scholarly journals Astaxanthin inhibits gemcitabine‑resistant human pancreatic cancer progression through EMT inhibition and gemcitabine resensitization

2017 ◽  
Author(s):  
Tao Yan ◽  
Hai‑Ying Li ◽  
Jian‑Song Wu ◽  
Qiang Niu ◽  
Wei‑Hong Duan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Human Pancreatic Cancer

scholarly journals HGF/c-Met Inhibition as Adjuvant Therapy Improves Outcomes in an Orthotopic Mouse Model of Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2763
Author(s):  
Tony C. Y. Pang ◽  
Zhihong Xu ◽  
Alpha Raj Mekapogu ◽  
Srinivasa Pothula ◽  
Therese Becker ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Primary Tumour ◽  
Human Pancreatic Cancer ◽  
Pancreatic Stellate Cell ◽  
Orthotopic Mouse Model ◽  
Pancreatic Cancer Cells ◽  
Angiogenic Effect

Background: Inhibition of hepatocyte growth factor (HGF)/c-MET pathway, a major mediator of pancreatic stellate cell (PSC)−PC cell interactions, retards local and distant cancer progression. This study examines the use of this treatment in preventing PC progression after resection. We further investigate the postulated existence of circulating PSCs (cPSCs) as a mediator of metastatic PC. Methods: Two orthotopic PC mouse models, produced by implantation of a mixture of luciferase-tagged human pancreatic cancer cells (AsPC-1), and human PSCs were used. Model 1 mice underwent distal pancreatectomy 3-weeks post-implantation (n = 62). One-week post-resection, mice were randomised to four treatments of 8 weeks: (i) IgG, (ii) gemcitabine (G), (iii) HGF/c-MET inhibition (HiCi) and (iv) HiCi + G. Tumour burden was assessed longitudinally by bioluminescence. Circulating tumour cells and cPSCs were enriched by filtration. Tumours of Model 2 mice progressed for 8 weeks prior to the collection of primary tumour, metastases and blood for single-cell RNA-sequencing (scRNA-seq). Results: HiCi treatments: (1) reduced both the risk and rate of disease progression after resection; (2) demonstrated an anti-angiogenic effect on immunohistochemistry; (3) reduced cPSC counts. cPSCs were identified using immunocytochemistry (α-smooth muscle actin+, pan-cytokeratin−, CD45−), and by specific PSC markers. scRNA-seq confirmed the existence of cPSCs and identified potential genes associated with development into cPSCs. Conclusions: This study is the first to demonstrate the efficacy of adjuvant HGF/c-Met inhibition for PC and provides the first confirmation of the existence of circulating PSCs.

scholarly journals Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Qing Hua ◽  
Tianjiao Li ◽  
Yixuan Liu ◽  
Xuefang Shen ◽  
Xiaoyan Zhu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Culture Media ◽  
Disease Free Survival ◽  
Mtor Pathway ◽  
Gene Set Enrichment Analysis ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a growing cause of cancer-related mortality worldwide. Kallikrein-related peptidase 8 (KLK8) has potential clinical values in many cancers. However, the clinicopathological significances of KLK8 in PDAC remain unknown. We explored the relationship of KLK8 to clinicopathological features of PDAC based on public databases. KLK8 expression was examined in human PDAC tissues. Cell proliferation and apoptosis were evaluated in KLK8-overexpressed human pancreatic cancer cell lines Mia-paca-2 and Panc-1. The related signaling pathways of KLK8 involved in pancreatic cancer progression were analyzed by gene set enrichment analysis (GSEA) and further verified in in vitro studies. We found that KLK8 was up-regulated in tumor tissues in the TCGA-PAAD cohort, and was an independent prognostic factor for both overall survival and disease-free survival of PDAC. KLK8 mRNA and protein expressions were increased in PDAC tissues compared with para-cancerous pancreas. KLK8 overexpression exerted pro-proliferation and anti-apoptotic functions in Mia-paca-2 and Panc-1 cells. GSEA analysis showed that KLK8 was positively associated with PI3K-Akt-mTOR and Notch pathways. KLK8-induced pro-proliferation and anti-apoptotic effects in Mia-paca-2 and Panc-1 cells were attenuated by inhibitors for PI3K, Akt, and mTOR, but not by inhibitor for Notch. Furthermore, overexpression of KLK8 in Mia-paca-2 and Panc-1 cells significantly increased epidermal growth factor (EGF) levels in the culture media. EGF receptor (EGFR) inhibitor could block KLK8-induced activation of PI3K/Akt/mTOR pathway and attenuate pro-proliferation and anti-apoptotic of KLK8 in Mia-paca-2 and Panc-1 cells. In conclusion, KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via EGF signaling-dependent activation of PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.

Abstract 2295: Succession of transiently active TIC clones drives long-term human pancreatic cancer progression .

2013 ◽  
Author(s):  
Felix Oppel ◽  
Claudia R. Ball ◽  
Christopher M. Hoffmann ◽  
Sebastian M. Dieter ◽  
Taronish D. Dubash ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Human Pancreatic Cancer

scholarly journals TGF Beta Induces Vitamin D Receptor and Modulates Mitochondrial Activity of Human Pancreatic Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2932
Author(s):  
Camilla Fiz ◽  
Giulia Apprato ◽  
Chiara Ricca ◽  
Alessia Aillon ◽  
Loredana Bergandi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Vitamin D ◽  
Cancer Progression ◽  
Vitamin D Receptor ◽  
Metabolic Effects ◽  
Human Pancreatic Cancer ◽  
Mitochondrial Activity ◽  
Low Doses ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

The inflammatory cytokine TGFβ is both a tumor suppressor during cancer initiation and a promoter of metastasis along cancer progression. Inflammation and cancer are strictly linked, and cancer onset often correlates with the insufficiency of vitamin D, known for its anti-inflammatory properties. In this study, we investigated the interplay between TGFβ and vitamin D in two models of human pancreatic cancer, and we analyzed the metabolic effects of a prolonged TGFβ treatment mimicking the inflammatory environment of pancreatic cancer in vivo. We confirmed the induction of the vitamin D receptor previously described in epithelial cells, but the inhibitory effects of vitamin D on epithelial–mesenchymal transition (EMT) were lost when the hormone was given after a long treatment with TGFβ. Moreover, we detected an ROS-mediated toxicity of the acute treatment with TGFβ, whereas a chronic exposure to low doses had a protumorigenic effect. In fact, it boosted the mitochondrial respiration and cancer cell migration without ROS production and cytotoxicity. Our observations shed some light on the multifaceted role of TGFβ in tumor progression, revealing that a sustained exposure to TGFβ at low doses results in an irreversibly increased EMT associated with a metabolic modulation which favors the formation of metastasis.

scholarly journals Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition

2021 ◽  
Vol 22 (4) ◽  
pp. 1870
Author(s):  
Shin Hamada ◽  
Ryotaro Matsumoto ◽  
Yu Tanaka ◽  
Keiko Taguchi ◽  
Masayuki Yamamoto ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Therapeutic Interventions ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancers ◽  
Pancreatic Cancer Cells ◽  
Nrf2 Activation

Pancreatic cancer remains intractable owing to the lack of effective therapy for unresectable cases. Activating mutations of K-ras are frequently found in pancreatic cancers, but these have not yet been targeted by cancer therapies. The Keap1-Nrf2 system plays a crucial role in mediating the oxidative stress response, which also contributes to cancer progression. Nrf2 activation reprograms the metabolic profile to promote the proliferation of cancer cells. A recent report suggested that K-ras- and Nrf2-active lung cancer cells are sensitive to glutamine depletion. This finding led to the recognition of glutaminase inhibitors as novel anticancer agents. In the current study, we used murine pancreatic cancer tissues driven by mutant K-ras and p53 to establish cell lines expressing constitutively activated Nrf2. Genetic or pharmacological Nrf2 activation in cells via Keap1 deletion or Nrf2 activation sensitized cells to glutaminase inhibition. This phenomenon was confirmed to be dependent on K-ras activation in human pancreatic cancer cell lines harboring mutant K-ras, i.e., Panc-1 and MiaPaCa-2 in response to DEM pretreatment. This phenomenon was not observed in BxPC3 cells harboring wildtype K-ras. These results indicate the possibility of employing Nrf2 activation and glutaminase inhibition as novel therapeutic interventions for K-ras mutant pancreatic cancers.

scholarly journals Loss of HNF6 expression correlates with human pancreatic cancer progression

2014 ◽  
Vol 94 (5) ◽  
pp. 517-527 ◽  
Author(s):  
Kelly R Pekala ◽  
Xidi Ma ◽  
Peter A Kropp ◽  
Christine P Petersen ◽  
Courtney W Hudgens ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Human Pancreatic Cancer

scholarly journals DDR1-INDUCED NEUTROPHIL EXTRACELLULAR TRAPS DRIVE PANCREATIC CANCER METASTASIS

2020 ◽  
Author(s):  
Jenying Deng ◽  
Yaan Kang ◽  
Chien-Chia Cheng ◽  
Xinqun Li ◽  
Bingbing Dai ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Neutrophil Extracellular Traps ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Extracellular Traps ◽  
Pancreatic Cancer Cells

AbstractPancreatic ductal adenocarcinoma (PDAC) tumors are characterized by a desmoplastic reaction and dense collagen that is known to promote cancer progression. A central mediator of pro-tumorigenic collagen signaling is the receptor tyrosine kinase discoid domain receptor 1 (DDR1). DDR1 is a critical driver of a mesenchymal and invasive cancer cell PDAC phenotype. Previous studies have demonstrated that genetic or pharmacologic inhibition of DDR1 prevents PDAC tumorigenesis and metastasis. Here, we investigated whether DDR1 signaling has cancer cell non-autonomous effects that promote PDAC progression and metastasis. We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs) and subsequent cancer cell invasion and metastasis. Moreover, we have identified that collagen-induced CXCL5 production was mediated by a DDR1-PKCθ-SYK-NFκB signaling cascade. Together, these results highlight the critical contribution of collagen I-DDR1 interaction in the formation of an immune microenvironment that promotes PDAC metastasis.SummaryDeng et al find that collagen signaling via DDR1 on human pancreatic cancer cells drives production and release of the cytokine, CXCL5, into systemic circulation. CXCL5 then triggers infiltration of neutrophils into the tumor where they promote cancer cell progression.

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