scholarly journals PROBING CLINICAL RELEVANCE: ESTABLISHING THE EFFICACY OF C. NOVYI AGAINST A PANEL OF 2D CULTURED PANCREATIC CANCER CELLS

2021 ◽  
Vol 57 (2) ◽  
pp. 92-99
Author(s):  
K.M. Dailey ◽  
◽  
R.I. Jacobson ◽  
J. Kim ◽  
S. Mallik ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Survival Rates ◽  
Tumor Model ◽  
Design Decision ◽  
Unique Challenge ◽  
Pancreatic Cancer Cells ◽  
Anti Cancer ◽  
Type C ◽  
The Impact

Pancreatic cancer presents a unique challenge for the development of effective oncotherapies. The tumor microenvironment (TME) of this type of tumor typically contains a dense desmoplastic barrier composed of aberrant extracellular matrix proteins, as well as an acidic, hypoxic and necrotic core. Additionally, the immune system surrounding this type of tumor has often been suppressed by the TME. Hence, choosing the correct model of the tumor microenvironment within which to test a potential anti-cancer therapy is a critical experimental design decision. While the typical solid tumor contains a complex microenvironment including both phenotypic and genotypic heterogeneity, the methods used to model this disease state often do not reflect this complexity. This simplistic approach may have contributed to stagnant five-year survival rates experienced over the past four decades. Oncolytic bacteria, a class of bacteria with the innate ability to seek and destroy solid tumors has been revived from historical anecdotes in an attempt to overcome these challenges. Regardless of the promise of oncolytic bacteria, accurate assessment of their potential requires choosing the proper tumor model. This study explores the impact of cancer cell lines co-cultured with Wild-Type C. novyi to establish the efficacy of this oncolytic bacteria in a monolayer culture.

scholarly journals RAD51 is a potential marker for prognosis and regulates cell proliferation in pancreatic cancer

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaomeng Zhang ◽  
Ningyi Ma ◽  
Weiqiang Yao ◽  
Shuo Li ◽  
Zhigang Ren
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Overall Survival ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Aerobic Glycolysis ◽  
Cell Counting ◽  
Survival Prediction ◽  
Pancreatic Cancer Cells ◽  
The Impact

Abstract Background The DNA damage and repair pathway is considered a promising target for developing strategies against cancer. RAD51, also known as RECA, is a recombinase that performs the critical step in homologous recombination. RAD51 has recently received considerable attention due to its function in tumor progression and its decisive role in tumor resistance to chemotherapy. However, its role in pancreatic cancer has seldom been investigated. In this report, we provide evidence that RAD51, regulated by KRAS, promotes pancreatic cancer cell proliferation. Furthermore, RAD51 regulated aerobic glycolysis by targeting hypoxia inducible factor 1α (HIF1α). Methods TCGA (The Cancer Genome Atlas) dataset analysis was used to examine the impact of RAD51 expression on overall survival of pancreatic cancer patients. Lentivirus-mediated transduction was used to silence RAD51 and KRAS expression. Quantitative real-time PCR and western blot analysis validated the efficacy of the knockdown effect. Analysis of the glycolysis process in pancreatic cancer cells was also performed. Cell proliferation was determined using a CCK-8 (Cell Counting Kit-8) proliferation assay. Results Pancreatic cancer patients with higher levels of RAD51 exhibited worse survival. In pancreatic cancer cells, RAD51 positively regulated cell proliferation, decreased intracellular reactive oxygen species (ROS) production and increased the HIF1α protein level. KRAS/MEK/ERK activation increased RAD51 expression. In addition, RAD51 was a positive regulator of aerobic glycolysis. Conclusion The present study reveals novel roles for RAD51 in pancreatic cancer that are associated with overall survival prediction, possibly through a mechanism involving regulation of aerobic glycolysis. These findings may provide new predictive and treatment targets for pancreatic cancer.

scholarly journals Microfluidic modelling of the tumor microenvironment for anti-cancer drug development

Lab on a Chip ◽  
2019 ◽  
Vol 19 (3) ◽  
pp. 369-386 ◽  
Author(s):  
Menglin Shang ◽  
Ren Hao Soon ◽  
Chwee Teck Lim ◽  
Bee Luan Khoo ◽  
Jongyoon Han
Keyword(s):  
Tumor Microenvironment ◽  
Drug Development ◽  
Tumor Model ◽  
Cancer Drug ◽  
Microfluidic Systems ◽  
Anti Cancer

Microfluidic tumor model has the unique advantage of recapitulating tumor microenvironment in a comparatively easier and representative fashion. In this review, we aim to focus more on the possibility of generating clinically actionable information from these microfluidic systems, not just scientific insight.

scholarly journals TGF-βRII Knock-down in Pancreatic Cancer Cells Promotes Tumor Growth and Gemcitabine Resistance. Importance of STAT3 Phosphorylation on S727

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 254 ◽  
Author(s):  
Vincent Drubay ◽  
Nicolas Skrypek ◽  
Lucie Cordiez ◽  
Romain Vasseur ◽  
Céline Schulz ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Locally Advanced ◽  
Western World ◽  
Pancreatic Cancer Cells ◽  
Stat3 Phosphorylation ◽  
The Impact

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the Western world because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cells also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatments for PDAC. Proteins involved in TGF-β signaling pathway (SMAD4 or TGF-βRII) are frequently mutated in PDAC (50–80%). TGF-β signalling pathway plays antagonistic roles during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as both tumor suppressor and oncogenic pathways. In order to decipher the role of TGF-β in pancreatic carcinogenesis and chemoresistance, we generated CAPAN-1 and CAPAN-2 cell lines knocked down for TGF-βRII (first actor of TGF-β signaling). The impact on biological properties of these TGF-βRII-KD cells was studied both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to gemcitabine. TGF-βRII silencing also leads to S727 STAT3 and S63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype. These markers associated with TGF-β signaling pathways may thus appear as potent therapeutic tools to better treat/manage pancreatic cancer.

scholarly journals Differential Gemcitabine Sensitivity in Primary Human Pancreatic Cancer Cells and Paired Stellate Cells Is Driven by Heterogenous Drug Uptake and Processing

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3628
Author(s):  
Manoj Amrutkar ◽  
Nils Tore Vethe ◽  
Caroline S. Verbeke ◽  
Monica Aasrum ◽  
Anette Vefferstad Finstadsveen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Stellate Cells ◽  
Drug Uptake ◽  
Pancreatic Stellate Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
The Impact

Gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) is attributed to cancer cell-intrinsic drug processing and the impact of the tumor microenvironment, especially pancreatic stellate cells (PSCs). This study uses human PDAC-derived paired primary cancer cells (PCCs) and PSCs from four different tumors, and the PDAC cell lines BxPC-3, Mia PaCa-2, and Panc-1, to assess the fate of gemcitabine by measuring its cellular uptake, cytotoxicity, and LC-MS/MS-based metabolite analysis. Expression analysis and siRNA-mediated knockdown of key regulators of gemcitabine (hENT1, CDA, DCK, NT5C1A) was performed. Compared to PSCs, both the paired primary PCCs and cancer cell lines showed gemcitabine-induced dose-dependent cytotoxicity, high uptake, as well as high and variable intracellular levels of gemcitabine metabolites. PSCs were gemcitabine-resistant and demonstrated significantly lower drug uptake, which was not influenced by co-culturing with their paired PCCs. Expression of key gemcitabine regulators was variable, but overall strong in the cancer cells and significantly lower or undetectable in PSCs. In cancer cells, hENT1 inhibition significantly downregulated gemcitabine uptake and cytotoxicity, whereas DCK knockdown reduced cytotoxicity. In conclusion, heterogeneity in gemcitabine processing among different pancreatic cancer cells and stellate cells results from the differential expression of molecular regulators which determines the effect of gemcitabine.

Anti-proliferative and anti-cancer properties of Achyranthes aspera: Specific inhibitory activity against pancreatic cancer cells

2010 ◽  
Vol 131 (1) ◽  
pp. 78-82 ◽  
Author(s):  
Pochi R. Subbarayan ◽  
Malancha Sarkar ◽  
Stefania Impellizzeri ◽  
Francisco Raymo ◽  
Balakrishna L. Lokeshwar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Inhibitory Activity ◽  
Achyranthes Aspera ◽  
Pancreatic Cancer Cells ◽  
Anti Cancer

scholarly journals Linc-DYNC2H1-4 promotes EMT and CSC phenotypes by acting as a sponge of miR-145 in pancreatic cancer cells

2017 ◽  
Vol 8 (7) ◽  
pp. e2924-e2924 ◽  
Author(s):  
Yuran Gao ◽  
Zhicheng Zhang ◽  
Kai Li ◽  
Liying Gong ◽  
Qingzhu Yang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Ectopic Expression ◽  
Pancreatic Cancer Cell Line ◽  
Mesenchymal Transition ◽  
Gemcitabine Resistance ◽  
Pancreatic Cancer Cells ◽  
Sense Strand ◽  
The Impact

AbstractThe acquisition of epithelial–mesenchymal transition (EMT) and/or existence of a sub-population of cancer stem-like cells (CSC) are associated with malignant behavior and chemoresistance. To identify which factor could promote EMT and CSC formation and uncover the mechanistic role of such factor is important for novel and targeted therapies. In the present study, we found that the long intergenic non-coding RNA linc-DYNC2H1-4 was upregulated in pancreatic cancer cell line BxPC-3-Gem with acquired gemcitabine resistance. Knockdown of linc-DYNC2H1-4 decreased the invasive behavior of BxPC-3-Gem cells while ectopic expression of linc-DYNC2H1-4 promoted the acquisition of EMT and stemness of the parental sensitive cells. Linc-DYNC2H1-4 upregulated ZEB1, the EMT key player, which led to upregulation and downregulation of its targets vimentin and E-cadherin respectively, as well as enhanced the expressions of CSC makers Lin28, Nanog, Sox2 and Oct4. Linc-DYNC2H1-4 is mainly located in the cytosol. Mechanically, it could sponge miR-145 that targetsZEB1,Lin28,Nanog,Sox2,Oct4to restore these EMT and CSC-associated genes expressions. We proved thatMMP3, the nearby gene of linc-DYNC2H1-4 in the sense strand, was also a target of miR-145. Downregulation ofMMP3by miR-145 was reverted by linc-DYNC2H1-4, indicating that competing with miR-145 is one of the mechanisms for linc-DYNC2H1-4 to regulateMMP3. In summary, our results explore the important role of linc-DYNC2H1-4 in the acquisition of EMT and CSC, and the impact it has on gemcitabine resistance in pancreatic cancer cells.

Gastrin vaccine and immune checkpoint antibody therapy for pancreatic cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 259-259
Author(s):  
Jill P Smith ◽  
Nicholas Osborne ◽  
Rebecca Sundseth ◽  
Julian Burks ◽  
Hong Cao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Cell Response ◽  
Combined Therapy ◽  
T Cell Response ◽  
Effector Memory ◽  
Antibody Treatment ◽  
Pancreatic Cancer Cells

259 Background: Pancreatic cancer is poorly responsive to therapy due to fibrosis in the tumor microenvironment and nonspecificity of treatments. The peptide gastrin stimulates growth of pancreatic cancer in an autocrine fashion. Polyclonal Antibody Stimulator (PAS) is a gastrin vaccine that in clinical trials prolongs survival of patients who develop neutralizing gastrin antibodies. We hypothesized that PAS also elicits a memory and T-cell response that would improve effectiveness of immune checkpoint antibodies. Methods: C57BL/6 mice were injected sc with syngeneic mT3 murine pancreatic cancer cells. After 1 week (tumors evident), groups were treated with PBS (control); PAS (100 μg or 250 μg); PD-1 antibody (150 μg); or combined therapy with PAS100/PD-1. PAS was given ip at weeks 0, 1 and 3. Anti-PD-1 was given on days 0, 4, 8, 15 and 21. On day 31 spleens were collected for T-cell surface analysis and cytokine activation by flow cytometry. Tumors were stained for fibrosis and with immunohistochemical stains for CD8+ and FoxP3+ tumor infiltrating lymphocytes (TILs). Results: PAS resulted in T-cell activation; however, the portion of terminally differentiated effector memory double negative T-cells (CD4- CD8-) in CD3+cells from mice treated with the combination PAS100/PD-1 was two-fold higher than those portions from mice treated with PBS, PD-1 or PAS100. Lymphocytes from PAS-treated mice elicited cytokine release (Interferon-γ, granzyme, perforin, and TNF-α) upon re-stimulation with gastrin in vitro, whereas PAS100/PD-1-treated mice show the highest endogenous cytokines levels. PAS250 monotherapy decreased tumor growth. Neither PAS100 nor anti-PD-1 monotherapy decreased tumor size, but combination PAS100/PD-1 antibody tumors were smaller, had less fibrosis, fewer T-regulatory lymphocytes, and increased CD8+ TILs. Conclusions: In addition to eliciting a B-cell response, PAS activates T-lymphocytes rendering tumors susceptible to immune checkpoint antibody treatment. Smaller tumors with combined therapy may be due to the anti-fibrotic effect of PAS on the tumor microenvironment and changes in CD8+ TILs. This study supports that PAS is an important immunotherapy that elicits both B- and T-cell anti-cancer responses.

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