BackgroundCancer stem cells (CSCs) are considered responsible for the recurrence and chemoresistance of cancer. Dysregulated autophagy is highly prevalent in many types of cancer including pancreatic cancer and has been implicated in cytoprotection and tumor promotion. This study aimed to investigate the role of autophagy in regulating cancer stemness and chemoresistance of pancreatic cancer.MethodsThe correlation between autophagy and CSCs and its clinical significance were analyzed using pancreatic cancer tissue microarrays. Genetic and pharmacological approaches were applied to explore the function of autophagy on CSC activity and gemcitabine resistance of pancreatic cancer cells in vitro and in vivo.ResultsLC3 expression positively correlated with the expression of CSC markers aldehyde dehydrogenase 1 (ALDH1), CD44, and CD133 in pancreatic cancer tissues. High coexpression of LC3/ALDH1 was associated with both poor overall survival and progression-free survival. In pancreatic cancer cell lines, higher LC3-II expression was observed in the sphere-forming cells than in the bulk cells. Blockade of autophagy by silencing ATG5, ATG7, and BECN1 or the administration of autophagy inhibitor chloroquine markedly reduced the CSC populations, ALDH1 activity, sphere formation, and resistance to gemcitabine in vitro and in vivo. Furthermore, osteopontin (OPN) was found to stimulate LC3-II, ALDH1, CD44, and CD133 expression in PANC-1 cells, whereas this effect could be prevented by OPN knockdown and autophagy blockade. After treatment with various inhibitors against the major signaling pathways downstream of OPN, only the inhibitor of NF-κB activation, BAY 1170–82, could effectively counteract OPN-induced autophagy and CSC activity. According to the histochemical results, pancreatic cancer patients manifesting high levels of OPN/LC3/ALDH1 and OPN/CD44/CD133 had poor survival.ConclusionsInduction of autophagy mediated by OPN/NF-κB signaling is required for maintenance of pancreatic CSC activity. Combination of gemcitabine with pharmacological autophagy inhibitors is a promising therapeutic strategy for pancreatic cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0449-3) contains supplementary material, which is available to authorized users.
BACKGROUNDThe interactions between cancer stem cells (CSCs) and tumor-associated macrophages (TAMs) can promote tumor progression, maintain the CSCs population, and reduce therapeutic effects. The objective of this study was to investigate the coexpression of CSCs and TAMs and its clinical significance in pancreatic ductal adenocarcinoma (PDAC).METHODSNinety-six patients with PDAC were included in this study. Tissue microarrays were constructed for immunostaining of the CSCs markers CD44 and CD133 and the TAMs marker CD204. Correlations between the expression of CSCs and TAMs markers and clinicopathologic characteristics or disease progression were analyzed.RESULTSExpression levels of CD44/CD133 and CD204 were significantly higher in tumor tissues than in normal tissues (P < .0001). The variables associated with survival were high coexpression of CD44/CD133 (P = .000), high expression of CD204 (P = .011), and tumor grade (P = .014). There was a positive correlation between CD44/CD133 and CD204 expression (r = 0.294; P = .004). Survival analysis indicated that high coexpression of CD44/CD133 and CD204 was associated significantly with shorter overall survival (P = .000) and disease-free survival (P = .003). Multivariate analysis revealed that high CD44/CD133 expression was an independent prognostic factor for disease-free survival, whereas high CD204 expression was an independent predictor for both overall and disease-free survival.CONCLUSIONSCoexpression of CD44/CD133 and CD204 is a useful survival prediction marker for patients with PDAC. Cancer 2014;120:2766–2777. © The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.The clinical significance of pancreatic cancer stem cells and tumor-associated macrophages is explored in patients with pancreatic ductal adenocarcinoma. The results clearly demonstrate that coexpression of 2 cancer stem cell markers (CD44 and CD133) and a tumor-associated macrophage marker (CD204) is a useful prognostic factor for predicting the survival of patients with pancreatic ductal adenocarcinoma after surgery.
Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. Accumulating evidence suggests that CSCs employ immunosuppressive effects to evade immune system recognition. However, the clinical implications of the associations among CD8+ T cells infiltration, programmed death receptor ligand-1 (PD-L1) expression, and CSCs existence are poorly understood in PC. Immunostaining and quantitative analysis were performed to assess CD8+ T cells infiltration, PD-L1 expression, and their relationship with CD44+/CD133+ CSCs and disease progression in PC. CD8+ T cells infiltration was associated with better survival while PD-L1 expression was correlated with PC recurrence. Both the low CD8+ T cells infiltration/high PD-L1 expression group and the high CD8+ T cells infiltration/high PD-L1 expression group show high levels of CD44+/CD133+ CSCs, but patients with low CD8+ T cells infiltration/high PD-L1 expression had worse survival and higher recurrence risk than those with high CD8+ T cells infiltration/high PD-L1 expression. Moreover, high infiltration of CD8+ T cells could reduce unfavorable prognostic effect of high co-expression of PD-L1 and CD44/CD133. Our study highlights an interaction among CD8+ T cells infiltration, PD-L1 expression, and CD44+/CD133+ CSCs existence, which contributes to PC progression and immune evasion.
Purpose: KIT mutations, the most prevalent genetic event in gastrointestinal stromal tumors (GIST), are associated with malignant features and poor prognosis. Aggressive GISTs possess a high propensity to spread to the liver. This study aimed to explore the role of KIT mutations in GIST liver metastasis.Experimental Design: A total of 170 GISTs were used to determine the association between KIT mutations and liver metastasis. Immunohistochemistry was performed to assess the correlation of KIT mutations with CXCR4 and ETV1 expression. Genetic and pharmacologic methods were used to study the regulation of CXCR4 and ETV1 by KIT mutations.Results: Codons 557 and 558 in KIT exon 11 were deletion hot spots in GISTs. KIT exon 11 deletions involving codons 557-558 were highly associated with liver metastasis. Overexpression of mutant KIT with exon 11 codons 557-558 deletion (KIT D557-558) increased GIST cell motility and liver metastasis. Mechanistically, overexpression of KIT D557-558 in GIST cells increased ETV1 and CXCR4 expression. CXCR4 knockdown counteracted KIT D557-558-mediated cell migration. Moreover, KIT D557-558-induced CXCR4 expression could be abolished by silencing ETV1. The chromatin immunoprecipitation assay showed that ETV1 directly bound to the CXCR4 promoter. After ERK inhibitor PD325901 treatment, the upregulation of ETV1 by KIT D557-558 was prevented. In addition, KIT exon 11 codons 557-558 deletion enhanced CXCL12-mediated GIST cell migration and invasion.Conclusions: KIT exon 11 557-558 deletion upregulates CXCR4 through increased binding of ETV1 to the CXCR4 promoter in GIST cells, which thus promotes liver metastasis. These findings highlighted the potential therapeutic targets for metastatic GISTs.
Background: The dense fibrotic stroma enveloping pancreatic tumors is a major cause of drug resistance. Pancreatic stellate cells (PSCs) in the stroma can be activated to induce intra-tumor fibrosis and worsen patient survival; however, the molecular basics for the regulation of PSC activation remains unclear.Methods: The in vitro coculture system was used to study cancer cell-PSC interactions. Atomic force microscopy was used to measure the stiffness of tumor tissues and coculture gels. Cytokine arrays, qPCR, and Western blotting were performed to identify the potential factors involved in PSC activation and to elucidate underlying pathways.Results: PSC activation characterized by α-SMA expression was associated with increased pancreatic tumor stiffness and poor prognosis. Coculture with cancer cells induced PSC activation, which increased organotypic coculture gel stiffness and cancer cell invasion. Cancer cells-derived PAI-1 identified from coculture medium could activate PSCs, consistent with pancreatic cancer tissue microarray analysis showing a strong positive correlation between PAI-1 and α-SMA expression. Suppression by knocking down PAI-1 in cancer cells demonstrated the requirement of PAI-1 for coculture-induced PSC activation and gel stiffness. PAI-1 could be upregulated by KRAS in pancreatic cancer cells through ERK. In PSCs, inhibition of LRP-1, ERK, and c-JUN neutralized the effect of PAI-1, suggesting the contribution of LRP-1/ERK/c-JUN signaling. Furthermore, activated PSCs might exacerbate malignant behavior of cancer cells via IL-8 because suppression of IL-8 signaling reduced pancreatic tumor growth and fibrosis in vivo.Conclusions: KRAS-mutant pancreatic cancer cells can activate PSCs through PAI-1/LRP-1 signaling to promote fibrosis and cancer progression.
Estrogens contribute to the pathogenesis of female lung cancer and function mainly through estrogen receptor-β (ERβ). However, the way in which ERβ expression is regulated in lung cancer cells remains to be explored. We have found that signal transducer and activator of transcription 3 (Stat3) activation up-regulates ERβ expression in PC14PE6/AS2 lung cancer cells in a preliminary Affymetrix oligonucleotide array study, and we sought to confirm the findings. In this study, we show that IL-6 induced ERβ mRNA and protein expression in lung cancer cells. The induction of ERβ in response to IL-6 was abolished by Janus kinase 2 inhibitor-AG490, dominant-negative mutant of Stat3, and Stat3-targeting short interfering RNA. The luciferase reporter assay and chromatin immunoprecipitation assay confirmed that IL-6-activated Stat3 binds to the ERβ promoter. Besides the Janus kinase 2/Stat3 pathway, the MEK/Erk pathway contributes to ERβ up-regulation induced by IL-6; however, the phosphoinositide 3'-kinase/Akt pathway does not. We also found that epidermal growth factor (EGF) stimulation or L858R mutation in EGF receptor (EGFR) induced Stat3 activation as well as ERβ expression in lung cancer cells. Inhibiting Stat3 activity by pharmacological or genetic approaches reduced EGF- and L858R mutant EGFR-induced ERβ expression, indicating that Stat3 activation is required for EGFR signaling-mediated ERβ up-regulation. Silencing ERβ decreased cell proliferation in lung cancer cells that overexpress L858R mutant EGFR. In conclusion, we have identified that Stat3 activation is essential for ERβ induction by IL-6, EGF, and the presence of EGFR mutation. The findings shed light on new therapeutic targets for female lung cancer, especially for those with EGFR mutations.
Single-port laparoscopic surgery (SLS), which utilises one major incision, has become increasingly popular in the healthcare sector in recent years. However, this technique suffers from several problems particularly the inability of current SLS instruments to provide the optimum angulation that is required during SLS operations. In this paper, the development of a novel latching-type electromagnetic actuator is reported, which is aimed to enhance the function of SLS instruments. This new actuator is designed to be embedded at selected joints along SLS instruments to enable the surgeon to transform them from their straight and slender shape to an articulated posture. The developed electromagnetic actuator is comprised of electromagnetic coil elements, a solid magnetic shell, and a permanent magnet used to enhance the magnetic field interaction along the force generation path and also to provide the latching effect. In this investigation, electromagnetic finite element analyses were conducted to design and optimise the actuator’s electromagnetic circuit. In addition, the performance of the new actuator was numerically and experimentally determined when output magnetic forces and torques in excess of 9 N and 45 mNm, respectively together with an angulation of 30° were achieved under a short pulse of current supply to the magnetic circuit of the actuator.
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