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Review article
Gastrin: from pathophysiology to cancer prevention and treatment Gemma Maddaloa, Ylenia Spolveratoa, Massimo Ruggeb and Fabio Farinatia Gastrin has been identified as the principal effector of gastric secretion, but several studies have demonstrated its role as a biomarker of cancer risk and as a growth factor for colorectal, stomach, liver, and pancreatic cancer. Hypergastrinemia characterizes autoimmune gastritis, with body and fundic gland atrophy and increased risk for both gastric adenocarcinoma and neuroendocrine tumors. Gastric type I carcinoids develop in the context of autoimmune gastritis because of the stimulus exerted by gastrin on enterochromaffin-like cells and remain gastrinsensitive for long durations because the removal of hypergastrinemia leads to tumor regression. The treatment of gastric carcinoid is still open to debate, but when the disease frequently relapses, or is multicentric or infiltrating, surgery is advocated or, in the alternative, a costly and long-lasting treatment with long-acting somatostatin analogues is prescribed. A technology allowing the preparation of an immunogen eliciting an immune system response with generation of antibodies against G17 has been developed. This vaccine has been tested in patients with colorectal, pancreatic or advanced gastric cancer.
The vaccine has also been used in the treatment of gastric type I carcinoids, and the administration of G17DT in patients harboring these lesions leads to carcinoid regression. Antigastrin vaccination in the treatment of gastrointestinal cancer obviously needs validation, but this immunotherapy may well represent a simple, inexpensive, and active ‘adjuvant’ treatment. European Journal of c 2014 Wolters Kluwer Cancer Prevention 23:258–263 Health | Lippincott Williams & Wilkins.
Gastrin and gastric physiology
predominant in the gastric antrum (Copps et al., 2009). Gastrin release is stimulated by vagal impulses, by intramural neural reflexes, and by the presence of food in the gastric lumen (Larsson, 2000). The secreted gastrin binds to CCK-2 receptors on ECL cells, inducing the production of histamine; this in turn binds to H2 receptors on parietal cells, stimulating acid secretion (Waldum et al., 2009).
The human stomach is divided into two functionally and anatomically different zones, the body and fundic area, with oxyntic mucosa, and the antral area, and contains four types of terminally differentiated cells: parietal (oxyntic) cells, chief (zymogenic) cells, mucous foveolar cells, and hormone-secreting enteroendocrine cells (Mills and Shivdasani, 2011). Parietal cells, located in the body and fundic area, are involved in acid secretion, aimed at calcium, iron, and protein digestion and at limitation of bacterial overgrowth (Schubert and Shamburek, 1990), and are controlled by neural and hormonal effectors (Schubert, 2010). Histamine, produced by enterochromaffin-like cells (ECL cells), directly stimulates parietal cells by binding to the parietal cell H2 receptor, triggering hydrochloric acid secretion. Acetylcholine modulates parietal cell function directly and indirectly by binding to their receptors and inhibiting serotonine secretion. Gastrin is produced in antral and duodenal Brunner’s glands by neuroendocrine G cells as a precursor, preprograstrin, that, after post-translational modification, is cleaved to form two principal peptides (G34-Gly and G17-Gly). From the former G34 and, in part, G17 derives, both involved in the control of acid secretion. From the latter, only G17 is obtained. G17, more active, is c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-8278
European Journal of Cancer Prevention 2014, 23:258–263 Keywords: autoimmune gastritis, G17DT, gastric atrophy, gastric carcinoids, hypochlorhydria, neuroendocrine tumors, vaccine a Department of Surgery, Oncology and Gastroenterology, Padua University Hospital and bDepartment of Medicine, Padua University, Padova, Italy
Correspondence to Fabio Farinati, MD, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, 35128 Padova, Italy Tel: + 39 049 821 305; fax: + 39 049 876 0820; e-mail: [email protected] Received 27 May 2013 Accepted 26 November 2013
Beyond gastric acid secretion, gastrin stimulates the migration of gastric epithelial cells, the release of fibroblast growth factor and the activation of its receptor and of the protein kinase pathway (Czinn and Blanchard, 2011). Hypergastrinemia is a physiologic response to achlorhydria (Schubert, 2011) but may also indicate the presence of gastrin-secreting tumors such as gastrinoma, Zollinger–Ellison syndrome, and a physiological response to suppressed gastric acid secretion as occurs in chronic autoimmune atrophic gastritis, a gastric precancerous condition (Burkitt et al., 2009). If hypergastrinemia is therefore to be considered as a marker of risk for gastric cancer, gastric carcinoid, or gastrinoma, hypogastrinemia has also be suggested as a biomarker of an increased risk of gastric cancer (Farinati et al., 1991; Kikuchi et al., 2011) because of reduced release of the hormone in cases of severe atrophy of the DOI: 10.1097/CEJ.0000000000000008
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Gastrin: from pathophysiology to cancer Maddalo et al.
gastric antrum, associated with an increased risk of antral adenocarcinoma.
Atrophic gastritis and cancer risk Atrophy, with loss of the appropriate glandular structure and development of intestinal metaplasia, is a byproduct of chronic inflammation (Rugge et al., 2002). High-grade atrophy and intestinal metaplasia, as assessed by a recently introduced specific scoring system, the OLGA system (Operative Link for Gastritis Assessment), are linked to an increased risk of cancer, therefore being useful as tumor markers (Rugge et al., 2007). Two different subtypes of gastric atrophy with different pathophysiology can be identified in the stomach: the socalled type A, corpus-predominant, autoimmune chronic atrophic gastritis and the Helicobacter pylori-related chronic atrophic gastritis, involving first the antrum and then spreading to the body area (antrum predominantpangastritis) (Dai et al., 2011). Antibiotic-mediated H. pylori eradication is linked to a reduced risk of developing gastric precancerous conditions and cancer in the latter, whereas no specific treatment blocking the progression of autoimmune gastritis (AIG), characterized by hypergastrinemia, is available. The prevalence of the latter disease is unknown, but AIG is more prevalent in women (Toh et al., 2012) and is associated with other autoimmune diseases, in particular with Hashimoto thyroiditis (Betterle and Zanchetta, 2003). Antiparietal cell antibodies in (90% of the patients) and, in a smaller proportion of patients (30–50% of the cases), anti-intrinsic factor antibodies are characteristic of AIG (De Block et al., 2008). A role for H. pylori infection as a trigger in the development of AIG has been advocated by many authors (Veijola et al., 2010) and AIG is characterized by iron and vitamin B12 malabsorption associated, in the long run and when not properly treated, with pernicious anemia (Biermer’s disease) (Andres and Serraj, 2012). The long-lasting and progressive hypergastrinemia induces hyperproliferation of ECL cells, the most represented gastric neuroendocrine cells, leading to ECL-cell hyperplasia that eventually evolves with the development,
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probably in genetically predisposed individuals, of a neuroendocrine tumor, the so-called gastric type I carcinoid, a tumor with uncertain biological behavior (Vannella et al., 2012).
Carcinoid Carcinoids are neuroendocrine tumors derived from enterochromaffin cells, presenting a benign biological behavior, but microscopically mimicking a malignant carcinoma (Pinchot et al., 2008) and producing 5hydroxytryptamine, a peptide responsible, when released in large amounts, for the clinical syndrome called carcinoid syndrome, which is very rarely present in gastric carcinoids (Van der Lely and de Herder, 2005). Carcinoid tumors, traditionally classified on the basis of their localization (foregut, midgut, and hindgut), are now universally classified on the basis of the WHO classification, shown in Table 1 (Rindi et al., 2010). Once considered as rare tumors, their increasing incidence and the underestimation of their actual prevalence makes the definition of ‘rare’ inadequate nowadays. Gastric carcinoid represent about 9% of all gastrointestinal tract carcinoids and 2% of endoscopically resected polyps (Modlin et al., 2003; 2004). Rindi et al. (1993), defined three different subtypes of gastric carcinoids: (1) Type I is associated with AIG, where its incidence is between 5 and 10%; it develops in the body area and is very rarely characterized by malignant behavior and metastasis. The 5-year survival rate (> 90%) is not different from that of the general population. (2) Type II, characterized by an intermediate malignant potential, is associated with gastrinoma and Zollinger–Ellison syndrome and is frequently associated with MEN1, multiple endocrine neoplasia syndrome type 1. These carcinoids, usually localized in the antrum, present a risk of malignant progression definitely higher than that of type I carcinoids. (3) Type III carcinoids are characterized by definite malignant behavior. Their prevalence is higher in men, they are not associated with hypergastrinemia,
Table 1 Clinical and histologic features of the three subtypes of gastric carcinoids: the most frequent and less aggressive are the type I neuroendocrine tumors, associated with autoimmune gastritis and characterized by a prognosis not significantly different from that of unaffected controls
Prevalence (%) Endoscopic appearance Association Grading Ki67 index (%) Serum gastrin Secondaries (%) Mortality
Type I
Type II
Type III
70–80 Small (5 mm–2 cm), multiple polypoid lesions Autoimmune gastritis NET G1 20 Normal > 50 25–30%
MEN1, multiple endocrine neoplasia type I; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumors; ZES, Zolllinger–Ellison syndrome.
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are frequently diagnosed in metastatic phase, and the 5-year survival rate does not exceed 75–80% (Burkitt and Pritchard, 2006). Endoscopically, gastric type I carcinoids appear as relatively small (5–10 mm in general) sessile, polypoid, hypervascularized lesions. CgA, proposed as a marker for gastric carcinoid, shows increased levels in 80–90% of patients with type I carcinoid (Wiedenmann et al., 1986). Unfortunately, CgA is not a specific marker and increased levels can be found because of long-term proton pump inhibitor treatment or hypergastrinemia of different origin. In addition, other tumors of neuroendocrine origin (thyroid, pancreas, or lung) can also show elevated CgA levels (Nobels et al., 1997). At the time of diagnosis, many carcinoids (either of Type I or II) are still gastrin-sensitive and the removal of hypergastrinemia can lead to tumor regression, as confirmed by the administration of long-acting somatostatin analogues (Kvols et al., 1986). In the past, the only therapy considered was surgery, targeted to either the excision of the carcinoid or to the removal of the source of gastrin secretion, by antrectomy or, under the worst hypothesis, to total gastrectomy. There is now an increasing tendency toward endoscopic treatment (Kadikoylu et al., 2006), whenever feasible, of gastric type I carcinoids. Small tumors (< 1 cm) can be endoscopically resected. Recent studies have reported the successful removal of larger lesions, even with deep infiltration, by endoscopic mucosal resection or endoscopic submucosal dissection, with no evidence of recurrence (Ahlman, 1999). Local excision may then be advocated in case of rapid, multifocal recurrence. When endoscopic ablation is not feasible and surgery is contraindicated or refused by the patient, gastric carcinoid can be treated medically with long-acting somatostatin analogues (Ferraro et al., 1996; Oberg et al., 2004). This treatment is well tolerated but, among the side effects, gallbladder stones, constipation, or diarrhea can be observed. The treatment is life-long and costly and can hardly be indicated in young patients, the indication being restricted to elderly patients with surgical contraindications and multifocal/relapsing disease, not eligible for endoscopic treatment.
Gastrin in gastric cancer and its therapeutic potential Several lines of evidence suggest a role for gastrin in gastric carcinogenesis. First, the expression of the gastrinCCK-2 receptor increases with the progression of gastric atrophy, a precancerous condition (Henwood et al., 2001). Second, immunohistochemical studies on gastric cancer resection specimens showed that over 50% of the tumors expressed the CCK-2 receptor and had detectable gastrin levels within the tumor (Hur et al., 2006), secreted by
gastric carcinoma cells, acting as a growth factor in an autocrine or a paracrine manner. In addition, gastrin upregulates mucosal cell proliferation, as shown in several gastric cancer cell lines, with increased levels of heparin binding epidermal growth factor (HB-EGF) (Dickson et al., 2006), as confirmed in the INS-GAS hypergastrinemic mice, in which overexpression of HB-EGF was also shown in premalignant lesions (Wang et al., 2000). In general, gastrin increases the susceptibility of gastric epithelial cells ‘in vivo’ to apoptosis by signaling through the CCK-2 receptor, as has been reported in animal models (Kidd et al., 2000) as well as in hypergastrinemic patients with H. pylori infection, but the opposite condition has been described in transformed cells. For instance, gastrin inhibits apoptosis in AGS-GR gastric cancer cells by acting on the antiapoptotic protein mcl-1, whose expression is also increased in type I gastric neuroendocrine tumors (Pritchard et al., 2008). Finally, gastrin increases the level of expression of matrix metalloproteinase 9, involved in tissue remodeling in patients with gastric cancer and carcinoids (Burkitt and Pritchard, 2006), and a role of tissue proteases in gastric cancer and gastric precancerous changes has also been confirmed by our previous studies (Plebani et al., 1995). Consequently, the hypothesis was proposed that the inhibition of gastrin could prevent tumor growth or even cancer development (Watson et al., 1999; Gilliam et al., 2004; Ajani et al., 2006) and one of the approaches attempted was to try to induce an immune response capable of neutralizing the effects of gastrin.
G17–diphtheria toxoid A technology was developed that allowed the preparation of immunogens, eliciting an immune system response with generation of antibodies binding specific portions of the administered immunogen. These antibodies crossreact with targeted ‘self ’ molecules, such as hormones. Diseases resulting from hormone hyperproduction have not been traditionally viewed as eligible for a treatment on the basis of a stimulation of the body’s immune system response but such an approach has been shown to produce, as we will see, clinically significant results. One of the examples of such targeted stimulations was indeed the development of the gastrin-17–diphtheria toxoid immunogen (G17DT). This includes a synthetic peptide similar to a portion of G17, to obtain an antibodymediated neutralization, and a ‘carrier’, the diphtheria toxoid, conjugated with the synthetic peptide, not recognized as ‘self ’ by the patient’s immune system. The diphtheria toxoid makes G17 bind to and become internalized by circulating B-cells and the epitopes, once internalized and presented on B-cells and macrophages,
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are bound by T-cells, with consequent T-cell proliferation and activation of signaling to B-cells. These cells in turn again bind to the G17-derived peptide with mass production of the desired antibodies. Early studies with G17DT, carried out in SCID mice injected with a human gastric cancer cell line, showed a prolongation of mouse survival similar to that achieved by treating the animals with 5-fluorouracile and leucovorin, the standard protocol in several gastrointestinal cancers in humans (Watson et al., 1999). In the only phase II trial carried out in patients with advanced gastric cancer administered G17DT immunogen at different doses, 60% of the G17DT-treated patients successfully developed antigastrin-17 antibodies (Gilliam et al., 2004) and patients treated with higher G17DT doses showed a more pronounced antibody response. Data on patient survival following G17DT administration were lacking and therefore an open-label, multinational, phase II study in 96 patients with advanced gastric or gastroesophageal cancer was planned to evaluate the response rate and survival of patients treated with G17DT, cisplatin, and 5fluorouracil (Ajani et al., 2006). G17DT was intramuscularly injected at a higher dose: time to progression and overall survival were significantly longer in responders than in nonresponders and the study was a sound demonstration of the role of gastrin in modulating cancer progression and of the potential for gastric cancer treatment with G17DT. Additional studies have also been published on the effects of G17DT in other types of cancer. Gastrin neutralization reduced the growth of a rat colon cancer line that expresses cholecystokininB/gastrin receptors and secretes glycine-extended gastrin-17 (G17), with a significant reduction in the cross-sectional tumor area and tumor weight, and a higher degree of tumor necrosis. Later, a phase I/II clinical trial of G17DT in patients with colorectal cancer (Smith et al., 2000), assessing the safety and efficacy of stimulating the production of antigastrin antibodies, was published. The hypotheses supporting the use of G17DT in colorectal cancer were that colon cancer may indeed produce gastrin precursors playing a paracrine or an autocrine role, and that gastrin peptides may play an endocrine role in promoting colorectal neoplasia (Hoosein et al., 1988; Watson et al., 1989; Ciccotosto et al., 1995; Smith et al., 1996; 1998; Aly et al., 2004). No oncological responses were observed, and only two patients with stable disease were registered. The limited role of circulating gastrin peptides in colorectal cancer was confirmed recently by the demonstration of a low risk of colorectal cancer (Lahner et al., 2012) in hypergastrinemia and by the negative association between Zollinger–Ellison syndrome and colon cancer (Orbuch et al., 1996), even though an autocrine/paracrine role of locally released nonamidated gastrin precursors
(Seva et al., 1994; Ciccotosto et al., 1995) in colorectal carcinogenesis cannot be excluded. Substantial evidence supports the role of gastrin and of its receptor (CCK2R) also in pancreatic cancer. Both are upregulated in human pancreatic adenocarcinoma as well as in preneoplastic lesions (Caplin et al., 2000; Goetze et al., 2000); the stimulation of CCK2R activates several kinases (Todisco et al., 1997; Daulhac et al., 1999a), the JAK2/STAT3 pathway (Kowalski-Chauvel et al., 1996; Ferrand et al., 2005), the Src-related tyrosine kinases, and the p125FAK, which have been shown to play a crucial role in the effects of gastrin (Daulhac et al., 1999b). Recently, French researchers, using a ‘cancer genes’ array, were able to identify aV integrin as a new gastrin target gene in human pancreatic cancer cells (Cayrol et al., 2011). On the bases of this evidence, a prospective, randomized, placebo-controlled randomized multicenter study has been carried out in patients with advanced pancreatic cancer unwilling to receive or unsuitable for standard chemotherapy. The study started in 2001 but its publication was delayed by the bankruptcy of Aphton, which produced G17DT (Gilliam et al., 2012). In essence, administration of G17DT resulted in a borderline significant increase in survival, but the patients who developed an antiG17DT response (64%) survived significantly longer than both the nonresponders and the placebo-treated patients, with a two to three times increase in median survival.
G17DT in gastric neuroendocrine tumors type I Type I gastric carcinoid, now identified as ‘well differentiated gastric neuroendocrine tumor’, is strictly correlated with gastrin biologic activity (Rindi et al., 2010). In the recently published algorithms for carcinoid treatment (Delle Fave et al., 2005), in contrast with the previous scenario, dominated by surgery, endoscopy plays the major role. However, as repeated endoscopy or polypectomy is an invasive and costly approach, a less invasive management is eagerly awaited. In the search for a noninvasive, inexpensive treatment of gastric type I carcinoids, we aimed to investigate the effects of G17DT administration in patients harboring these lesions (Tieppo et al., 2011). The G17DT vaccine pilot study in patients with multifocal, recurrent carcinoid, not amenable to endoscopic removal, was formally approved by the Ethical Committee of Padua University Hospital. Pretreatment staging was based on abdominal ultrasound, chest computed tomography and octreoscan. No patient showed signs of the presence of extragastric disease or presented menin gene mutations. The patients routinely underwent an endoscopic examination every 6 months; the mean follow-up is presently 55 months and the patients have already undergone six post-treatment endoscopies.
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Two out of the three patients treated presented a longlasting regression of the lesions, to micronodular or nodular ECL-cell hyperplasia, with no carcinoid relapse, whereas in the third, evidence of tumor persistence was found. These findings need to be confirmed by a longer followup and by larger size studies but indicate the possibility of a new therapeutic approach to gastric type I carcinoids when endoscopic resection is not feasible.
Conclusion In summary, hypergastrinemia is both a risk factor and a biomarker for gastric cancer and gastric carcinoid, and antigastrin vaccination, with G17DT, provides new perspectives in the treatment of gastric and pancreatic cancer, but particularly in gastric carcinoids. In all these cancers, the results obtained so far need validation with additional prospective randomized studies in patients with advanced disease who are no longer candidates for standard chemotherapy, as well as in multifocal and relapsing gastric type I carcinoid. The point is obviously open to debate but these prospective, large-size randomized studies are, in our minds, eagerly awaited.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
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Review article
Gastrin: from pathophysiology to cancer prevention and treatment Gemma Maddaloa, Ylenia Spolveratoa, Massimo Ruggeb and Fabio Farinatia Gastrin has been identified as the principal effector of gastric secretion, but several studies have demonstrated its role as a biomarker of cancer risk and as a growth factor for colorectal, stomach, liver, and pancreatic cancer. Hypergastrinemia characterizes autoimmune gastritis, with body and fundic gland atrophy and increased risk for both gastric adenocarcinoma and neuroendocrine tumors. Gastric type I carcinoids develop in the context of autoimmune gastritis because of the stimulus exerted by gastrin on enterochromaffin-like cells and remain gastrinsensitive for long durations because the removal of hypergastrinemia leads to tumor regression. The treatment of gastric carcinoid is still open to debate, but when the disease frequently relapses, or is multicentric or infiltrating, surgery is advocated or, in the alternative, a costly and long-lasting treatment with long-acting somatostatin analogues is prescribed. A technology allowing the preparation of an immunogen eliciting an immune system response with generation of antibodies against G17 has been developed. This vaccine has been tested in patients with colorectal, pancreatic or advanced gastric cancer.
The vaccine has also been used in the treatment of gastric type I carcinoids, and the administration of G17DT in patients harboring these lesions leads to carcinoid regression. Antigastrin vaccination in the treatment of gastrointestinal cancer obviously needs validation, but this immunotherapy may well represent a simple, inexpensive, and active ‘adjuvant’ treatment. European Journal of c 2014 Wolters Kluwer Cancer Prevention 23:258–263 Health | Lippincott Williams & Wilkins.
Gastrin and gastric physiology
predominant in the gastric antrum (Copps et al., 2009). Gastrin release is stimulated by vagal impulses, by intramural neural reflexes, and by the presence of food in the gastric lumen (Larsson, 2000). The secreted gastrin binds to CCK-2 receptors on ECL cells, inducing the production of histamine; this in turn binds to H2 receptors on parietal cells, stimulating acid secretion (Waldum et al., 2009).
The human stomach is divided into two functionally and anatomically different zones, the body and fundic area, with oxyntic mucosa, and the antral area, and contains four types of terminally differentiated cells: parietal (oxyntic) cells, chief (zymogenic) cells, mucous foveolar cells, and hormone-secreting enteroendocrine cells (Mills and Shivdasani, 2011). Parietal cells, located in the body and fundic area, are involved in acid secretion, aimed at calcium, iron, and protein digestion and at limitation of bacterial overgrowth (Schubert and Shamburek, 1990), and are controlled by neural and hormonal effectors (Schubert, 2010). Histamine, produced by enterochromaffin-like cells (ECL cells), directly stimulates parietal cells by binding to the parietal cell H2 receptor, triggering hydrochloric acid secretion. Acetylcholine modulates parietal cell function directly and indirectly by binding to their receptors and inhibiting serotonine secretion. Gastrin is produced in antral and duodenal Brunner’s glands by neuroendocrine G cells as a precursor, preprograstrin, that, after post-translational modification, is cleaved to form two principal peptides (G34-Gly and G17-Gly). From the former G34 and, in part, G17 derives, both involved in the control of acid secretion. From the latter, only G17 is obtained. G17, more active, is c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-8278
European Journal of Cancer Prevention 2014, 23:258–263 Keywords: autoimmune gastritis, G17DT, gastric atrophy, gastric carcinoids, hypochlorhydria, neuroendocrine tumors, vaccine a Department of Surgery, Oncology and Gastroenterology, Padua University Hospital and bDepartment of Medicine, Padua University, Padova, Italy
Correspondence to Fabio Farinati, MD, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, 35128 Padova, Italy Tel: + 39 049 821 305; fax: + 39 049 876 0820; e-mail: [email protected] Received 27 May 2013 Accepted 26 November 2013
Beyond gastric acid secretion, gastrin stimulates the migration of gastric epithelial cells, the release of fibroblast growth factor and the activation of its receptor and of the protein kinase pathway (Czinn and Blanchard, 2011). Hypergastrinemia is a physiologic response to achlorhydria (Schubert, 2011) but may also indicate the presence of gastrin-secreting tumors such as gastrinoma, Zollinger–Ellison syndrome, and a physiological response to suppressed gastric acid secretion as occurs in chronic autoimmune atrophic gastritis, a gastric precancerous condition (Burkitt et al., 2009). If hypergastrinemia is therefore to be considered as a marker of risk for gastric cancer, gastric carcinoid, or gastrinoma, hypogastrinemia has also be suggested as a biomarker of an increased risk of gastric cancer (Farinati et al., 1991; Kikuchi et al., 2011) because of reduced release of the hormone in cases of severe atrophy of the DOI: 10.1097/CEJ.0000000000000008
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Gastrin: from pathophysiology to cancer Maddalo et al.
gastric antrum, associated with an increased risk of antral adenocarcinoma.
Atrophic gastritis and cancer risk Atrophy, with loss of the appropriate glandular structure and development of intestinal metaplasia, is a byproduct of chronic inflammation (Rugge et al., 2002). High-grade atrophy and intestinal metaplasia, as assessed by a recently introduced specific scoring system, the OLGA system (Operative Link for Gastritis Assessment), are linked to an increased risk of cancer, therefore being useful as tumor markers (Rugge et al., 2007). Two different subtypes of gastric atrophy with different pathophysiology can be identified in the stomach: the socalled type A, corpus-predominant, autoimmune chronic atrophic gastritis and the Helicobacter pylori-related chronic atrophic gastritis, involving first the antrum and then spreading to the body area (antrum predominantpangastritis) (Dai et al., 2011). Antibiotic-mediated H. pylori eradication is linked to a reduced risk of developing gastric precancerous conditions and cancer in the latter, whereas no specific treatment blocking the progression of autoimmune gastritis (AIG), characterized by hypergastrinemia, is available. The prevalence of the latter disease is unknown, but AIG is more prevalent in women (Toh et al., 2012) and is associated with other autoimmune diseases, in particular with Hashimoto thyroiditis (Betterle and Zanchetta, 2003). Antiparietal cell antibodies in (90% of the patients) and, in a smaller proportion of patients (30–50% of the cases), anti-intrinsic factor antibodies are characteristic of AIG (De Block et al., 2008). A role for H. pylori infection as a trigger in the development of AIG has been advocated by many authors (Veijola et al., 2010) and AIG is characterized by iron and vitamin B12 malabsorption associated, in the long run and when not properly treated, with pernicious anemia (Biermer’s disease) (Andres and Serraj, 2012). The long-lasting and progressive hypergastrinemia induces hyperproliferation of ECL cells, the most represented gastric neuroendocrine cells, leading to ECL-cell hyperplasia that eventually evolves with the development,
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probably in genetically predisposed individuals, of a neuroendocrine tumor, the so-called gastric type I carcinoid, a tumor with uncertain biological behavior (Vannella et al., 2012).
Carcinoid Carcinoids are neuroendocrine tumors derived from enterochromaffin cells, presenting a benign biological behavior, but microscopically mimicking a malignant carcinoma (Pinchot et al., 2008) and producing 5hydroxytryptamine, a peptide responsible, when released in large amounts, for the clinical syndrome called carcinoid syndrome, which is very rarely present in gastric carcinoids (Van der Lely and de Herder, 2005). Carcinoid tumors, traditionally classified on the basis of their localization (foregut, midgut, and hindgut), are now universally classified on the basis of the WHO classification, shown in Table 1 (Rindi et al., 2010). Once considered as rare tumors, their increasing incidence and the underestimation of their actual prevalence makes the definition of ‘rare’ inadequate nowadays. Gastric carcinoid represent about 9% of all gastrointestinal tract carcinoids and 2% of endoscopically resected polyps (Modlin et al., 2003; 2004). Rindi et al. (1993), defined three different subtypes of gastric carcinoids: (1) Type I is associated with AIG, where its incidence is between 5 and 10%; it develops in the body area and is very rarely characterized by malignant behavior and metastasis. The 5-year survival rate (> 90%) is not different from that of the general population. (2) Type II, characterized by an intermediate malignant potential, is associated with gastrinoma and Zollinger–Ellison syndrome and is frequently associated with MEN1, multiple endocrine neoplasia syndrome type 1. These carcinoids, usually localized in the antrum, present a risk of malignant progression definitely higher than that of type I carcinoids. (3) Type III carcinoids are characterized by definite malignant behavior. Their prevalence is higher in men, they are not associated with hypergastrinemia,
Table 1 Clinical and histologic features of the three subtypes of gastric carcinoids: the most frequent and less aggressive are the type I neuroendocrine tumors, associated with autoimmune gastritis and characterized by a prognosis not significantly different from that of unaffected controls
Prevalence (%) Endoscopic appearance Association Grading Ki67 index (%) Serum gastrin Secondaries (%) Mortality
Type I
Type II
Type III
70–80 Small (5 mm–2 cm), multiple polypoid lesions Autoimmune gastritis NET G1 20 Normal > 50 25–30%
MEN1, multiple endocrine neoplasia type I; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumors; ZES, Zolllinger–Ellison syndrome.
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are frequently diagnosed in metastatic phase, and the 5-year survival rate does not exceed 75–80% (Burkitt and Pritchard, 2006). Endoscopically, gastric type I carcinoids appear as relatively small (5–10 mm in general) sessile, polypoid, hypervascularized lesions. CgA, proposed as a marker for gastric carcinoid, shows increased levels in 80–90% of patients with type I carcinoid (Wiedenmann et al., 1986). Unfortunately, CgA is not a specific marker and increased levels can be found because of long-term proton pump inhibitor treatment or hypergastrinemia of different origin. In addition, other tumors of neuroendocrine origin (thyroid, pancreas, or lung) can also show elevated CgA levels (Nobels et al., 1997). At the time of diagnosis, many carcinoids (either of Type I or II) are still gastrin-sensitive and the removal of hypergastrinemia can lead to tumor regression, as confirmed by the administration of long-acting somatostatin analogues (Kvols et al., 1986). In the past, the only therapy considered was surgery, targeted to either the excision of the carcinoid or to the removal of the source of gastrin secretion, by antrectomy or, under the worst hypothesis, to total gastrectomy. There is now an increasing tendency toward endoscopic treatment (Kadikoylu et al., 2006), whenever feasible, of gastric type I carcinoids. Small tumors (< 1 cm) can be endoscopically resected. Recent studies have reported the successful removal of larger lesions, even with deep infiltration, by endoscopic mucosal resection or endoscopic submucosal dissection, with no evidence of recurrence (Ahlman, 1999). Local excision may then be advocated in case of rapid, multifocal recurrence. When endoscopic ablation is not feasible and surgery is contraindicated or refused by the patient, gastric carcinoid can be treated medically with long-acting somatostatin analogues (Ferraro et al., 1996; Oberg et al., 2004). This treatment is well tolerated but, among the side effects, gallbladder stones, constipation, or diarrhea can be observed. The treatment is life-long and costly and can hardly be indicated in young patients, the indication being restricted to elderly patients with surgical contraindications and multifocal/relapsing disease, not eligible for endoscopic treatment.
Gastrin in gastric cancer and its therapeutic potential Several lines of evidence suggest a role for gastrin in gastric carcinogenesis. First, the expression of the gastrinCCK-2 receptor increases with the progression of gastric atrophy, a precancerous condition (Henwood et al., 2001). Second, immunohistochemical studies on gastric cancer resection specimens showed that over 50% of the tumors expressed the CCK-2 receptor and had detectable gastrin levels within the tumor (Hur et al., 2006), secreted by
gastric carcinoma cells, acting as a growth factor in an autocrine or a paracrine manner. In addition, gastrin upregulates mucosal cell proliferation, as shown in several gastric cancer cell lines, with increased levels of heparin binding epidermal growth factor (HB-EGF) (Dickson et al., 2006), as confirmed in the INS-GAS hypergastrinemic mice, in which overexpression of HB-EGF was also shown in premalignant lesions (Wang et al., 2000). In general, gastrin increases the susceptibility of gastric epithelial cells ‘in vivo’ to apoptosis by signaling through the CCK-2 receptor, as has been reported in animal models (Kidd et al., 2000) as well as in hypergastrinemic patients with H. pylori infection, but the opposite condition has been described in transformed cells. For instance, gastrin inhibits apoptosis in AGS-GR gastric cancer cells by acting on the antiapoptotic protein mcl-1, whose expression is also increased in type I gastric neuroendocrine tumors (Pritchard et al., 2008). Finally, gastrin increases the level of expression of matrix metalloproteinase 9, involved in tissue remodeling in patients with gastric cancer and carcinoids (Burkitt and Pritchard, 2006), and a role of tissue proteases in gastric cancer and gastric precancerous changes has also been confirmed by our previous studies (Plebani et al., 1995). Consequently, the hypothesis was proposed that the inhibition of gastrin could prevent tumor growth or even cancer development (Watson et al., 1999; Gilliam et al., 2004; Ajani et al., 2006) and one of the approaches attempted was to try to induce an immune response capable of neutralizing the effects of gastrin.
G17–diphtheria toxoid A technology was developed that allowed the preparation of immunogens, eliciting an immune system response with generation of antibodies binding specific portions of the administered immunogen. These antibodies crossreact with targeted ‘self ’ molecules, such as hormones. Diseases resulting from hormone hyperproduction have not been traditionally viewed as eligible for a treatment on the basis of a stimulation of the body’s immune system response but such an approach has been shown to produce, as we will see, clinically significant results. One of the examples of such targeted stimulations was indeed the development of the gastrin-17–diphtheria toxoid immunogen (G17DT). This includes a synthetic peptide similar to a portion of G17, to obtain an antibodymediated neutralization, and a ‘carrier’, the diphtheria toxoid, conjugated with the synthetic peptide, not recognized as ‘self ’ by the patient’s immune system. The diphtheria toxoid makes G17 bind to and become internalized by circulating B-cells and the epitopes, once internalized and presented on B-cells and macrophages,
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Gastrin: from pathophysiology to cancer Maddalo et al. 261
are bound by T-cells, with consequent T-cell proliferation and activation of signaling to B-cells. These cells in turn again bind to the G17-derived peptide with mass production of the desired antibodies. Early studies with G17DT, carried out in SCID mice injected with a human gastric cancer cell line, showed a prolongation of mouse survival similar to that achieved by treating the animals with 5-fluorouracile and leucovorin, the standard protocol in several gastrointestinal cancers in humans (Watson et al., 1999). In the only phase II trial carried out in patients with advanced gastric cancer administered G17DT immunogen at different doses, 60% of the G17DT-treated patients successfully developed antigastrin-17 antibodies (Gilliam et al., 2004) and patients treated with higher G17DT doses showed a more pronounced antibody response. Data on patient survival following G17DT administration were lacking and therefore an open-label, multinational, phase II study in 96 patients with advanced gastric or gastroesophageal cancer was planned to evaluate the response rate and survival of patients treated with G17DT, cisplatin, and 5fluorouracil (Ajani et al., 2006). G17DT was intramuscularly injected at a higher dose: time to progression and overall survival were significantly longer in responders than in nonresponders and the study was a sound demonstration of the role of gastrin in modulating cancer progression and of the potential for gastric cancer treatment with G17DT. Additional studies have also been published on the effects of G17DT in other types of cancer. Gastrin neutralization reduced the growth of a rat colon cancer line that expresses cholecystokininB/gastrin receptors and secretes glycine-extended gastrin-17 (G17), with a significant reduction in the cross-sectional tumor area and tumor weight, and a higher degree of tumor necrosis. Later, a phase I/II clinical trial of G17DT in patients with colorectal cancer (Smith et al., 2000), assessing the safety and efficacy of stimulating the production of antigastrin antibodies, was published. The hypotheses supporting the use of G17DT in colorectal cancer were that colon cancer may indeed produce gastrin precursors playing a paracrine or an autocrine role, and that gastrin peptides may play an endocrine role in promoting colorectal neoplasia (Hoosein et al., 1988; Watson et al., 1989; Ciccotosto et al., 1995; Smith et al., 1996; 1998; Aly et al., 2004). No oncological responses were observed, and only two patients with stable disease were registered. The limited role of circulating gastrin peptides in colorectal cancer was confirmed recently by the demonstration of a low risk of colorectal cancer (Lahner et al., 2012) in hypergastrinemia and by the negative association between Zollinger–Ellison syndrome and colon cancer (Orbuch et al., 1996), even though an autocrine/paracrine role of locally released nonamidated gastrin precursors
(Seva et al., 1994; Ciccotosto et al., 1995) in colorectal carcinogenesis cannot be excluded. Substantial evidence supports the role of gastrin and of its receptor (CCK2R) also in pancreatic cancer. Both are upregulated in human pancreatic adenocarcinoma as well as in preneoplastic lesions (Caplin et al., 2000; Goetze et al., 2000); the stimulation of CCK2R activates several kinases (Todisco et al., 1997; Daulhac et al., 1999a), the JAK2/STAT3 pathway (Kowalski-Chauvel et al., 1996; Ferrand et al., 2005), the Src-related tyrosine kinases, and the p125FAK, which have been shown to play a crucial role in the effects of gastrin (Daulhac et al., 1999b). Recently, French researchers, using a ‘cancer genes’ array, were able to identify aV integrin as a new gastrin target gene in human pancreatic cancer cells (Cayrol et al., 2011). On the bases of this evidence, a prospective, randomized, placebo-controlled randomized multicenter study has been carried out in patients with advanced pancreatic cancer unwilling to receive or unsuitable for standard chemotherapy. The study started in 2001 but its publication was delayed by the bankruptcy of Aphton, which produced G17DT (Gilliam et al., 2012). In essence, administration of G17DT resulted in a borderline significant increase in survival, but the patients who developed an antiG17DT response (64%) survived significantly longer than both the nonresponders and the placebo-treated patients, with a two to three times increase in median survival.
G17DT in gastric neuroendocrine tumors type I Type I gastric carcinoid, now identified as ‘well differentiated gastric neuroendocrine tumor’, is strictly correlated with gastrin biologic activity (Rindi et al., 2010). In the recently published algorithms for carcinoid treatment (Delle Fave et al., 2005), in contrast with the previous scenario, dominated by surgery, endoscopy plays the major role. However, as repeated endoscopy or polypectomy is an invasive and costly approach, a less invasive management is eagerly awaited. In the search for a noninvasive, inexpensive treatment of gastric type I carcinoids, we aimed to investigate the effects of G17DT administration in patients harboring these lesions (Tieppo et al., 2011). The G17DT vaccine pilot study in patients with multifocal, recurrent carcinoid, not amenable to endoscopic removal, was formally approved by the Ethical Committee of Padua University Hospital. Pretreatment staging was based on abdominal ultrasound, chest computed tomography and octreoscan. No patient showed signs of the presence of extragastric disease or presented menin gene mutations. The patients routinely underwent an endoscopic examination every 6 months; the mean follow-up is presently 55 months and the patients have already undergone six post-treatment endoscopies.
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Two out of the three patients treated presented a longlasting regression of the lesions, to micronodular or nodular ECL-cell hyperplasia, with no carcinoid relapse, whereas in the third, evidence of tumor persistence was found. These findings need to be confirmed by a longer followup and by larger size studies but indicate the possibility of a new therapeutic approach to gastric type I carcinoids when endoscopic resection is not feasible.
Conclusion In summary, hypergastrinemia is both a risk factor and a biomarker for gastric cancer and gastric carcinoid, and antigastrin vaccination, with G17DT, provides new perspectives in the treatment of gastric and pancreatic cancer, but particularly in gastric carcinoids. In all these cancers, the results obtained so far need validation with additional prospective randomized studies in patients with advanced disease who are no longer candidates for standard chemotherapy, as well as in multifocal and relapsing gastric type I carcinoid. The point is obviously open to debate but these prospective, large-size randomized studies are, in our minds, eagerly awaited.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
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