scholarly journals In vivo bioluminescence tomography-guided radiation research platform for pancreatic cancer: an initial study using subcutaneous and orthotopic pancreatic tumor models

2020 ◽  
Author(s):  
Zijian Deng ◽  
Xiangkun Xu ◽  
Hamid Dehghani ◽  
Juvenal Reyes ◽  
Lei Zheng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Tumor ◽  
Initial Study ◽  
Tumor Models ◽  
Bioluminescence Tomography ◽  
Research Platform ◽  
Radiation Research

scholarly journals TM4SF1 Regulates Pancreatic Cancer Migration and Invasion In Vitro and In Vivo

2016 ◽  
Vol 39 (2) ◽  
pp. 740-750 ◽  
Author(s):  
Jia Cao ◽  
Jia-chun Yang ◽  
Vijaya Ramachandran ◽  
Thiruvengadam Arumugam ◽  
De-feng Deng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Tumor ◽  
Migration And Invasion ◽  
Qrt Pcr ◽  
Pancreatic Cancer Cells ◽  
Cancer Tissues ◽  
Immunohistochemical Analyses ◽  
Expression And Activity

Background/Aims: The cell surface protein transmembrane 4 L6 family member 1 (TM4SF1) has been detected in various tumors and plays a major role in the development of cancer. We aimed to investigate the effects of TM4SF1 on the migration and invasion of pancreatic cancer in vitro and in vivo and explore its related molecular mechanisms. Methods: qRT-PCR and immunohistochemical analyses were used to measure the expression of TM4SF1 in pancreatic cancer tissues and adjacent tissues. TM4SF1 was silenced using siRNA and shRNA to investigate the role of this protein in the proliferation and metastasis of pancreatic cancer cells. MTS and Transwell assays were used to examine the effect of TM4SF1 on pancreatic cancer cell lines. The expression and activity of MMP-2 and MMP-9 were determined by qRT-PCR, western blots and gelatin zymography. In vivo, orthotopic pancreatic tumor models were used to examine the formation of metastasis. Results: qRT-PCR and immunohistochemical analyses showed that TM4SF1 was highly expressed in pancreatic cancer tissues compared with the adjacent tissues. In in vitro experiments the silencing of TM4SF1 reduced cell migration and invasion and down-regulated the expression and activity of MMP-2 and MMP-9. However, no significant difference in cell proliferation was detected after silencing TM4SF1. Additionally, knocking down TM4SF1 decreased the formation of lung and liver metastases in orthotopic pancreatic tumor models. Conclusion: Our results demonstrate that the expression of TM4SF1 is higher in pancreatic cancer tissues and pancreatic cancer cell lines than controls. Knockdown of TM4SF1 inhibited the migration and invasion of pancreatic cancer cells by regulating the expression and activity of MMP-2 and MMP-9, which suggests that TM4SF1 may play a significant role in metastasis in pancreatic cancer.

Deposition characteristics and resulting DNA damage patterns of liposomal irinotecan (nal-IRI) in pancreatic cancer xenografts.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 335-335
Author(s):  
Shannon C. Leonard ◽  
Nancy Paz ◽  
Stephan G Klinz ◽  
Daniel Gaddy ◽  
Helen Lee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Tumor Cells ◽  
Stromal Cells ◽  
Pancreatic Tumor ◽  
Tumor Models ◽  
Deposition Area ◽  
The Us ◽  
Liposomal Irinotecan ◽  
Repeated Dosing

335 Background: Liposomal irinotecan (nal-IRI, ONIVYDE) is approved in the US, EU and other countries in combination with 5-fluorouracil/leucovorin for treatment of patients with metastatic pancreatic cancer after disease progression following gemcitabine-based therapy. We report pharmacokinetic and extended pharmacodynamic effects of nal-IRI in pancreatic tumor models compared to non-liposomal irinotecan HCl. Methods: AsPC-1, BxPC-3 and CFPAC-1 tumors were grown in NOD-SCID mice. For efficacy animals were dosed q7d with 25-50 mg/kg irinotecan HCl or at 5x lower doses of nal-IRI. For PK-PD studies doses of 10-50 mg/kg of fluorescently-labeled nal-IRI were used; samples were collected up to 72 hr for irinotecan HCl and up to 168 hr for nal-IRI. Tumor samples were evaluated for liposome localization, macrophage and tumor markers, vessels, DNA damage and apoptosis. Results: nal-IRI yields sustained circulation and delivery of its payload to tumors compared to irinotecan HCl. This results in improved control of growth rates across a range of pancreatic tumor models even at 5x lower doses. DNA damage in BxPC-3 tumors has a comparable extent with both formulations, but is maximal at 6 hr after irinotecan HCl (50 mg/kg) and at 72 hr after nal-IRI (10 mg/kg). Liposomes deposit in tumors heterogeneously around functional vessels. Accumulation peaks at 6 - 24 hr with similar deposition patterns in cell- or patient-derived xenografts. Liposomes are predominantly taken up by macrophages and to a lesser extent by tumor or other stromal cells. DNA damage is mostly confined to tumor cells, a majority of which have not internalized liposomes. DNA damage and apoptosis are seen only minimally in non-tumor cells even when displaying high liposome uptake. Conclusions: nal-IRI improves tumoral deposition of its payload in pancreatic tumor models. Deposition is heterogeneous and restricted to perivascular areas. DNA damage predominantly in tumor cells outside of the liposomal deposition area suggests sufficient intratumoral levels of the SN-38 active metabolite, possibly after payload release by stromal macrophages and concomitant conversion. Effects of repeated dosing cycles should be explored.

scholarly journals Evaluation of a Gene-Directed Enzyme-Product Therapy (GDEPT) in Human Pancreatic Tumor Cells and Their Use as In Vivo Models for Pancreatic Cancer

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e40611 ◽  
Author(s):  
Juraj Hlavaty ◽  
Helga Petznek ◽  
Harry Holzmüller ◽  
Angelika Url ◽  
Gerrit Jandl ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Pancreatic Tumor ◽  
In Vivo Models ◽  
Enzyme Product

scholarly journals Pimavanserin: A Novel Autophagy Modulator for Pancreatic Cancer Treatment

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5661
Author(s):  
Sharavan Ramachandran ◽  
Itishree S. Kaushik ◽  
Sanjay K. Srivastava
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Pancreatic Tumor ◽  
Tumor Model ◽  
Annexin V ◽  
Pancreatic Tumors ◽  
Transmission Electron Microscopy Analysis ◽  
Genomic Databases ◽  
Apoptotic Effects

Pancreatic tumors exhibit high basal autophagy compared to that of other cancers. Several studies including those from our laboratory reported that enhanced autophagy leads to apoptosis in cancer cells. In this study, we evaluated the autophagy and apoptosis inducing effects of Pimavanserin tartrate (PVT). Autophagic effects of PVT were determined by Acridine Orange assay and Transmission Electron Microscopy analysis. Clinical significance of ULK1 in normal and pancreatic cancer patients was evaluated by R2 and GEPIA cancer genomic databases. Modulation of proteins in autophagy signaling was assessed by Western blotting and Immunofluorescence. Apoptotic effects of PVT was evaluated by Annexin-V/APC assay. Subcutaneous xenograft pancreatic tumor model was used to evaluate the autophagy-mediated apoptotic effects of PVT in vivo. Autophagy was induced upon PVT treatment in pancreatic ducal adenocarcinoma (PDAC) cells. Pancreatic cancer patients exhibit reduced levels of autophagy initiator gene, ULK1, which correlated with reduced patient survival. Interestingly, PVT induced the expression of autophagy markers ULK1, FIP200, Atg101, Beclin-1, Atg5, LC3A/B, and cleavage of caspase-3, an indicator of apoptosis in several PDAC cells. ULK1 agonist LYN-1604 enhanced the autophagic and apoptotic effects of PVT. On the other hand, autophagy inhibitors chloroquine and bafilomycin blocked the autophagic and apoptotic effects of PVT in PDAC cells. Notably, chloroquine abrogated the growth suppressive effects of PVT by 25% in BxPC3 tumor xenografts in nude mice. Collectively, our results indicate that PVT mediated pancreatic tumor growth suppression was associated with induction of autophagy mediated apoptosis.

Effect of macrophages on pancreatic cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 324-324 ◽  
Author(s):  
Evan Scott Glazer ◽  
Leighton F. Reed ◽  
Charlie J. Freeburg ◽  
S. Mazher Husain ◽  
Jeremiah Lee Deneve ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Line ◽  
Pancreatic Tumor ◽  
Tumor Promoter ◽  
Pdac Cell ◽  
Pancreatic Cell ◽  
Aggressive Phenotype ◽  
Pdac Cell Line

324 Background: Pancreatic Ductal Adenocarcinoma (PDAC) is expected to be the second leading cause of cancer related deaths by 2030. TGF-β is a well-studied PDAC mediator with a context dependent role as initially a tumor suppressor with potential to convert to a tumor promoter in later stages. Tumor associated macrophages and interleukins, such as the pro-inflammatory interleukin, IL23, are not well studied regarding PDAC. We hypothesized PDAC treated with TGF-β and macrophages would induce a more aggressive phenotype. Methods: We investigated aggressive behavior with a primary PDAC cell line in vivo and a metastatic PDAC cell line in vitro. A primary pancreatic cell line, Panc-1 cells, were pre-treated with PBS, IL23, macrophages (10:1 ratio of Panc-1 cells to macrophages), IL23 + macrophages, TGF-ß, TGF-ß + macrophages, or TGF-ß + macrophages + IL23. After treatment, cells were orthotopically implanted into the pancreas of NOD SCID gamma mice with 5 mice per group. Mice weights were recorded twice weekly for 4-weeks. Primary lesions and metastasis were investigated with ANOVA. AsPC-1 cells, a metastatic pancreatic cell line, were pre-treated with the same seven treatments. We investigated pSTAT3 expression and the streak closure in vitro. Results: Panc-1 cells treated with macrophages had the largest pancreatic tumor weight and diameter compared to PBS control, IL23 alone, and TGF-β alone (P < 0.001). When macrophages treatment included TGF-β, pancreatic tumor weights and diameters decreased as compared to macrophages alone and macrophages + IL23 (P < 0.001). Macrophage treatment induced higher liver weights and higher number of surface liver metastatic lesions suggesting higher metastatic disease burden (P < 0.03). AsPC-1 cells treated with combinations of macrophages and TGF-β increased pSTAT3 expression compared to PBS control. AsPC-1 cells treated with macrophages closed the gap in the scratch assay faster than PBS control 24 hours after treatment (P < 0.001). Conclusions: We demonstrated macrophages have a key role in converting primary pancreatic cancer into a more aggressive phenotype in vivo whereas they have less effect on metastatic pancreatic cancer in vitro.

scholarly journals Overexpression of DCLK1-AL Increases Tumor Cell Invasion, Drug Resistance, and KRAS Activation and Can Be Targeted to Inhibit Tumorigenesis in Pancreatic Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Dongfeng Qu ◽  
Nathaniel Weygant ◽  
Jiannan Yao ◽  
Parthasarathy Chandrakesan ◽  
William L. Berry ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Mouse Models ◽  
Pancreatic Tumor ◽  
Fold Increase ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Pdac Tissue

Oncogenic KRAS mutation plays a key role in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis with nearly 95% of PDAC harboring mutation-activated KRAS, which has been considered an undruggable target. Doublecortin-like kinase 1 (DCLK1) is often overexpressed in pancreatic cancer, and recent studies indicate that DCLK1+ PDAC cells can initiate pancreatic tumorigenesis. In this study, we investigate whether overexpressing DCLK1 activates RAS and promotes tumorigenesis, metastasis, and drug resistance. Human pancreatic cancer cells (AsPC-1 and MiaPaCa-2) were infected with lentivirus and selected to create stable DCLK1 isoform 2 (alpha-long, AL) overexpressing lines. The invasive potential of these cells relative to vector control was compared using Matrigel coated transwell assay. KRAS activation and interaction were determined by a pull-down assay and coimmunoprecipitation. Gemcitabine, mTOR (Everolimus), PI3K (LY-294002), and BCL-2 (ABT-199) inhibitors were used to evaluate drug resistance downstream of KRAS activation. Immunostaining of a PDAC tissue microarray was performed to detect DCLK1 alpha- and beta-long expression. Analysis of gene expression in human PDAC was performed using the TCGA PAAD dataset. The effects of targeting DCLK1 were studied using xenograft and Pdx1CreKrasG12DTrp53R172H/+ (KPC) mouse models. Overexpression of DCLK1-AL drives a more than 2-fold increase in invasion and drug resistance and increased the activation of KRAS. Evidence from TCGA PAAD demonstrated that human PDACs expressing high levels of DCLK1 correlate with activated PI3K/AKT/MTOR-pathway signaling suggesting greater KRAS activity. High DCLK1 expression in normal adjacent tissue of PDAC correlated with poor survival and anti-DCLK1 mAb inhibited pancreatic tumor growth in vivo in mouse models.

scholarly journals Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

2016 ◽  
Vol 113 (36) ◽  
pp. E5328-E5336 ◽  
Author(s):  
Amira Elgogary ◽  
Qingguo Xu ◽  
Brad Poore ◽  
Jesse Alt ◽  
Sarah C. Zimmermann ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trials ◽  
Combination Therapy ◽  
Pancreatic Tumor ◽  
Glycogen Synthesis ◽  
Glutamine Metabolism ◽  
Antitumor Effects ◽  
Novel Therapy ◽  
Metabolic Heterogeneity

Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.

scholarly journals METTL3 Promotes Pancreatic Tumor Progression Through Regulating the miR-196a/CPEB3 Axis

2020 ◽  
Author(s):  
Pingping Ge ◽  
Dong Fan ◽  
Lei He ◽  
Qiong Wu ◽  
Jin Sun ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Pancreatic Tumor ◽  
Luciferase Reporter ◽  
Pancreatic Cancer Cells ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background: Methyltransferase-like 3(METTL3)-mediated N6-methyladenosine (m6A) modification has been reported to regulate microRNAs maturation. Here, the study was designed to investigate the regulatory effect of m6A-dependent miRNA maturation on pancreatic cancer progression which is still limited before.Results: We found that METTL3 significantly upregulated in the pancreatic tumor tissues. Overexpression of METTL3 promoted cancer cell proliferation and migration in vitro and tumor progression in vivo. METTL3-mediated m6A modification facilitated miR-196a maturation in pancreatic cancer cells, and miR-196a increased the proliferation and migration of cancer cells in vitro. Luciferase reporter assay verified that cytoplasmic polyadenylation element binding protein 3 (CPEB3) was a direct target gene of miR-196a. In vivo studies proved that overexpression of miR-196a inhibited the anti-tumor effect of knockdown of METTL3, and overexpression of CPEB3 inhibited the miR-196a-enhanced tumor progression. Conclusions: We identified that METTL3 was upregulated in pancreatic cancer, leading to the upregulation of miR-196a, resulting in the downregulation of CPEB3, which promoted the pancreatic tumor progression. We first demonstrated that CPEB3 was a tumor suppressor gene in pancreatic cancer, and the METTL3 regulated miR-196a/CPEB3 axis may be a therapeutic target for pancreatic cancer therapy.

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