cholecystokinin and Liver-Neoplasms

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated deaths worldwide. Treatment with immune checkpoint antibodies has shown promise in advanced HCC, but the response is only 15-20%. We discovered a potential target for the treatment of HCC, the cholecystokinin-B receptor (CCK-BR). This receptor is overexpressed in murine and human HCC and not in normal liver tissue. Mice bearing syngeneic RIL-175 HCC tumors were treated with phosphate buffer saline (PBS; control), proglumide (a CCK-receptor antagonist), an antibody to programmed cell death protein 1 (PD-1Ab), or the combination of proglumide and the PD-1Ab. In vitro, RNA was extracted from untreated or proglumide-treated murine Dt81Hepa1-6 HCC cells and analyzed for expression of fibrosis-associated genes. RNA was also extracted from human HepG2 HCC cells or HepG2 cells treated with proglumide and subjected to RNA sequencing. Results showed that proglumide decreased fibrosis in the tumor microenvironment and increased the number of intratumoral CD8+ T cells in RIL-175 tumors. When proglumide was given in combination with the PD-1Ab, there was a further significant increase in intratumoral CD8+ T cells, improved survival, and alterations in genes regulating tumoral fibrosis and epithelial-to-mesenchymal transition. RNAseq results from human HepG2 HCC cells treated with proglumide showed significant changes in differentially expressed genes involved in tumorigenesis, fibrosis, and the tumor microenvironment. The use of the CCK receptor antagonist may improve efficacy of immune checkpoint antibodies and survival in those with advanced HCC.

Topics: Animals; Carcinoma, Hepatocellular; Cholecystokinin; Fibrosis; Immune Checkpoint Inhibitors; Liver Neoplasms; Mice; Proglumide; Receptors, Cholecystokinin

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Chemokines, CC; Cholecystokinin; Diet, High-Fat; Disease Models, Animal; Female; Gene Knockout Techniques; Hepatic Stellate Cells; Humans; Liver; Liver Neoplasms; Male; Mice; Non-alcoholic Fatty Liver Disease; Proglumide; Receptor, Cholecystokinin B

Neuroendocrine tumors in the pancreas and the gastrointestinal tract may secrete hormones which cause specific syndromes. Well-known examples are gastrinomas, glucagonomas, and insulinomas. Cholecystokinin-producing tumors (CCKomas) have been induced experimentally in rats, but a CCKoma syndrome in man has remained unknown until now.. Using a panel of immunoassays for CCK peptides and proCCK as well as for chromogranin A, we have examined plasma samples from 284 fasting patients with gastroenteropancreatic neuroendocrine tumors. In hyperCCKemic samples, plasma CCK was further characterized by chromatography.. One of the patients displayed gross hyperCCKemia. She was a 58-year old woman with a pancreatic endocrine tumor, liver metastases, 500-1000-fold elevated basal CCK concentration in plasma, diarrhea, severe weight loss, recurrent peptic ulcer and bilestone attacks from a contracted gallbladder. The CCK concentrations in plasma were not affected by resection of the pancreatic tumor, but decreased to normal after hemihepatectomy with removal of the metastases.. A CCKoma syndrome with severe hypersecretion of CCK exists in man. The duodenal ulcer disease and diarrhea with permanently low gastrin in plasma suggest that CCKomas may mimic gastrinoma-like symptoms, because CCK peptides are full agonists of the gastrin/CCK-B receptor.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Child; Cholecystokinin; Denmark; Female; Gastrinoma; Gastrins; Humans; Intestinal Neoplasms; Liver Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Pancreas; Pancreatic Neoplasms; Rats; Stomach Neoplasms; Young Adult

Topics: Animals; Cholecystokinin; Chromogranin A; Diagnosis, Differential; Fatal Outcome; Female; Gastrins; Humans; Liver; Liver Neoplasms; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

A 68-year-old female with colorectal cancer developed a metachronous isolated fluorodeoxyglucose-avid (FDG-avid) segment 5/6 gallbladder fossa hepatic lesion and was referred for percutaneous ablation. Pre-procedure computed tomography (CT) images demonstrated a distended gallbladder abutting the segment 5/6 hepatic metastasis. In order to perform ablation with clear margins and avoid direct puncture and aspiration of the gallbladder, cholecystokinin was administered intravenously to stimulate gallbladder contraction before hydrodissection. Subsequently, the lesion was ablated successfully with sufficient margins, of greater than 1.0 cm, using microwave with ultrasound and FDG PET/CT guidance. The patient tolerated the procedure very well and was discharged home the next day.

Topics: Aged; Catheter Ablation; Cholagogues and Choleretics; Cholecystokinin; Dissection; Female; Fluorodeoxyglucose F18; Gallbladder; Humans; Liver; Liver Neoplasms; Multimodal Imaging; Positron-Emission Tomography; Radiography, Interventional; Radiopharmaceuticals; Tomography, X-Ray Computed

To study the therapeutic effect of recombinant plasmid pcDNA3.1/CCK containing porcine gene of cholecystokinin (CCK).. The confirmed fragments of porcine CCK cDNA were cloned into the pcDNA3.1 vector. Recombinant plasmid pcDNA3.1/CCK was injected into the muscles of Syrian golden hamsters. Before gene transfer, orthotopic tumor model and liver metastasis model of hamster pancreatic cancer have been established by injection of 1 x 10(6) PGHAM-1 cells into the pancreas and spleen of golden hamsters. Then the CCK expression in vivo and the tumor inhibiting effect were analyzed.. Our data revealed that recombinant plasmid pcDNA3.1/CCK had long-term expression in hamsters and induced generation of specific antibody. Antibody level correlated with the number of inoculations. Compared to the control, significant reduction in tumor volume, decrease in number of liver metastasis and a remarkable enhancement of survival rate were detected.. Intramuscular injection of recombinant plasmid pcDNA3.1/CCK has significant antitumor and antimetastatic effect in vivo.

Topics: Animals; Antibodies; Apoptosis; Cell Proliferation; Cholecystokinin; Cricetinae; Female; Gene Expression; Genetic Therapy; Injections; Liver Neoplasms; Muscle, Skeletal; Pancreatic Neoplasms; Plasmids; RNA, Messenger; Swine; Xenograft Model Antitumor Assays

Effects of caerulein (CCK), 5-FU and CCK antagonist, loxiglumide (CR1505), were studied on the growth of human pancreatic cancer cell line, KP-1 N, in vitro. And effects of UFT and CR 1505 were also studied on liver metastasis in nude mice. The growth of KP-1 N was stimulated approximately 40% by addition of 10(-10) M of CCK in vitro. CR1505 antagonized the action of CCK, that is, the 40% growth rate increase was suppressed by addition of 25 microM of CR1505. Moreover, the growth rate of the cells dose-dependently decreased by the addition of CR1505. 5-FU also dose-dependently inhibited the growth of KP-1 N in culture. 5-FU additionally decreased the growth rate of KP-1 N in combination with CR1505. A number of metastatic nodules were found in the liver of nude mice a month after injections of KP-1 N cells into the spleen CR1505 suppressed the liver metastasis in nude mice which were administered with UFT. These results suggest that CR1505 would be useful for the treatment of human pancreatic cancer in combination with UFT.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Cholecystokinin; Humans; Liver Neoplasms; Mice; Mice, Nude; Pancreatic Neoplasms; Proglumide; Tegafur; Tumor Cells, Cultured; Uracil

The Human pancreatic carcinoma cell line KP-1N and its clone KP-1NL which has a high rate of liver metastasis were established. Ki-ras DNA point mutation on the codon 12 was found. The growth of KP-1N was stimulated by a physiological range of concentration (10(-11)-10(-10) M) of cholecystokinin and the increase was inhibited by the addition of a cholecystokinin receptor antagonist (CR 1505). Daily injections of CR 1505 (35 mg/kg) diminished the number of tumor colonies in the liver that were formed after an intrasplenic injection of the highly liver metastatic KP-1NL cells. These results suggest that cholecystokinin antagonists may be useful as growth inhibitors for some pancreatic cancer.

Topics: Adenocarcinoma; Animals; Ceruletide; Cholecystokinin; Humans; In Vitro Techniques; Liver Neoplasms; Mice; Mice, Nude; Pancreatic Neoplasms; Proglumide; Tumor Cells, Cultured

Cholecystokinin (CCK) inhibits pancreatic cancer but not hepatic tumor induction by N-nitrosobis (2-oxopropyl) amine (BOP) in hamsters when administered with or shortly before BOP. In this study, we evaluated the capability of sulfated CCK-8 to inhibit DNA alkylation in the hamster pancreas. We examined the pattern of O6-methylguanine (G6-Me) and N7-methylguanine (G7-Me) in pancreatic ductal, acinar and liver tissues from Syrian hamsters treated with a single dose of BOP (20 mg/kg s.c.) and with five s.c. injections of CCK-8 (200 pM/kg, 30 min apart). The first CCK injection was given either 90 min before, or together, or 3 h after POP administration. The amount of G6-Me in liver DNA did not differ significantly. We observed a decrease of G7-Me in the liver of the group treated with CCK together with POP as compared to POP alone (P less than 0.005). Lower amounts of G6-Me were found in ductal preparations (P less than 0.01) of the animals treated with CCK before POP as compared to POP alone. CCK also modified the pattern of alkylation in the acinar tissue, but without a clear relationship with the timing of administration. The results suggest that the inhibitory effect of CCK-8 on pancreatic carcinogenicity of BOP could be related to its capability to modify DNA alkylation by yet unknown mechanisms.

Topics: Alkylation; Animals; Cholecystokinin; Cricetinae; DNA; Guanine; Liver Neoplasms; Nitrosamines; Pancreas; Sincalide

Gastrointestinal hormones regulate growth of cancers as well as normal tissues. We investigated whether long-term cholecystokinin (CCK) administration might affect growth or metabolism of human tumors xenografted in nude mice. In each experiment, approximately 20 nude mice bearing subcutaneous xenografts of the particular cancer line being studied were used. Half received CCK and half received saline solution intraperitoneally twice daily for 14 days. Tumor volume and body weight were measured every 3 days. If the tumors produced marker substances, these were measured in nude mouse serum and also in the xenografts. Tumor growth was significantly retarded by CCK in two of the six cancers studied. In each case, DNA, RNA, and protein reflected tumor volumes. In one of these tumors (SLU 077), serum carcinoembryonic antigen (CEA) levels paralleled the tumor volumes. In another tumor (SLU 132), serum CEA levels and tumor immunolabeling for CEA and pancreatic oncofetal antigen increased in response to CCK administration, whereas tumor volumes did not. These findings suggest that exogenous highdose CCK altered the growth and metabolism in two of six human cancers studied.

Topics: alpha-Fetoproteins; Animals; Antigens, Neoplasm; Biliary Tract Neoplasms; Biomarkers, Tumor; Carcinoembryonic Antigen; Cell Line; Cholecystokinin; Gastrointestinal Neoplasms; Humans; Liver Neoplasms; Male; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Stomach Neoplasms

A liver metastasis (MSL) with a remarkable in vitro proliferation potential has been identified in an NEDH rat carrying a transplantable x-ray-induced islet cell tumor. Two insulin-secreting cell lines, MSL-G and MSL-H, with doubling times of 3-5 d were established by repeated limiting dilution cloning. In vivo inoculation of MSL-G cells induced severe hypoglycemia caused by a small but highly heterogeneous tumor as revealed by immunocytochemistry. Whereas most cells stained for the islet hormones, insulin, glucagon, and somatostatin, clustered cells were discovered to contain cholecystokinin (CCK). Additional in vitro-limiting dilution cloning, followed by immunocytochemical characterization, clearly demonstrated the capacity of single cell clones to simultaneously express the same four hormones. Radioimmunoassays with a panel of site-specific antisera of culture supernatants and purified cell extracts showed the MSL-G2 cells to produce, store, and secrete readily detectable amounts of processed and unprocessed CCK. Gastrin was not detected while coexpression of glucagon and CCK were demonstrated. Mutant clones selected for resistance to 6-thioguanine (frequency, 2 X 10(-7] and checked for HAT (hypoxanthine, aminopterin, thymidine) sensitivity retained the capacity for multi-hormone expression. We propose that the MSL tumor contains pluripotent endocrine stem cells. The MSL tumor and the MSL-G2 cells in particular will allow studies of not only CCK biosynthesis and processing but also of mechanisms involved in tumor and islet cell differentiation.

Topics: Adenoma, Islet Cell; Animals; Cholecystokinin; Glucagon; Insulin; Liver Neoplasms; Pancreatic Neoplasms; Rats; Somatostatin

A clinicopathological and immunohistochemical study was carried out on 32 cases of neuroendocrine tumors of the rectum. Typical carcinoids consisted of 27 cases, histologically showing uniform round to columnar cells forming solid alveolar nests and ribbon-like or trabecular arrangement. Neuroendocrine carcinomas consisted of 5 cases in which tumor cells with prominent nuclear atypism were arranged in a ribbon-like or trabecular fashion and formed gland-like structures. There were also small round tumor cells resembling lymphocytes. The prognosis of neuroendocrine carcinomas is very poor with marked tumor invasion of lymphatics and veins resulting in liver metastases and death within one year after operation. Thirty cases out of the 32 showed a positive argyrophil reaction, while immunohistochemistry of 29 cases revealed more than one peptide hormone in 23 cases. The most common hormone was somatostatin being present in 18 of the 23 tumors and glucagon in 16 of the 23 tumors. Gastrin/CCK and calcitonin were proven in 6 of the 23 tumors and in 4 of the 23 tumors, respectively. On the other hand, more than two hormones was present in 15 of the 23 tumors examined. Histologically, neuroendocrine tumors have a very wide spectrum. Histogenetically, typical carcinoids and neuroendocrine carcinomas are considered to be of the same origin with the former showing morphological and functional differentiation to endocrine cells and the latter being more undifferentiated.

Topics: Adult; Aged; Calcitonin; Carcinoid Tumor; Cholecystokinin; Female; Gastrins; Glucagon; Humans; Liver Neoplasms; Male; Middle Aged; Prognosis; Rectal Neoplasms; Somatostatin

Cholecystokinin (CCK) has trophic actions on abdominal viscera. To determine whether CCK enhances malignant growth in a similar fashion, we gave hamsters CCK together with di-isopropanol nitrosamine (DIPN), a known pancreatic and hepatic carcinogen. After 40 weeks of injections, those animals receiving both DIPN and CCK developed no cancers, while the control animals receiving DIPN alone developed pancreatic and hepatic carcinomas. This suggests that CCK inhibits carcinogenesis in this model. Although the mechanism of this effect is unknown, some implications for human carcinogenesis are testable by currently available methods.

Topics: Animals; Cholecystokinin; Cricetinae; Liver Neoplasms; Male; Mesocricetus; Neoplasms, Experimental; Nitrosamines; Pancreatic Neoplasms

Topics: Achlorhydria; Adenoma, Islet Cell; Adult; Animals; Bile; Biological Assay; Cholecystokinin; Diarrhea; Dogs; Female; Gastric Acidity Determination; Glucagon; Histamine; Humans; Hypokalemia; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Secretin; Tissue Extracts