Does Neoplastic Cholecystokinin Expression Reflect the Embryonal Pattern of the Protein? A Study in Human Pancreas

Abstract

Aim: To determine the immunoreactivity of cholecystokinin (CCK) during the development of the human fetal pancreas and pancreatic adenocarcinoma, given that, CCK positive cells were demonstrated either in its embryonic anlage or in pancreatic cancer. In order to obtain possible parallels in the expression pattern of neoplastic cells in adults (well – moderately – poorly differentiated), we investigated the pattern of CCK expression in the pancreatic tissue during the various stages of development and compared these with the proliferation of tissue assessed by proliferating cell nuclear antigen (PCNA) immunohistochemistry. Experimental design: Tissue sections from 15 pancreatic fetal specimens, and equal number of ductal adenocarcinoma specimens, were assessed using immunohistochemical methods for CCK. Results: The density of positive cells in the primitive exocrine ductal walls and outgrowing buds was significantly higher than the relevant density in the neoplastic pancreatic tissue of mixed (ductal – endocrine) and pure ductal type (p1=0.004, p2<0.0005, p3<0.0005 and p4=0.023 respectively). The above values were estimated from 20th to 22nd weeks of gestation. There was no significant difference in the density of positive cells in the islet cell epithelium from 25–30 weeks, and the neoplastic tissue of mixed (p5=0.10) and pure ductal type (p6=0.15). Conclusions: The immunostaining for CCK identifies a subgroup of pancreatic ductal adenocarcinomas with a neuroendocrine component (initially considered as pure ductal tumors), and mixed ductal-endocrine tumors. This pattern of expression in neoplasms recapitulates the normal pattern during the embryonal development of the organ, and may be important for the development of new therapeutic approaches with eventual clinical utility.

Role of endogenous cholecystokinin on growth of human pancreatic cancer

“…CCK immunoreactivity was found predominantly in the cytoplasm but slight nuclear immunoreactivity also observed. This pattern of staining previously described by Tamiolakis and colleagues (17) appears to be characteristic of CCK immunoreactivity.…”

“…The current report confirms and the expression of CCK peptide or mRNA in pancreatic cancer (17) and is the first report documenting the use of RNAi technology to down regulate CCK in this cancer. Our study validates two novel RNAi targets sites within the CCK mRNA: the mRNA sequences beginning at nucleotide −6 and at nucleotide +141.…”

“…Although conflicting publications both support(17) and oppose (16) the presence of endogenous CCK in human pancreatic cancer by immunohistochemistry, we demonstrate and confirm both the presence and quantity of CCK mRNA and peptide in pancreatic cancer by sensitive cellular and molecular techniques. Autocrine gastrin and its receptors have been known to play a role in proliferation of pancreatic cancer (3, 23) but the role of CCK has not been directly examined.…”

“…Although this group found high levels of α-amidated gastrins and its precursor forms in 74% of the pancreatic tumor specimens, CCK was not found (16). In contrast, Tamiolakis and coworkers (17) reported CCK immunoreactivity in ten out of fifteen surgical specimens with the CCK positive cells identified in the duct-like structures of the pancreatic tumors. Therefore, the literature has conflicting reports on whether pancreatic cancer cells synthesize CCK and whether this peptide serves a physiological role in the stimulation of cancer cell growth.…”

Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice

“…Researchers have used a decapeptide analog of CCK, cerulein, to accelerate pancreatic carcinogenesis in animal models, such as the nitrosamine model [4] or in the KRAS transgenic mouse model [5]. Gastrin is found in the fetal pancreas [6, 7], but levels rapidly decrease to zero after birth in the pancreas, and gastrin expression is then only detected in the stomach [8]. However, gastrin is re-expressed during pancreatic carcinogenesis in early pancreatic intraepithelial neoplasia (PanIN) lesions [9] and is overexpressed in pancreatic cancer where it regulates the growth of pancreatic cancer by an autocrine mechanism [10, 11].…”