral decades later, the application of functional genomics approaches and the de elopment of mouse models o er5e0pressing or deficient in gastrin allo"ed more detailed studies of its ne" 3iology, Many pre iously unrecogniBed gene targets of gastrin "ere identified, and the importance of the amidated peptides for maintaining functional integrity of the gastric epithelium is 3ecoming clear, *lucidation in the 1%;4s of the cDCA se=uence encoding gastrin underpinned su3se=uent "or. to identify mechanisms of post translational processing and identification of additional peptides originating from the gastrin precursor, These non5classical gastrins, in particular the glycine5e0tended gastrins and progastrin, ha e distinct 3iological actions of their o"n, nota3ly proliferati e effects in colonic and possi3ly oesophageal epithelia, and ha e 3een implicated in cancer de elopment, The actions of amidated gastrins are effected through the CC)/ receptorD "hether this is the case for all acti e products of the gastrin gene is currently unresol ed,
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)igure *egends
/4
)igure #. A. #chematic representation of preprogastrin, The initial clea age products of 3iosynthetic processing are sho"n, CEP, C5terminal flan.ing peptide, 71>57ly, glycine5e0tended 71>, 7&:57ly, glycine5e0tended 7&:, B. #chematic representation of preprogastrin processing sho"ing the maFor 3iologically acti e products secreted ia the regulated or constituti e routes of e0ocytosis,
)igure 2. Targets of classical gastrins in the gastric epithelium, *0amples of the most "ell studied direct and indirect actions of amidated gastrins in the gastric epithelium, 6here good e idence e0ists for the identity of cell types and paracrine mediators these are indicated, 7astrin is secreted from the 75cell of the gastric antrum and acts through the CC)/ receptor,
/1
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J Physiol 2014 Dimaline Jphysiol.2014.272435

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Novel Roles of Gastrin Rod Dimaline and Andrea Varro

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