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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 411-416

Heterogeneous expression of cholecystokinin and gastrin receptor in stomach and pancreatic cancer: An immunohistochemical study


1 School of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk 712-749, Korea; Department of Surgical Oncology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 School of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk 712-749, Korea
3 Department of Surgical Oncology, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Date of Web Publication03-Nov-2015

Correspondence Address:
Rajani Rai
School of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk 712-749

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.168970

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 > Abstract 


Aim: Cholecystokinin (CCK) and gastrin (Gs) are a well known trophic factor for the gastrointestinal tract and their trophic effects are shown mainly toward pancreas and stomach, respectively. Though, the exact characterization of CCK and Gs receptors subtype (cholecystokinin type A receptor [CCKAR] and cholecystokinin type B receptor/gastrin receptor [CCKBR/GR]) in stomach cancer (SC) and pancreatic cancer (PC) is still controversial and necessities further validation.
Subjects and Methods: CCKAR and CCKBR/GR expression was analyzed by immunohistochemistry in 55 SC, 25 benign gastric diseases (BGDs), 38 PC (including periampullary carcinoma), and 10 normal pancreatic tissue. The results were statistically correlated with the patient's clinical history to observe the prognostic significance if any.
Result: CCKAR expression was detected in 18.2% of SC, 20% of BGD, 65.8% of PC, and 30.0% of normal pancreas tissue samples. The CCKBR/GR expression was detected in 58.2% of SC, 48.0% of BGD, 18.4% of PC, and 60.0% of normal pancreas tissue samples. CCKBR/GR expression was significantly high in well and moderately differentiated SC samples as compared to poorly differentiated samples.
Conclusion: Our study showed significantly higher expression of CCKAR and down regulation of CCKBR in PC as compared to control while CCKBR/GR was detected in majority of SC samples. Thus, our study suggests that CCK and Gs receptors may have diagnostic and therapeutic implications. However, study need to be validated in significantly bigger sample size and need to be replicated in different cohorts.

Keywords: Cholecystokinin, cholecystokinin type A receptor, cholecystokinin type B receptor/gastrin receptor, gastrin, pancreatic cancer, stomach cancer


How to cite this article:
Rai R, Kim JJ, Tewari M, Shukla HS. Heterogeneous expression of cholecystokinin and gastrin receptor in stomach and pancreatic cancer: An immunohistochemical study. J Can Res Ther 2016;12:411-6

How to cite this URL:
Rai R, Kim JJ, Tewari M, Shukla HS. Heterogeneous expression of cholecystokinin and gastrin receptor in stomach and pancreatic cancer: An immunohistochemical study. J Can Res Ther [serial online] 2016 [cited 2019 Nov 14];12:411-6. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/411/168970




 > Introduction Top


Cholecystokinin (CCK) and gastrin (Gs) are a group of regulatory brain-gut peptide hormone with multiple functions in the gastrointestinal tract (gallbladder contraction, regulation of gastrointestinal motility, pancreatic enzyme, and gastric acid secretion).[1] In addition, these act as physiological growth factors regulating proliferation and differentiation of normal tissue. All these biological functions of CCK and Gs are mediated by two receptors cholecystokinin type A receptor (CCKAR) and cholecystokinin type B receptor/gastrin receptor (CCKBR/GR).[2],[3]

An increasing body of evidence wires the fact that CCK and Gs act via their receptor promoting development and progression of cancer.[4],[5] Furthermore, receptors for these hormones have been established to be expressed in a variety of human neoplastic tissue.[6] CCKARs were found primarily in significant numbers in gastroentero-pancreatic tumors (38%), meningiomas (30%), and neuroblastomas (19%) while, CCKBR/GR have been reported in high percentage of medullary thyroid cancer (MTC, 92%), small cell lung carcinomas (57%), astrocytomas (65%), stromal tumors (100%), gastrointestinal adenocarcinomas, neuroendocrine tumor, and malignant glioma.[7],[8] In our previous study, we have found an increased expression of CCKAR in gallbladder cancer tissue samples as compared to gallstone disease tissue samples, suggesting a possibility of a trophic effect of CCK toward the gallbladder mucosa.[9]

Investigation of expression profile of various regulatory peptides in most of the human tumor has got a front point in oncology for the diagnosis and therapy in nuclear medicine.[10] Radiolabeled somatostatin analogs are widely used for detection of human neuroendocrine tumors and their metastases as they show a high density of somatostatin receptor.[11],[12] CCKBR/GR ligand also allows sensitive and reliable staging of patients with metastatic MTC.[8] Thus, CCKAR and CCKBR seems promising for clinical applications. Concomitantly, radiolabelled CCK and Gs derivatives have been developed for successful imaging of tumors expressing either CCKAR or CCKBR, proving the feasibility of targeting CCK and Gs receptors in human tumors in vivo.[13]

Several studies have been carried out the expression analysis of these receptors in stomach cancer (SC),[14],[15],[16],[17] and pancreatic cancer (PC),[18],[19],[20],[21],[22] hitherto there has been considerable confusion over the extent of CCKAR or CCKBR/GR in normal and human PC, as well as in SC, requiring further validation. Moreover, no study is reported from India. Hence, this study was designed to solve the dilemma of expression of these receptor subtype in normal and tumor tissue of stomach and pancreas by immunohistochemistry (IHC) with specific CCK receptor subtype antibodies.


 > Subjects and Methods Top


Subject details

This study included 55 tissue samples of SC, 25 tissue samples of nonmalignant/benign gastric disease (chronic gastritis and ulcer disease; BGD), 38 tissue samples of PC (including periampullary and ampullary carcinoma), and 10 normal pancreatic tissue from patients undergoing surgery in the Department of Surgical Oncology, S.S. Hospital, Banaras Hindu University, Varanasi, Uttar Pradesh, India, from 2007 to July 2010. Tissue samples for SC were taken following laparotomy for gastric cancer (radical gastrectomy). Samples for control were taken by upper gastroendoscopy in patients complaining of gastritis and peptic ulcer disease without any evidence of malignancy. PC tissue samples were collected from patients who underwent whipple resection or pylorus preserving pancreatodudenctomy for cancer head pancreas or periampullary carcinoma. We took the normal pancreatic tissue away from the tumor in patients with adenocarcinoma of papilla of Vater.

The study was approved by the Institute's Ethics Committee. A detailed clinical history and informed consent from each patient were noted on predesigned proforma. Patients who had received prior chemotherapy/radiotherapy/or surgery and patients with other cancers were excluded from the study.

Immunohistochemistry

All the resected tissue samples were fixed in 10% buffered formalin and embedded in paraffin. Three to four micrometer thick section was taken on poly-lysine coated slide and used for immunohistochemical staining as reported previously.[9] Primary antibodies used for CCKAR and CCKBR/GR expression were CCK-AR (H-60) antibody (sc-33220) and CCK-BR (4A5) antibody (sc-53522), respectively. Secondary staining was done by Super Sensitive Link-Lable IHC Detection System (QD000-5L) from BiogGenex, San Ramon, CA, USA.

A section known to stain positively on gallbladder muscle layer component and on pancreatic islet cells were included in each batch of staining as a positive control for CCKAR and CCKBR/GR, respectively. For negative control, primary antibody was replaced with tris buffer solution (TBS) [Figure 1].
Figure 1: (a) CCKAR positive control (a section showing CCKAR positivity on gallbladder muscle layer component), (b) CCKBR/GR positive control (pancreatic section showing CCKBR/GR positivity in islets cells), and (c) negative control (Primary antibody was replaced with TBS). CCKAR = Cholecystokinin type-A receptor, CCKBR/GR = Cholecystokinin type-B receptor/gastrin receptor. One hundred micrometer rulers are provided for scale

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Briefly, all sections were dewaxed and rehydrated in xylene and graded alcohol, respectively and microwaved in citrate buffer (pH = 6.0) for 15 min. Primary antibody incubation (at 1:200 dilutions) was performed for overnight at 4°C. After washing with TBS, sections were incubated with multilink for 30 min and washed, followed by secondary antibody incubation for 30 min. Color was developed using diamino benzidine as the chromogen and slides were counter stained with Mayer's hematoxylene and mounted with DPX mount.

Evaluation of staining pattern

All slides were observed under a light microscope to record the presence or absence of staining and color intensity. Immunohistochemical staining was scored as strong, +3 (at least as strong as the positive control); moderate, +2 (weaker than positive control, but visible in a low power field); weak, + (visible only in high power field); no staining, −. Moderate and strong intensity were considered significant positive staining.[15]

Statistical analysis

All the statistical analysis were executed utilizing the”Statistical Package for Social Sciences version 16 (SPSS, Chicago, IL, USA)” and “MSTAT.” And the difference was considered significant when P < 0.05.


 > Results Top


Positive immunohistochemical staining of CCKAR and CCKBR/GR were found mainly in cytosol of tumor cells and nonneoplastic cells in our study.

Stomach cancer

The mean age of SC and BGD patients was 59.07 ± 11.99 years and 46.88 ± 10.30 years, respectively. The male to female ratio for SC was 2:1 and for BGD was 1.7:1.

The CCKAR expression was detected in 20.0% of BGD and in 18.2% of SC tissue samples, [Figure 2]a and [Figure 2]b while CCKBR/GR expression was detected in 48.0% BGD and in 58.2% SC tissue samples [Figure 2]c,[Figure 2]d,[Figure 2]e. The frequency of CCKAR and CCKBR/GR did not differ significantly among the cancer and control [Table 1]. Correlations of CCKAR and CCKBR/GR expression with a clinical history of SC patients were presented in [Table 2]. Both CCKAR and CCKBR did not revealed any significant association with age, gender, stage, and grade of the SC patient except, CCKBR/GR expression was significantly high in well differentiated (WD) and moderately differentiated (MD) tissue samples (72.4%) as compared to poorly differentiated (PD) samples (42.3%).
Figure 2: CCKAR positivity in stomach: (a) In chronic gastritis and (b) in PD carcinoma, CCKBR positivity in stomach: (c) In intestinal type stomach cancer, (d and e) in SRC (PD) of stomach cancer. CCKAR = Cholecystokinin type-A receptor, PD = Poorly differentiated, CCKBR/GR = Cholecystokinin type-B receptor/gastrin receptor, SRC = Signet ring cell carcinoma. One hundred micrometer rulers are provided for scale

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Table 1: Distribution of CCKAR and CCKBR/GR expression in SC and BGD tissue samples

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Table 2: Correlation of CCKAR and CCKBR/GR expression with clinical history of SC patients

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Pancreatic cancer

Mean age of the PC patients was 58.84 ± 17.99 years and the male to female ratio was 1.7:1. CCKAR expression was significantly high in PC (65.8%) as compared to normal pancreas tissue samples (30.0%) [Table 3] and [Figure 3]a,[Figure 3]b,[Figure 3]c,[Figure 3]d. On the other hand, 60.0% of normal pancreas tissue samples showed CCKBR/GR expression which was significantly higher than that seen in PC tissue samples (18.4%) [Table 3], [Figure 3]e and [Figure 3]f. Correlation of CCKBR/GR and CCKAR expression with age, gender, differentiation, and clinical stage of PC patients did not show any significant association [Table 4]. Though, the frequency of CCKAR positivity was found to increase with increasing stage. On the other hand, expression of CCKBR/GR was found to decrease with increasing stage of PC patients and none of the stage IV patients showed its expression.
Table 3: Distribution of CCKAR and CCKBR/GR expression amongst pancreatic cancer and normal tissue samples

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Figure 3: CCKAR positivity in pancreas: (a) In chronic pancreatitis, (b and c) in periampulary carcinoma and (d) in pancreatic ductal carcinoma, CCKBR/GR positivity in pancreas: (e) In periampullary carcinoma (f) in pancreatic ductal carcinoma. CCKAR = Cholecystokinin type-A receptor, CCKBR/GR = Cholecystokinin type-B receptor/gastrin receptor. One hundred micrometer rulers are provided for scale

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Table 4: Correlation of CCKAR and CCKBR/GR expression with clinical history of pancreatic cancer patients

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 > Discussion Top


Gs is well known pro-proliferative, anti-apoptotic hormone and its long-standing condition is associated with malignant progression.[23] It maintains autocrine/paracrine growth pathways in gastrointestinal cancer cells by CCKBR/GR isoforms.[24] CCK, an important mediator of pancreatic growth,[24] is also responsible for pancreatic hyperplasia via CCKAR.[25],[26] Thus, CCK and Gs receptor subtypes seem to be the fundamentals key to unravel controversial responses of CCK and Gs in normal cell physiology and cancer development. Hence, evaluation of their respective cellular location in normal and cancerous organs is warranted.

We demonstrated CCKAR expression only in a minority of SC (18.2%) and BGD (20%) tissue samples. The frequency of CCKAR positivity in our study was less than previously reported (36% or 63%) by Okada et al.,[17] and Clerc et al.,[14] using revrese transcriptase polymerase chain reaction (RT-PCR). Another study failed to detect CCKAR expression in SC.[16]

CCKBR/GR expression was found in both BGD samples (58.2%) and SC (48%) samples. This is in concordance with previous studies, showing a similar frequency of CCKBR/GR expression (≈56%) in SC by IHC, suggesting a trophic action of Gs in stomach by autocrine/paracrine way.[9],[27] In normal stomach, CCKBR/GR is expressed primarily in the parietal cells.[28] CCKBR/GR positivity has also been documented on parietal and enterochromaffin-like cells, in glands with pseudopyloric metaplasia (focally) and foveolar epithelium with intestinal metaplasia.[29] Other studies have reported somewhat higher frequency of CCKBR/GR expression in SC.[9],[29],[30],[31] On the other hand, Okada et al.,[17] Reubi et al.,[16] and Matsushima et al.[32] have detected these receptors only in minority (7%) of cancer. Similar to previous studies, we found a significant association of CCKBR/GR expression with differentiated tumors (WD and MD).[15],[27],[29] This may be due to the fact that dedifferentiation and loss of tissue specific receptors may more often be associated with PD type of cancer.[17] CCKBR/GR expression was not linked to the stage of the SC patient though it appeared to decrease with increasing stage. Hur et al. also failed to find any significant association between CCKBR and prognostic factors for SC.[15]

In our study, CCKAR expression was found to be significantly increased (P = 0.047), while CCKBR/GR expression was found to be significantly decreased (P = 0.016) in PC than normal pancreas tissue samples. Our results are coherent with previous studies suggesting increased expression of CCKAR as the mechanism contributing significant growth to pancreatic malignancies. Consequently, CCKAR was suggested to be a marker of pancreatic carcinogenesis in humans.[19],[20] Goetze et al. have also shown a similar frequency of CCKAR expression (67%) in PC.[21] Higher expression of CCKBR/GR in normal tissue samples is consistent with the observation that CCKBR/GR predominates in normal pancreas with CCKAR expression only on nerves, islets, or stroma [19] and CCK induced pancreatic secretion is mediated by neurogenic mechanism via vagal afferent pathway, instead of direct activation of pancreatic acinar cells.[33] Tang et al. also showed CCKBR/GR only in normal pancreas and none of the PCs,[34] though, Ji et al. have shown only inadequate expression level these receptors in human pancreatic acinar cells.[35] In contrary, some studies have provided evidence for a growth promoting the role of Gs and its receptor in human pancreatic carcinoma.[21],[36],[37],[38]

Though, CCKAR expression was found to increase with increasing stage of PC while CCKBR/GR showed an inverse relation, we did not observe any significant prognostic effect of the expression profile of CCKAR and CCKBR/GR in PC. The human PC cells show different behavioral response to the hormone in vivo and in vitro. Accordingly, the trophic effect of CCK and Gs in human cancer has been intensively studied, and many reports have been published.[39],[40],[41] Moreover, the cellular location and characteristics of the receptor type associated with pancreatic function vary from species to species and can shift in a single species during development and malignant transformation.[42] Since, the relative role of these hormones and detailed characterization of CCK receptor subtype in human pancreatic carcinoma is lacking our result seems to be of therapeutic importance with selective and appropriate hormone and receptor antagonist.

Most of the previous studies are based on RT-PCR that is unable to ascertain the cellular site for receptor expression and do not exclude receptor expression in nonmalignant tissue. Further, all the transcribed m-RNA may be not translated into protein. Receptor autoradiography study also has its limitations due to lower-sensitivity, specificity, and resolution. We have provided the true localization of expression pattern of CCKAR and CCKBR in SC and PC. The discrepancy in our results may be explained in part, due to different sensitivity of the methodology used to analyze protein expression.


 > Conclusion Top


Our study showed higher expression of CCKBR/GR in SC rather than CCKAR. Our results also suggested that cancer progression from normal pancreas may lead to loss of CCKBR/GR expression and increased expression of CCKAR. The presence of CCKAR and CCKBR/GR in most of the pancreatic carcinoma and SC, respectively, may provide the opportunity for the use of appropriate receptor antagonist or a cytotoxic toxin linked to specific ligand of these receptors for treatment of these cancers. Since the trophic response of hormone to its target cell is influenced by the presence and degree of expression of the corresponding receptor, these results may have diagnostic and therapeutic implications. However, further work with many more samples focusing the functional characterization of CCK, Gs and their receptors in tumor induction and progression is warranted.

Financial support and sponsorship

Nil

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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    Figures

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    Tables

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