胃泌素和结直肠癌研究进展

胃泌素（Gas）是一种重要的胃肠激素，具有调节胃酸分泌和促进消化道黏膜上皮增殖作用。近年来研究表明，Gas对结直肠癌（CRC）有促生长作用。Gas有多种活性形式，作用于不同CCK受体，发挥该生物学作用。Gas前体、Gly-G17、甘氨酸延伸性Gas受体、肿瘤的自分泌／旁分泌途径、Gas及Gas受体作为CRC分子靶向治疗等是研究新进展。     

胃泌素和结肠肿瘤

近年来胃泌素与结肠肿瘤的研究取得了很大突破。其中，胃泌素前体的作用和不同于CCK－A、CCK－B的新受体存在已得到公认。进一步的研究已开始探讨胃泌素的作用方式；并研制新的胃泌素受体拮抗剂。本重点介绍这些新成就。     

人结肠癌细胞胃泌素-黏着斑激酶通路的研究

目的研究胃泌素对人结肠癌细胞信号分子黏着斑激酶(FAK)酪氨酸磷酸化和蛋白质表达的影响。方法使用胆囊收缩素2受体(CCK2R)的真核表达载体pCR3.1/CCK2R,转染人结肠癌细胞株Colo320,上调胃泌素作用;使用胃泌素拮抗剂下调胃泌素作用。使用胃泌素按浓度和时间梯度刺激细胞,以免疫沉淀和蛋白质印迹法检测FAK酪氨酸磷酸化和蛋白质表达情况。结果胃泌素能够引起FAK酪氨酸磷酸化,具有时间和剂量依赖性;CCK2R表达上调可以增强此作用;胃泌素拮抗剂具有相反作用。结论FAK是胃泌素发挥效应的下游信号分子,以酪氨酸磷酸化的形式发挥作用。胃泌素CCKRFAK信号通路在胃泌素引起的肿瘤细胞增殖过程中发挥重要作用。     

消化道肿瘤内分泌治疗的研究进展

近 2 0年里 ,消化道激素在消化道肿瘤发生发展中的作用受到了人们的普遍关注 ,其中最有意义、研究最为广泛的是同属一族的胃泌素 (Gastrin)和胆囊收缩素 (CCK)。大量研究表明 ,在消化道上皮细胞转化和肿瘤演进过程中 ,Gastrin/CCK基因常异常表达 ,合成、分泌相当数量的不同加工程度的产物 ,包括成熟的酰胺化分子形式 (G NH2 /CCK NH2 )、甘氨酸延伸型中间产物 (G gly/CCK gly)、Gastrin/CCK原 (ProG/ProCCK) ,与其相应的自身受体形成自分泌环路 ,以自分泌方式对消化道肿瘤细胞的增殖、凋亡及浸润转移等生物学过程进行重要调控。…     

胃泌素受体在胰腺癌发生、发展中的作用

胃泌素(gastrin,GAS)对肿瘤的发生和发展有促进作用已得到一致的认可,如在胃癌、大肠癌、胰腺癌及小细胞肺癌等肿瘤组织中均有GAS及其受体的基因表达.经分子克隆实验证明[1],胃泌素受体(gastrin receptors,GR)就是胆囊收缩素2受体(cholecystokinin2 receptors,CCK2R),统称为胃泌素/胆囊收缩素2受体(GAS/CCK2R,简写为GR).GAS对肿瘤的作用是通过GR介导的.     

胃泌素和结肠肿瘤

近年来胃泌素与结肠肿瘤的研究取得了很大突破。其中,胃泌素前体的作用和不同于CCK-A、CCK-B的新受体存在已得到公认。进一步的研究已开始探讨胃泌素的作用方式;并研制新的胃泌素受体拮抗剂。本文重点介绍这些新成就。     

甘氨酸延伸型胃泌素受体在结肠和结直肠肿瘤中的研究

目的建立甘氨酸延伸型胃泌素胞浆膜受体结合试验,并应用该方法检测甘氨酸延伸型胃泌素受体的部分特性及其在正常结肠和人结直肠肿瘤中的表达.方法用人结直肠肿瘤细胞株DLD-1建立胞浆膜制备方法,125I标记的甘氨酸延伸型胃泌素进行受体结合试验.结果胞浆膜受体结合试验的条件为5～10mg胞浆膜(离心25000r/min45min制备),37℃温育60min.正常Sprague-Dawley大鼠结肠粘膜和从结肠粘膜制备的胞浆膜有特异结合,而从完整结肠制备的胞浆膜无特异结合.胞浆膜甘氨酸延伸型胃泌素受体抑制50%结合的非标记配体浓度(IC50)为3.64μmol/L±1.93μmol/L;特异性胆囊收缩素(CCK)-A受体拮抗剂L364和特异性CCK-B受体拮抗剂L365不能拮抗该受体;非特异性受体拮抗剂氯苯酰色氨酸则能拮抗.结论甘氨酸延伸型胃泌素受体位于正常大鼠结肠粘膜、结肠粘膜和结直肠肿瘤细胞膜上,属单结合位点、低亲和力受体,不能被特异性CCK-A或CCK-B受体拮抗剂拮抗,是一种新受体.     

Gastrin/CCK在消化道肿瘤发生中的作用

胃泌素(Gastrin)和胆囊收缩素(CCK)对消化道上皮的生长营养作用20多年来一直激励着人们对其与消化道肿瘤关系的不懈探索,但除起源于ECL(Enterchromaffin-like)细胞的胃类癌外,胃肠G/I细胞分泌的成熟酰胺化Gastrin/CCK(G-NH_2/CCK-NH_2)与消化道肿瘤发生的关系尚不明确。近年研究表明,在消化道上皮细胞转化过程中,自身的Gastrin/CCK基因也异常激活,同时其翻译后加工能力又受到不同程度的损害,常经固有性途径分泌大量Gastrin/CCK原(Pro G/Pro CCK)及甘氨酸延伸型中间产物(G-gly/CCK-gy),与其自身的相应受体形成自分     

胆囊收缩素对细胞的促生长作用是通过A型还是B型受体亚型介导的?

胆囊收缩素(CCK)对正常和肿瘤组织的营养作用日益受到重视。现已证实CCK具有A、B两种受体亚型,CCK A型受体介导胰酶分泌、胆囊收缩和对胰腺组织的营养作用,B型受体即胃泌素受体(也是中枢神经系统的主要CCK受体)介导壁细胞泌酸作用和神经细胞的某些功能。CCK具有对     

胃泌素及其受体拮抗剂丙谷胺对肝癌细胞株生长的影响

目的: 研究胃泌素及胃泌素受体拮抗剂丙谷胺对肝癌细胞株的增殖的影响,并探讨肝癌患者非细胞毒内分泌治疗的可能性.方法:采用MTT比色分析法研究在不同浓度胃泌素和其受体拮抗剂丙谷胺的干预下, 4种人肝癌细胞株的增殖情况, 选取1种细胞株, 用流式细胞仪分析在胃泌素及丙谷胺作用下的周期分布.结果: 胃泌素在接近生理浓度下促进QGY-7701和Bel-7402的增殖, 丙谷胺对胃泌素的作用有抑制作用. 过量的胃泌素对QGY-7701有抑制效果. 胃泌素对HepG2和SMMC-7721无明显促增殖作用. 丙谷胺在高浓度下对所有细胞株皆有明显的抑制作用. 胃泌素可促使Bel-7402 G0/G1期细胞向S、G2/M期转化, 加用丙谷胺后胃泌素的上述作用消失.结论:胃泌素对肝癌细胞株有促增殖作用及促进DNA合成, 丙谷胺对其有抑制作用, 可能成为肝癌内分泌辅助治疗的一个新的途径.     

老年人大肠癌组织胃泌素表达及其与血清胃泌素水平的关系

目的探讨老年人大肠癌组织中胃泌素表达的临床病理意义及其与血清胃泌素水平的关系。方法对４６例老年人大肠癌、３２例非老年人大肠癌组织胃泌素表达进行免疫组化观察,并用放免法测定其血清胃泌素水平。结果癌组织中胃泌素表达阳性率,老年组４７．８％（２２例）,非老年组１８．８％（６例）（Ｐ＜０．０１）;老年组胃泌素的表达与肿瘤分化程度、ＴＮＭ分期、淋巴结转移有关,非老年组未显示这些关系。老年组和非老年组血清胃泌素水平与健康对照组比较差异均无显著性（Ｐ＞０．０５）,癌组织中胃泌素的表达不影响血清胃泌素水平（Ｐ＞０．０５）。结论胃泌素在癌组织中的表达可作为老年人大肠癌恶性度的一项指标,其表达对血清胃泌素水平无影响。     

Role of gastrin-peptides in Barrett's and colorectal carcinogenesis

Gastrin is the main hormone responsible for the stimulation of gastric acid secretion; in addition, gastrin and its derivatives exert proliferative and antiapoptotic effects on several cell types. Gastrin synthesis and secretion are increased in certain situations, for example, when proton pump inhibitors are used. The impact of sustained hypergastrinemia is currently being investigated. In vitro experiments and animal models have shown that prolonged hypergastrinemia may be related with higher cancer rates; although, this relationship is less clear in human beings. Higher gastrin levels have been shown to cause hyperplasia of several cell types; yet, the risk for developing cancer seems to be the same in normo- and hypergastrinemic patients. Some tumors also produce their own gastrin, which can act in an autocrine manner promoting tumor growth. Certain cancers are extremely dependent on gastrin to proliferate. Initial research focused only on the effects of amidated gastrins, but there has been an interest in intermediates of gastrin in the last few decades. These intermediates aren’t biologically inactive; in fact, they may exert greater effects on proliferation and apoptosis than the completely processed forms. In certain gastrin overproduction states, they are the most abundant gastrin peptides secreted. The purpose of this review is to examine the gastrin biosynthesis process and to summarize the results from different studies evaluating the production, levels, and effects of the main forms of gastrin in different overexpression states and their possible relationship with Barrett’s and colorectal carcinogenesis.     

Elevated plasma gastrin,CEA, and CA 19-9 levels decrease after colorectal cancer resection

BACKGROUND AND AIMS: Gastrin stimulates mucosal growth of much of the gastrointestinal tract and has also been implicated in promoting growth of colonic tumors, but its role in colorectal carcinogenesis remains controversial. This study determined fasting serum gastrin levels before and after surgery for colorectal cancer (CRC) and the relationship to the clinical stage of the disease to investigate it possible prognostic role. PATIENTS AND METHODS: Fasting radioimmunoassay gastrin, CA 19-9, and CEA levels were measured before and after surgery for CRC. Helicobacter pylori status was also assessed since it causes significant hypergastrinemia. RESULTS: Mean fasting plasma gastrin level was significantly higher in CRC patients than in controls before surgery but not 59 days after surgery. Mean CEA and CA 19-9 levels were significantly higher in patients with CRC before surgery than after tumor resection. There was a significant positive correlation between the plasma gastrin, CEA, and CA 19-9 levels and the CRC stage (Dukes' classification). CONCLUSION: The significance of gastrin as a marker for diagnosis or prognostic purposes in colorectal cancer needs to be further examined.     

Differences in plasma gastrin,CEA, and CA 19-9 concentration in patients with proximal and distal colorectal cancer

Summary Aim. We investigated whether there are differences in plasma gastrin, as compared with carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 between patients with proximal and distal colorectal cancer. Gastrin concentration has also been analyzed, dependent on the tumor stage, in order to evaluate the possible prognostic role of this measurement. Methods. In 50 patients with colon cancer-fasting gastrin, CA 19-9 and CEA levels were evaluated. Results. Mean plasma-gastrin level in patients with distal tumor yielded 105.31 ± 12.5 μU/L and was significantly higher than in patients with the proximal tumor site (42.2 ± 3.1 μU/L) as well as in controls (p<0.001). No significant difference was observed between mean plasma gastrin in patients with proximal tumors and the control group. The mean CEA plasma level was significantly higher (p<0.01) in patients with distal tumors (9.1 ± 1.1 ng/mL) than in those with proximal tumors (1.48 ± 0.1 ng/mL). Similarly, the mean CA 19-9 plasma level was significantly higher (p<0.01) in patients with distal tumor (19.9 ± 2.1 U/mL) than in those with proximal tumor: 1.8 ± 0.2 U/mL. The mean gastrin plasma, CA 19-9, and CEA level was significantly higher in group of Duke’s stage C and D as compared to A and B. Conclusion. We speculate that observed differences in gastrin concentration in patients with distal and proximal tumors may contribute to the distinct pathogenesis and biological properties of those cancers. The significance of gastrin as a marker for diagnostic or prognostic purposes in colorectal cancer requires further study.     

Secretin-stimulated serum gastrin levels in hyperparathyroid patients from families with multiple endocrine adenomatosis type I.

Twenty-three patients with hyperparathyroidism from six families with the multiple endocrine adenomatosis (MEA) I-syndrome were tested by secretin provocation. In nine cases this led to increases in serum gastrin ranging from 298 to 13 300 pg/ml, whereas the maximum rise in gastrin in the other 14 patients was 32 pg/ml. In all nine patients with marked gastrin responses to secretin, the Zollinger-Ellison syndrome was diagnosed by gastric acid hypersecretion and large increases in gastrin after calcium administration. Six of these nine patients had, at most, minor postprandial rises in gastin and two had demonstrable tumors. In 34 normal subjects, 23 nonaffected members of families with MEA I-syndrome, and 42 patients with various diseases the maximum gastrin response to secretin was 21 pg/ml. We conclude that secretin provocation is helpful in the diagnosis of the Zollinger-Ellison syndrome, especially when basal serum gastrin levels are only slightly elevated.     

The role of gastrin and cholecystokinin in normal and neoplastic gastrointestinal growth

Abstract Gastrin and cholecystokinin (CCK) act as growth factors for the gastric mucosa and the pancreas, respectively. CCK is also responsible, via the CCK-A receptor, for the pancreatic hyperplasia observed following the feeding of protease inhibitors or pancreaticobiliary diversion. Hypergastrinaemia does not increase the incidence of spontaneous gastrointestinal carcinoma, but does stimulate the proliferation of gastric enterochromaffin-like cells via the gastrin/CCK-B receptor, with a consequent increase in the incidence of gastric carcinoids. Whether gastrin influences mutagen-induced gastrointestinal carcinogenesis is still controversial, but CCK clearly enhances the induction by carcinogens of acinar tumours in the pancreas. While gastrin increases xenograft growth of 50% of gastrointestinal tumours tested, effects on the proliferation of gastrointestinal tumour cell lines in vitro have been more difficult to demonstrate, perhaps because many cell lines are already maximally stimulated by autocrine gastrin. Gastrin mRNA and progastrin, but not mature amidated gastrin, have been detected in all gastrointestinal cell lines tested. Although cell proliferation is inhibited by gastrin/CCK receptor antagonists, the spectrum of antagonist affinities is not consistent with binding to either CCK-A or gastrin/CCK-B receptors. Definition of the molecular structure of the receptor involved in the autocrine loop may lead to novel therapies for gastrointestinal cancer.     

Expression of gastrin and its receptor in human gastric cancer tissues

Purpose: Gastrin is a growth factor of cancerous and normal cells of the gastrointestinal tract, and its effect is known to be mediated by gastrin/cholecystokinin B (CCKB) receptor. This study was performed to investigate the prognostic significance and the expression profiles of gastrin and gastrin receptor in human gastric carcinoma tissues. Methods: We analyzed the expressions of gastrin and gastrin receptor by immunohistochemical staining using anti-gastrin Ab (Sigma, St. Louis, MO, USA) and anti-gastrin receptor Ab (Aphton Corp., Woodland, CA, USA) in 279 gastric adenocarcinoma patients. Patients’ clinicopathologic features and prognoses were analyzed. Results: The gastrin expression rate in these patients was 47.7% (133/279) and the gastrin receptor expression rate was 56.5% (158/279). Gastrin expression was significantly higher in men than in women (54.3% vs. 34.1%), and higher in differentiated gastric adenocarcinoma than in the undifferentiated type (55.1% vs. 43.0%). The gastrin receptor expression rate was also significantly higher in men than in women (61.2% vs. 47.3%), and was higher in the differentiated type than in the undifferentiated type (72.9% vs. 46.5%), and significantly higher in the intestinal type than in the diffuse type (75.2% vs. 42.9%). Gastrin and gastrin/CCKB receptor expressions were not found to be significant prognostic factors in themselves. When focused on correlation between the co-expression of gastrin and gastrin/CCKB receptor and the survival, the prognosis of patients positive for both gastrin and gastrin receptor was significantly poorer than for those negative for gastrin and gastrin receptor in diffuse-type gastric cancer patients. However, multivariate analysis showed that only TNM stage was an independent prognostic factor of survival in diffuse-type gastric cancer patients. Conclusions: This study shows that the expression rates of gastrin and gastrin receptor are high (about a half) in gastric carcinoma tissues, and that there is an association between gastrin and gastrin receptor expression. We also found that patients with diffuse-type gastric carcinoma tissues expressing both gastrin and gastrin receptor have a poorer prognosis than those negative for both, which suggests that gastrin acts as an autocrine growth factor in a subgroup of gastric carcinomas.     

促胃液素促大肠癌生长调节的机制

目的研究促胃液素（Ｇａｓ）促进大肠癌生长的调节方式．方法采用免疫组化及放射性配体结合试验,检测７０例大肠癌其癌组织,癌近旁粘膜和癌远旁粘膜的Ｇａｓ表达及促胃液素受体（ＧａｓＲ）状况,用放射免疫法测定其手术前后血清促胃液素（ＳＧａｓ）水平．结果大肠癌癌组织２８５％（２０／７０）有不同程度的Ｇａｓ表达,癌近旁粘膜仅２８％（２／７０）呈Ｇａｓ弱阳性反应．癌远旁粘膜未见Ｇａｓ阳性细胞．癌组织ＧａｓＲ量及其最大结合量较癌近,远旁粘膜明显升高（Ｐ＜００５）．大肠癌Ｇａｓ表达阳性组和阴性组术前ＳＧａｓ值与正常对照组比较,前者明显升高（Ｐ＜００５）,后者升高不明显（Ｐ＞００５）．在Ｇａｓ表达阳性组中,只有强阳性者ＳＧａｓ较对照组极明显升高（Ｐ＜００１）,而弱阳性和阳性者虽有一定程度升高,但差异不明显（Ｐ＞００５）．结论促胃液素对大肠癌的促生长作用是通过自馈性方式调节的