Abstract：
:Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths in the United States. The deoxynucleoside analogue gemcitabine is among the most effective therapies to treat PDAC, however, nearly all patients treated with gemcitabine either fail to respond or rapidly develop resistance. One hallmark of PDAC is a striking accumulation of stromal tissue surrounding the tumor, and this accumulation of stroma can contribute to therapy resistance. To better understand how stroma limits response to therapy, we investigated cell-extrinsic mechanisms of resistance to gemcitabine. Conditioned media from pancreatic stellate cells (PSC), as well as from other fibroblasts, protected PDAC cells from gemcitabine toxicity. The protective effect of PSC-conditioned media was mediated by secretion of deoxycytidine, but not other deoxynucleosides, through equilibrative nucleoside transporters. Deoxycytidine inhibited the processing of gemcitabine in PDAC cells, thus reducing the effect of gemcitabine and other nucleoside analogues on cancer cells. These results suggest that reducing deoxycytidine production in PSCs may increase the efficacy of nucleoside analog therapies. SIGNIFICANCE: This study provides important new insight into mechanisms that contribute to gemcitabine resistance in PDAC and suggests new avenues for improving gemcitabine efficacy.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Dalin S,Sullivan MR,Lau AN,Grauman-Boss B,Mueller HS,Kreidl E,Fenoglio S,Luengo A,Lees JA,Vander Heiden MG,Lauffenburger DA,Hemann MTdoi
10.1158/0008-5472.CAN-19-0960subject
Has Abstractpub_date
2019-11-15 00:00:00pages
5723-5733issue
22eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-19-0960journal_volume
79pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract：:Dilution end point loss of heterozygosity (LOH) analysis, a novel approach for the analysis of LOH, was used to evaluate allelic losses with the use of 21 highly polymorphic microsatellite markers at nine chromosomal sites most frequently affected in smoking-related non-small cell lung cancers. Allelotyping was done f...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-04-3297
更新日期：2005-03-01 00:00:00
abstract：:Cross-coupling of active protein-1 (AP-1) and nuclear factor (NF)-kappaB has been reported. In the present study, we investigated the possibility that both of these two transcription factors might contribute to the process of tumor promoter-induced transformation. To establish a stable reporter cell system, two report...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1997-08-15 00:00:00
abstract：:Regulation of the expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) has been investigated in a number of human lymphoblastoid cell lines. In a number of Mex- cell lines that do not express methyltransferase activity, CpG sequences in the mgmt gene were hypomethylated with respect to met...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1992-10-01 00:00:00
abstract：:Glutamate-triggered signal transduction is thought to contribute widely to cancer pathogenesis. In melanoma, overexpression of the metabotropic glutamate receptor (GRM)-1 occurs frequently and its ectopic expression in melanocytes is sufficient for neoplastic transformation. Clinical evaluation of the GRM1 signaling i...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-13-1531
更新日期：2014-05-01 00:00:00
abstract：:Cancer research has long been hampered by the limitations of the current model systems. Both cultured cells and mouse xenografts grow in an environment highly dissimilar to that of their originating tumor, frequently resulting in promising treatments that are ultimately clinically ineffective. The development of highl...
journal_title：Cancer research
pub_type： 杂志文章,评审
doi：10.1158/0008-5472.CAN-16-1260
更新日期：2016-11-01 00:00:00
abstract：:Highly glycolytic cervical cancers largely resist treatment by cisplatin and coadministered pelvic irradiation as the present standard of care. In this study, we investigated the effects of inhibiting glycolysis and thiol redox metabolism to evaluate them as alternate treatment strategies in these cancers. In a panel ...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-17-2367
更新日期：2018-03-15 00:00:00
abstract：:2'-Deoxycoformycin (2'-dCF), a tight-binding inhibitor of adenosine deaminase, was administered to 26 pediatric patients with acute lymphoblastic leukemia in a Phase I study. Doses ranged from 0.25 to 1.0 mg/kg given i.v. for 3 consecutive days. Common toxicity included nausea, vomiting, diarrhea, hepatocellular enzym...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1981-09-01 00:00:00
abstract：:cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (NDDP), a lipophilic cisplatin analogue containing two branched leaving groups of 10 carbon atoms, is undergoing clinical evaluation in a liposomal formulation. In previous studies, NDDP entrapped in multilamellar vesicles composed of dimyristoylphosp...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1992-11-15 00:00:00
abstract：:SIRT6 is a SIR2 family member that regulates multiple molecular pathways involved in metabolism, genomic stability, and aging. It has been proposed previously that SIRT6 is a tumor suppressor in cancer. Here, we challenge this concept by presenting evidence that skin-specific deletion of SIRT6 in the mouse inhibits sk...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-14-1308
更新日期：2014-10-15 00:00:00
abstract：:Gliomas are primary brain tumors with high mortality and heterogeneous biology that is insufficiently understood. In this study, we performed a systematic analysis of the intrinsic organization of complex glioma transcriptome to gain deeper knowledge of the tumor biology. Gene coexpression relationships were explored ...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-10-2465
更新日期：2010-12-15 00:00:00
abstract：:Although phosphoramide mustard (PM) is generally recognized as being the most genotoxic metabolite of cyclophosphamide (CP), the contribution of acrolein to the cytogenetic toxicity of CP is unclear. Besides covalently binding to DNA, acrolein can inactivate critical proteins necessary for replicative DNA synthesis, R...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1990-08-01 00:00:00
abstract：:We have examined three methods that may be useful for improving the therapeutic efficacy of antibody-targeted radionuclides. The principal limitation of radioimmunotherapy is myelotoxicity and thrombocytopenia. These are due mainly to the length of time the radioantibody remains in the blood. The clearance time of a r...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1990-02-01 00:00:00
abstract：:Gene-targeted mice that contain a His6-tagged mouse c-Myc cDNA, Myc(His), inserted head to head into different sites of the mouse immunoglobulin heavy-chain locus, Igh, mimic the chromosomal T(12;15)(Igh-Myc) translocation that results in the activation of Myc in the great majority of mouse plasmacytomas. Mice carryin...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-05-1222
更新日期：2005-09-01 00:00:00
abstract：:Hormone stimulation of responsive neoplasms is a potential strategy for improving the target selectivity of cancer chemotherapy. Using an alkaline DNA-unwinding technique to detect drug-induced DNA strand breakage, we have shown that estrogen stimulation of T-47D human breast cancer cells enhances induction of DNA cle...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1988-01-15 00:00:00
abstract：:The serum concentration of alpha1-fetoprotein (alpha1F) was determined in rats following exposure to the hepatocarcinogen, 3'-methyl-4-dimethylaminoazobenzene, and its analogs. Small quantities of the carcinogen caused a rapid and significant elevation of alpha1F. Neither 2-methyl-4-dimethylaminoazobenzene nor p-amino...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1975-06-01 00:00:00
abstract：:Solid tumors contain a subset of stem-like cells that are resistant to the cytotoxic effects of chemotherapy/radiotherapy, but their susceptibility to cytolytic T lymphocyte (CTL) effector mechanisms has not been well characterized. Using a panel of early-passage human brain tumor stem/initiating cell (BTSC) lines der...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-09-2687
更新日期：2009-12-01 00:00:00
abstract：:Pyruvate kinase isozymes were studied in normal brain tissue (both fetal and adult) and in meningiomas and malignant gliomas. In fetal brain five different forms could be detected by electrophoresis (K4, K3M, K2M2, KM3, and M4). In adult brain the M4-type, K3M hybrid, and K4-type are present; the M isozyme is largely ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1978-12-01 00:00:00
abstract：:When L1210 cells growing logarithmically were exposed for 8 hr to a nonlethal dose of 5-fluorouracil (FU) (0.25 microgram/ml), the percentage of cells in S phase increased from 74.9% in the asynchronous culture to 93% in the FU-treated culture. This resulted in increased cell-kill by S-phase-specific inhibitors [1-bet...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1977-09-01 00:00:00
abstract：:The ability of the in vitro sister chromatid exchange (SCE) assay to predict in vivo tumor drug sensitivity was investigated using a spontaneous hepatocarcinoma in C3Hf/Kam mice and 3 chemotherapeutic agents: melphalan; cis-platinum; and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). For hepatocarcinoma cells grown in m...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1985-05-01 00:00:00
abstract：:The existence of two subgroups of BRCA1-associated breast cancer (BC) families has been recently posited: the first with highly proliferating tumors, and the second composed of cases with a low proliferation rate. Our aim was to test whether the proliferation rate of BRCA1-associated breast cancers was affected by the...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1996-07-15 00:00:00
abstract：:Valinomycin (NSC 122023) is a cyclic depsipeptide antibiotic with potassium selective ionophoric activity. This drug has been reported to display antitumor effects but its utilization has been limited by its extreme toxicity. Here we report that the incorporation of valinomycin into multilamellar liposomes composed of...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1986-11-01 00:00:00
abstract：:We have previously reported that rodent tumor cell lines secrete a potent vascular permeability factor with a molecular weight of 34,000-42,000 (Senger et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science (Wash. DC), 219: 983-985, 1983). This tumor-secreted vas...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1986-11-01 00:00:00
abstract：:Anti-idiotype monoclonal antibodies (Mabs) to mLL2, an anti-B-cell lymphoma and CD22-specific murine IgG2a-kappa Mab, were generated by hybridoma technology from splenocytes of Copenhagen rats immunized with mLL2 F(ab')2. Mab WN, an IgG2a-kappa, was selected based on its specific binding to mLL2 and not other IgG isot...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1995-12-01 00:00:00
abstract：:Prostacyclin has been evaluated for its ability to inhibit tumor cell-induced platelet aggregation (TCIPA) induced by several rodent tumor lines: B16a (melanoma); 3LL (carcinoma); 15091A (adenocarcinoma); and W256 (carcinosarcoma). Aggregation of human platelets by all four lines was inhibited by prostaglandin I2 (PGI...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1984-02-01 00:00:00
abstract：:Clonal variants of mouse epidermal JB6 cells that are genetically susceptible (P+) or resistant (P-) to tumor promoter-induced neoplastic transformation exhibit differential activator protein-1 (AP-1) response. Transactivation of AP-1 appears to be necessary but not sufficient to promote transformation in JB6 cells. I...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-05-15 00:00:00
abstract：:Glycogen synthase kinase 3beta (GSK3beta) is a multifunctional serine/threonine kinase. We showed that the expression of GSK3beta was drastically down-regulated in human cutaneous squamous cell carcinomas and basal cell carcinomas. Due to its negative regulation of many oncogenic proteins, we hypothesized that GSK3bet...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-06-4665
更新日期：2007-08-15 00:00:00
abstract：:In this study we describe the establishment of a leukemic cell line (BNML-CL/ara-C), originating from the 1-beta-D-arabinofuranosylcytosine (ara-C)-resistant brown Norway rat myelocytic leukemia model (BNML/ara-C), that retains the in vivo generated ara-C resistance. Its biological and biochemical characteristics have...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1990-10-15 00:00:00
abstract：:A phenolic amine compound, 4-S-cysteaminylphenol (4-S-CAP), is a potent depigmenting agent. To develop more efficacious antimelanoma agents, we synthesized four homologues of 4-S-CAP: N-acetyl-4-S-CAP (N-Ac-4-S-CAP), alpha-methyl-4-S-CAP, 4-S-homo-CAP, and N,N'-dimethyl-4-S-CAP. We tested these five compounds in mice ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1990-06-15 00:00:00
abstract：:Increasing evidence argues that the success of an anticancer treatment may rely on immunoadjuvant side effects including the induction of immunogenic tumor cell death. Based on the assumption that this death mechanism is a similar prerequisite for the efficacy of an active immunotherapy using killed tumor cells, we ex...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-10-1825
更新日期：2010-11-15 00:00:00
abstract：:The effects of vascular endothelial growth factor-A (VEGF-A/VEGF) and its receptors on endothelial cells function have been studied extensively, but their effects on tumor cells are less well defined. Studies of human colorectal cancer cells where the VEGF gene has been deleted suggest an intracellular role of VEGF as...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-15-1605
更新日期：2016-05-15 00:00:00
