To identify metabolic pathways that are perturbed in pancreatic ductal adenocarcinoma (PDAC), we investigated gene-metabolite networks with integration of metabolomics and transcriptomics.
We ...conducted global metabolite profiling analysis on two independent cohorts of resected PDAC cases to identify critical metabolites alteration that may contribute to the progression of pancreatic cancer. We then searched for gene surrogates that were significantly correlated with the key metabolites, by integrating metabolite and gene expression profiles.
Fifty-five metabolites were consistently altered in tumors as compared with adjacent nontumor tissues in a test cohort (N = 33) and an independent validation cohort (N = 31). Weighted network analysis revealed a unique set of free fatty acids (FFA) that were highly coregulated and decreased in PDAC. Pathway analysis of 157 differentially expressed gene surrogates revealed a significantly altered lipid metabolism network, including key lipolytic enzymes PNLIP, CLPS, PNLIPRP1, and PNLIPRP2. Gene expressions of these lipases were significantly decreased in pancreatic tumors as compared with nontumor tissues, leading to reduced FFAs. More importantly, a lower gene expression of PNLIP in tumors was associated with poorer survival in two independent cohorts. We further showed that two saturated FFAs, palmitate and stearate, significantly induced TRAIL expression, triggered apoptosis, and inhibited proliferation in pancreatic cancer cells.
Our results suggest that impairment in a lipolytic pathway involving lipases, and a unique set of FFAs, may play an important role in the development and progression of pancreatic cancer and provide potential targets for therapeutic intervention.
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with an immunosuppressive microenvironment that is resistant to most therapies. IL17 is involved in pancreatic tumorigenesis, but ...its role in invasive PDAC is undetermined. We hypothesized that IL17 triggers and sustains PDAC immunosuppression. We inhibited IL17/IL17RA signaling using pharmacological and genetic strategies alongside mass cytometry and multiplex immunofluorescence techniques. We uncovered that IL17 recruits neutrophils, triggers neutrophil extracellular traps (NETs), and excludes cytotoxic CD8 T cells from tumors. Additionally, IL17 blockade increases immune checkpoint blockade (PD-1, CTLA4) sensitivity. Inhibition of neutrophils or Padi4-dependent NETosis phenocopies IL17 neutralization. NMR spectroscopy revealed changes in tumor lactate as a potential early biomarker for IL17/PD-1 combination efficacy. Higher expression of IL17 and PADI4 in human PDAC corresponds with poorer prognosis, and the serum of patients with PDAC has higher potential for NETosis. Clinical studies with IL17 and checkpoint blockade represent a novel combinatorial therapy with potential efficacy for this lethal disease.
Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, remains one of the highly lethal malignancies. The highly refractory nature of clinically advanced disease and lack ...of a reliable biomarker for early detection are major obstructions in improving patient outcome. The recent efforts, however, in understanding the pancreatic tumor biology have resulted in the recognition of novel addictions as well as vulnerabilities of tumor cells and are being assessed for their clinical potential. This special issue highlights some of the recent progress, complexity and challenges towards improving disease outcome in patients with this lethal malignancy.
MIF is a proinflammatory cytokine and is implicated in cancer. A higher MIF level is found in many human cancer and cancer‐prone inflammatory diseases, including chronic pancreatitis and pancreatic ...cancer. We tested the hypothesis that MIF contributes to pancreatic cancer aggressiveness and predicts disease outcome in resected cases. Consistent with our hypothesis we found that an elevated MIF mRNA expression in tumors was significantly associated with poor outcome in resected cases. Multivariate Cox‐regression analysis further showed that MIF is independently associated with patients' survival (HR = 2.26, 95% CI = 1.17–4.37, p = 0.015). Mechanistic analyses revealed that MIF overexpression decreased E‐cadherin and increased vimentin mRNA and protein levels in pancreatic cancer cell lines, consistent with the features of epithelial‐to‐mesenchymal transition (EMT). Furthermore, MIF‐overexpression significantly increased ZEB1/2 and decreased miR‐200b expression, while shRNA‐mediated inhibition of MIF increased E‐cadherin and miR‐200b expression, and reduced the expression of ZEB1/2 in Panc1 cells. Re‐expression of miR‐200b in MIF overexpressing cells restored the epithelial characteristics, as indicated by an increase in E‐cadherin and decrease in ZEB1/2 and vimentin expression. A reduced sensitivity to the chemotherapeutic drug, gemcitabine, occurred in MIF‐overexpressing cells. Indicative of an increased malignant potential, MIF over‐expressing cells showed significant increase in their invasion ability in vitro, and tumor growth and metastasis in an orthotopic xenograft mouse model. These results support a role of MIF in disease aggressiveness, indicating its potential usefulness as a candidate target for designing improved treatment in pancreatic cancer.
What's new?
While the pro‐inflammatory cytokine macrophage migration inhibitory factor (MIF) has been implicated in cancer, its biological relevance in malignant disease has remained unclear. Here, MIF was discovered to serve as a novel independent predictor of clinical outcome in patients with surgically resected pancreatic tumors. Furthermore, MIF enhanced the aggressiveness of pancreatic tumors by inducing epithelial to mesenchymal transition (EMT) and caused resistance to the chemotherapeutic drug gemcitabine. The findings indicate that MIF may be a candidate therapeutic target for this lethal malignancy.
Inflammation is widely recognized as an inducer of cancer progression. The inflammation-associated enzyme, inducible nitric oxide synthase (NOS2), has emerged as a candidate oncogene in estrogen ...receptor (ER)-negative breast cancer, and its increased expression is associated with disease aggressiveness and poor survival. Although these observations implicate NOS2 as an attractive therapeutic target, the mechanisms of both NOS2 induction in tumors and nitric oxide (NO)-driven cancer progression are not fully understood. To enhance our mechanistic understanding of NOS2 induction in tumors and its role in tumor biology, we used stimulants of NOS2 expression in ER ⁻ and ER ⁺ breast cancer cells and examined downstream NO-dependent effects. Herein, we show that up-regulation of NOS2 occurs in response to hypoxia, serum withdrawal, IFN-γ, and exogenous NO, consistent with a feed-forward regulation of NO production by the tumor microenvironment in breast cancer biology. Moreover, we found that key indicators of an aggressive cancer phenotype including increased S100 calcium binding protein A8, IL-6, IL-8, and tissue inhibitor matrix metalloproteinase-1 are up-regulated by these NOS2 stimulants, whereas inhibition of NOS2 in MDA-MB-231 breast cancer cells suppressed these markers. Moreover, NO altered cellular migration and chemoresistance of MDA-MB-231 cells to Taxol. Most notably, MDA-MB-231 tumor xenographs and cell metastases from the fat pad to the brain were significantly suppressed by NOS2 inhibition in nude mice. In summary, these results link elevated NOS2 to signals from the tumor microenvironment that arise with cancer progression and show that NO production regulates chemoresistance and metastasis of breast cancer cells.
Pancreatic tumors express high level of nitric oxide synthases (NOSs) in particular inducible (iNOS/NOS2) and endothelial (eNOS/NOS3) forms. However, the role of nitric oxide (NO
) in the development ...and progression of pancreatic cancer is not clearly defined. Delineating the NO
-induced signaling in pancreatic cancer and its potential contribution in disease aggressiveness may provide therapeutic targets to improve survival in this lethal malignancy. Recent Advances: An increased expression of NOS2/iNOS in tumors is associated with poorer survival in early stage resected patients with pancreatic ductal adenocarcinoma (PDAC). Furthermore, genetic deletion of NOS2 enhanced survival in mice with autochthonous PDAC. Additionally, targeting NOS3/eNOS reduced the abundance of precursor lesions in mice, which trended toward improved survival.
The extremely poor prognosis in pancreatic cancer is due to the late diagnosis and lack of effective therapy in advanced disease. One of the most critical issues is to decipher the underlying mechanism of disease aggressiveness and therapeutic resistance for identifying potential therapeutic target and effective treatment. Given the evidence of a strong association between inflammation and pancreatic cancer and clinical evidence, which suggests an association between NOS2 and disease aggressiveness, it is critical to define the role of NO
signaling in this lethal malignancy.
Recent preclinical and clinical evidences indicate a potential therapeutic significance of targeting NO
signaling in pancreatic cancer. With the emergence of new preclinical models, including the patient-derived organoids, further preclinical evaluation using clinically tested NOS inhibitors is needed for designing future clinical investigation. Antioxid. Redox Signal. 26, 1000-1008.
Mutant KRAS in lung cancers induces molecular pathways that regulate cellular proliferation, survival and inflammation, which enhance tumorigenesis. Inducible nitric oxide synthase (NOS2) ...upregulation and sustained nitric oxide generation are induced during the inflammatory response and correlate positively with lung tumorigenesis. To explore the mechanistic contribution of NOS2 to KRAS‐induced lung tumorigenesis and inflammation, we used a genetic strategy of crossing NOS2 knockout (NOS2KO) C57BL6 inbred mice with a KRASG12D‐driven mouse lung cancer model. KRASG12D;NOS2KO mice exhibited delayed lung tumorigenesis and a longer overall survival time compared to that of KRASG12D;NOS2WT (wild‐type) controls. Correspondingly, tumors in KRASG12D;NOS2KO mice had reduced tumor cell proliferation in adenomas and carcinomas. NOS2 deficiency also led to markedly suppressed inflammatory response by attenuation of macrophage recruitment into alveoli and within tumor foci. In contrast, FOXP3+ regulatory T cells were increased in tumors from KRASG12D;NOS2KO mice. We further analyzed the expression of microRNA‐21 (miR‐21), an oncogenic noncoding RNA involved in oncogenic Ras signaling, by quantitative reverse‐transcription polymerase chain reaction and in situ hybridization. Lung carcinomas dissected from KRASG12D;NOS2KO mice showed a significantly reduced miR‐21 expression along with decreased tumor cell proliferation, suggesting that NOS2 deficiency could attenuate RAS signaling pathways that transactivate miR‐21 expression. Therefore, deletion of NOS2 decreases lung tumor growth as well as inflammatory responses initiated by oncogenic KRAS, suggesting that both KRAS and NOS2 cooperate in driving lung tumorigenesis and inflammation. Inhibition of NOS2 may have a therapeutic value in lung cancers with oncogenic KRAS mutations.
What's new?
Deficiency of inducible nitric oxide synthase (NOS2) was found to inhibit tumorigenesis in mice with lung cancers associated with activating mutations in the KRAS protooncogene. NOS2 deficiency further suppressed KRAS‐induced lung inflammation and decreased expression of microRNA‐21, a non‐coding RNA involved in oncogenic Ras signaling. The frequent over‐expression of NOS2 in human lung cancer and NOS2 nitric oxide production in mice suggest that the synthase could be a potential target for KRAS‐induced lung cancers.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. To identify biologically relevant genes with prognostic and therapeutic significance in PDAC, we first performed ...the microarray gene-expression profiling in 45 matching pairs of tumor and adjacent non-tumor tissues from resected PDAC cases. We identified 36 genes that were associated with patient outcome and also differentially expressed in tumors as compared with adjacent non-tumor tissues in microarray analysis. Further evaluation in an independent validation cohort (N = 27) confirmed that DPEP1 (dipeptidase 1) expression was decreased (T:N ratio ∼0.1, P<0.01) in tumors as compared with non-tumor tissues. DPEP1 gene expression was negatively correlated with histological grade (Spearman correlation coefficient = -0.35, P = 0.004). Lower expression of DPEP1 in tumors was associated with poor survival (Kaplan Meier log rank) in both test cohort (P = 0.035) and validation cohort (P = 0.016). DPEP1 expression was independently associated with cancer-specific mortality when adjusted for tumor stage and resection margin status in both univariate (hazard ratio = 0.43, 95%CI = 0.24-0.76, P = 0.004) and multivariate analyses (hazard ratio = 0.51, 95%CI = 0.27-0.94, P = 0.032). We further demonstrated that overexpression of DPEP1 suppressed tumor cells invasiveness and increased sensitivity to chemotherapeutic agent Gemcitabine. Our data also showed that growth factor EGF treatment decreased DPEP1 expression and MEK1/2 inhibitor AZD6244 increased DPEP1 expression in vitro, indicating a potential mechanism for DPEP1 gene regulation. Therefore, we provide evidence that DPEP1 plays a role in pancreatic cancer aggressiveness and predicts outcome in patients with resected PDAC. In view of these findings, we propose that DPEP1 may be a candidate target in PDAC for designing improved treatments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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