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.

In vitro characterization of different pancreatic stellate cell cultures commonly used for the study of human pancreatic cancer

Pancreatology ◽  
2019 ◽  
Vol 19 ◽  
pp. S10-S11
Author(s):  
Daniela Lenggenhager ◽  
Manoj Amrutkar ◽  
Petra Sántha ◽  
Monica Aasrum ◽  
J.-Matthias Löhr ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Cultures ◽  
Stellate Cell ◽  
Human Pancreatic Cancer ◽  
Pancreatic Stellate Cell ◽  
In Vitro Characterization

Effect of zeb1 and zeb2 on pancreatic fibrobast-induced epithelial-to-mesenchymal transition (EMT) in pancreatic cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21035-e21035
Author(s):  
Laura Visa ◽  
Esther Samper ◽  
Mariana Rickmann ◽  
Antonio Postigo ◽  
Esther Sanchez-Tillo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Smooth Muscle Actin ◽  
Human Pancreatic Cancer ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Epithelial Tumor ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells ◽  
E Cadherin

e21035 Background: EMT renders neoplastic cancer cells the ability to migrate and to invade distant organs. The hallmark of EMT is the loss of E-cadherin, which is a prerequisite for epithelial tumor cell invasion. In pancreatic cancer, loss of tumor E-cadherin is an independent predictor of poor outcome. Aims: To analyze the effect of pancreatic fibroblasts (PF) on inducing EMT in pancreatic cancer cells and to identify the transcription factors (Snail, Slug, ZEB1, ZEB2) that mediate EMT process. Methods: Human PFs were isolated from human pancreatic specimens obtained from chronic pancreatitis and from unaffected margins of pancreatic adenocarcinoma and serous cistoadenoma. PF were cultured until complete cellular activation, as assessed by expression of α-smooth muscle actin, vimentin and fibronectin. Human pancreatic cancer cells Panc-1 were exposed to PF conditioned medium (PF-CM) and EMT analyzed by cell morphology, migration, and E-cadherin expression (quantitative RT-PCR and immunoblot). Gene expression of Snail, Slug, ZEB1, and ZEB2 was analyzed by quantitative RT-PCR, and their activity modulated by siRNA Results: Conditioned media from all types of activated PFs induced EMT changes in Panc-1 cells, as shown by 1) morphological transition from cobblestone shaped to fibroblast-like cells, 2) stimulation of cell migration, and 3) E-cadherin down–regulation; mRNA expression of Snail transiently increased at 30 min after exposure to PF returning to basal levels afterwards; mRNA levels of ZEB1 were not up-regulated upon exposure to PF-CM. However, ZEB1 protein greatly accumulated after 48h incubation with PF-CM, suggesting that PF prevent ZEB1 degradation in Panc-1 cells. Combined RNA downregulation of ZEB1 and ZEB2, but not of Snail and/or Slug, suppressed E-cadherin repression induced by PF. Conclusions: Activated PFs promote the invasive phenotype of pancreatic cancer cells through ZEB1 and ZEB2 activation.

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.

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 PSME3 Promotes TGFB1 Secretion by Pancreatic Cancer Cells to Induce Pancreatic Stellate Cell Proliferation

2019 ◽  
Vol 10 (9) ◽  
pp. 2128-2138 ◽  
Author(s):  
Lianyuan Yu ◽  
Jun-Jie Li ◽  
Xiao-Long Liang ◽  
Huanwen Wu ◽  
Zhiyong Liang
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Stellate Cell ◽  
Pancreatic Stellate Cell ◽  
Pancreatic Cancer Cells

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.

scholarly journals Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

2020 ◽  
Author(s):  
Qing Hua ◽  
Tianjiao Li ◽  
Yixuan Liu ◽  
Xuefang Shen ◽  
Xiaoyan Zhu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Disease Free Survival ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells

Abstract Background: 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. Methods: The relationship of KLK8 to clinicopathological features of PDAC was investigated 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. Results: 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.Conclusion: KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.

Nrf2 expression in pancreatic stellate cells promotes progression of cancer

2021 ◽  
Author(s):  
Yu Tanaka ◽  
Shin Hamada ◽  
Ryotaro Matsumoto ◽  
Keiko Taguchi ◽  
Masayuki Yamamoto ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Immunodeficient Mice ◽  
Pancreatic Cancer Cells ◽  
Nrf2 Target Gene ◽  
Migration Capacity

It was previously identified that systemic Nrf2-deletion attenuates pancreatic cancer progression in a mutant K-ras/p53-expressing mouse model (KPC mouse). In this study, the type of cell that is responsible for the retarded cancer progression was elucidated. Human pancreatic cancers were first examined, and elevated expression of NRF2-target gene products in a-smooth muscle actin-positive cells was found, suggesting that pancreatic stellate cells (PSCs) are involved in this process. Closer examination of primary cultured PSCs from Nrf2-deleted mice revealed that the cells were less proliferative and retained a lower migration capacity. The conditioned medium of Nrf2-deleted PSCs exhibited reduced growth-stimulating effects in pancreatic cancer cells. KPC mouse-derived pancreatic cancer cells co-injected with wild-type PSCs developed significantly larger subcutaneous tumors in immunodeficient mice than those co-injected with Nrf2-deleted PSCs. These results demonstrate that Nrf2 actively contributes to the function of PSCs to sustain KPC cancer progression, thus, suggesting that Nrf2 inhibition in PSCs may be therapeutically important in pancreatic cancer.

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