Inhibition of cMET in an experimental model of pancreatic cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 185-185
Author(s):  
Sven A. Lang ◽  
Franziska Brandes ◽  
Edward K. Geissler
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Pancreatic Cancer ◽  
Oncogenic Signaling

185 Background: In human pancreatic cancer, expression of cMET is associated with poor survival. So far, activation/expression of cMET by hepatocyte growth factor (HGF) has been shown to induce proliferation and motility in cancer cells. Therefore, we hypothesized that inhibition of cMET in human pancreatic cancer cell lines impairs oncogenic signaling and tumor growth. Methods: Pancreatic cancer cell lines (HPAF-II, MiaPaCa2, L3.6pl, BxPC3, Panc02) and the cMET inhibitor INC280 (Novartis Oncology, Basel) were used. MiaPaCa2 and L3.6pl pancreatic cancer cells were grown with gemcitabine up to 500 and 250 nM, respectively (then called MiaPaCa2(G500) and L3.6pl(G250)). MTT and Boyden Chamber assays were used to determine effects of INC280 on growth and motility of cells in vitro. Expression of growth factor receptors, activation of signaling intermediates and expression of transcription factors were assessed by Western blotting. Finally, in vitro results were validated in an orthotopic tumor model using L3.6pl pancreatic cancer cell line. Results: All pancreatic cancer cell lines showed expression of cMET. In vitro treatment of cancer cells with INC280 led to a minor, dose-dependent inhibition of growth even when cells were supplemented with HGF. In contrast, migration assays showed a significant reduction of cancer cell motility upon INC280 when cells were stimulated with HGF (P<0.05). Regarding oncogenic signaling, INC280 led to inhibition of HGF-induced phosphorylation of AKT, ERK and FAK. In addition, c-Myc expression was diminished in cancer cells. Interestingly, gemcitabine resistant cell line MiaPaCa2(G500) showed higher cMET expression levels compared to the normal MiaPaCa2. Stimulation of MiaPaCa2(G500) with HGF led to strong induction of oncogenic signaling and tumor cell motility, an effect that was significantly diminished by INC280. Moreover, results from in vivo experiments show that therapy with INC280 (10 mg/kg/d) significantly reduces tumor growth as determined by final tumor weight (P<0.05). Conclusions: In pancreatic cancer cell lines, targeting cMET with INC280 abrogates oncogenic signaling in vitro and impairs tumor growth in vivo. Therefore, the concept of cMET inhibition warrants further preclinical evaluation.

Identification and characterization of CCK-B/gastrin receptors in human pancreatic cancer cell lines

1994 ◽  
Vol 266 (1) ◽  
pp. R277-R283 ◽  
Author(s):  
J. P. Smith ◽  
G. Liu ◽  
V. Soundararajan ◽  
P. J. McLaughlin ◽  
I. S. Zagon
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Pancreatic Cancer ◽  
Human Pancreatic Cancer Cell ◽  
Pancreatic Cancer Cells

The gastrointestinal peptide cholecystokinin (CCK) is known to stimulate growth of human pancreatic cancer in a receptor-mediated fashion. The purpose of this study was to characterize the receptor responsible for the trophic effects of CCK in cancer cells. With the use of homogenates of PANC-1 human pancreatic cancer cells grown in vitro, the binding characteristics and optimal conditions of radiolabeled selective CCK-receptor antagonists ([3H]L-365,260 and [3H]L-364,718) were examined. Specific and saturable binding was detected with [3H]L-365,260, and Scatchard analysis revealed that the data were consistent for a single site of binding with a binding affinity of 4.3 +/- 0.6 nM and a binding capacity (Bmax) of 283 +/- 68 fmol/mg protein in log phase cells. Binding was dependent on protein concentration, time, temperature, and pH and was sensitive to Na+, K+, Mg2+, and ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. In contrast to log phase cells, Bmax decreased by 80 and 92% in confluent and postconfluent cultures, respectively. Subcellular fractionation studies revealed that binding was in the membrane fraction. Competition experiments indicated that L-365,260 and gastrin were more effective at displacing the radiolabeled L-365,260 than CCK. No binding was detected with the CCK-A antagonist [3H]L-364,718. Assays performed with [3H]L-365,260 on five additional human pancreatic cancer cell lines in vitro and tumor tissue from xenografts in nude mice also revealed specific and saturable binding. These results provide the first identification of a CCK-B/gastrin receptor in human pancreatic cancer cells and tumors and explain the effects of CCK on the growth of this malignancy.

scholarly journals C-REV Retains High Infectivity Regardless of the Expression Levels of cGAS and STING in Cultured Pancreatic Cancer Cells

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1502
Author(s):  
Daishi Morimoto ◽  
Shigeru Matsumura ◽  
Itzel Bustos-Villalobos ◽  
Patricia Sibal ◽  
Toru Ichinose ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Pancreatic Cancer ◽  
Expression Levels ◽  
Anti Cancer ◽  
Sting Pathway

Oncolytic virus (OV) therapy is widely considered as a major breakthrough in anti-cancer treatments. In our previous study, the efficacy and safety of using C-REV for anti-cancer therapy in patients during stage I clinical trial was reported. The stimulator of interferon genes (STING)–TBK1–IRF3–IFN pathway is known to act as the central cellular host defense against viral infection. Recent reports have linked low expression levels of cGAS and STING in cancer cells to poor prognosis among patients. Moreover, downregulation of cGAS and STING has been linked to higher susceptibility to OV infection among several cancer cell lines. In this paper, we show that there is little correlation between levels of cGAS/STING expression and susceptibility to C-REV among human pancreatic cancer cell lines. Despite having a responsive STING pathway, BxPC-3 cells are highly susceptible to C-REV infection. Upon pre-activation of the STING pathway, BxPc-3 cells exhibited resistance to C-REV infection. However, without pre-activation, C-REV completely suppressed the STING pathway in BxPC-3 cells. Additionally, despite harboring defects in the STING pathway, other high-grade cancer cell lines, such as Capan-2, PANC-1 and MiaPaCa-2, still exhibited low susceptibility to C-REV infection. Furthermore, overexpression of STING in MiaPaCa-2 cells altered susceptibility to a limited extent. Taken together, our data suggest that the cGAS–STING pathway plays a minor role in the susceptibility of pancreatic cancer cell lines to C-REV infection.

In vitro chemosensitivity of human pancreatic cancer cell lines

1996 ◽  
Vol 20 (3) ◽  
pp. 185-190 ◽  
Author(s):  
Yasunori Sawabe ◽  
Hisakazu Yamagishi ◽  
Nozomi Yamaguchi ◽  
Yoshiro Yamamura ◽  
Takahiro Oka
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Pancreatic Cancer ◽  
Human Pancreatic Cancer Cell ◽  
In Vitro Chemosensitivity

Effect of apricoxib, a novel COX-2 inhibitor, on the efficacy of standard therapy in human pancreatic cancer cell lines in vitro and in vivo.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 227-227
Author(s):  
A. R. Kirane
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Pancreatic Cancer ◽  
Human Pancreatic Cancer Cell ◽  
Cox 2

227 Background: Gemcitabine-erlotinib is standard of care (SOC) for pancreatic cancer, but this regimen can still be improved upon with regard to prolonging patient survival. Cyclo-oxygenase-2 (COX-2) is overexpressed in pancreatic cancer and implicated in pancreatic tumor progression. Inhibition of COX-2 decreases tumor growth, augments the activity of both gemcitabine and EGFR inhibition, and may play a role in preventing or reversing EMT. This study characterized the effects of COX-2 inhibition on pancreatic cancer cell lines and determined if the addition of apricoxib enhances sensitivity to chemotherapy. Methods: Baseline EGFR and COX-2 expression were determined in 7 human pancreatic cancer cell lines and functional responses measured by changes in phospho-EGFR (p-EGFR) and prostaglandin E2 (PGE2) production by ELISA. Cytotoxicity was determined for gemcitabine, erlotinib, and apricoxib independently and in combination by MTS assay. The effect of SOC therapy alone or in combination with 10 or 30 mg/kg apricoxib PO on AsPC-1 and Colo357 tumors in vivo was determined in SCID mice bearing established orthotopic xenografts. Tissue was analyzed by IHC and VEGF levels were determined by ELISA. Results: All lines expressed EGFR and COX-2, but expression alone was not predictive of p-EGFR level, PGE2 production, or response to drug therapy. In vitro, AsPC-1 cells had negligible COX-2 activity, whereas Colo357 cells displayed high levels of COX-2 and PGE2 production. Cell growth and COX-2 activity decreased in all cell lines in the presence of apricoxib and addition of apricoxib improved response to chemotherapy. In vivo, addition of apricoxib to SOC significantly reduced primary tumor growth and almost eradicated metastases in mice bearing Colo357 but not AsPC-1 xenografts. Plasma VEGF levels were unaltered by apricoxib treatment in AsPC-1-bearing animals but were suppressed to undetectable levels in Colo357-bearing animals. Markers of EMT were significantly decreased in animals treated with apricoxib. Conclusions: Apricoxib enhances the efficacy of gemcitabine and erlotinib in vitro and in vivo and warrants clinical evaluation in patients with pancreatic cancer. A phase II study is ongoing. No significant financial relationships to disclose.

Gastrin regulates growth of human pancreatic cancer in a tonic and autocrine fashion

1996 ◽  
Vol 270 (5) ◽  
pp. R1078-R1084 ◽  
Author(s):  
J. P. Smith ◽  
A. Shih ◽  
Y. Wu ◽  
P. J. McLaughlin ◽  
I. S. Zagon
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Pancreatic Cancer ◽  
Growth Media ◽  
Human Pancreatic Cancer Cell ◽  
Cell Extracts

The gastrointestinal peptides gastrin and cholecystokinin (CCK) stimulate growth of human pancreatic cancer through a CCK-B/gastrin- like receptor. In the present study we evaluated whether growth of human pancreatic cancer is endogenously regulated by gastrin. Immunohistomical examination of BxPC-3 cells and tumor xenografts revealed specifc gastrin immunoreactivity. Gastrin was detected by radioimmunoassay in pancreatic cancer cell extracts and in pancreatic cancer cell extracts and in the growth media. With use of reverse-transcriptase polymerase chain reaction gastrin gene expression was detected in both cultured BxPC-3 cancer cells and transplanted tumors, as well as seven addition human pancreatic cancer cell lines. Growth of BxPC-3 human pancreatic cancer cell in serum-free medium was inhibited by the addition of the CCK-B/gastrin receptor antagonist L-365,260, and gastrin treatment reversed the inhibitory effect of the antagonist. A selective gastrin antibody (Ab repressed growth of BxPC-3 cells. Gastrin immunoreactivity was detected in fresh human pancreatic cancer specimens but not in normal human pancreatic tissue. These data provide the first evidence that growth of a human pancreatic cancer is tonically stimulated by the autocrine production of gastrin. Evidence for the ubiquity of this system was provided by the detection of gastrin gene expression in multiple human pancreatic cancer cell lines and detection of gastrin in cell lines and fresh pancreatic tumors.

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