Abstract:
:Repurposing "old" drugs can facilitate rapid clinical translation but necessitates novel mechanistic insight. Warfarin, a vitamin K "antagonist" used clinically for the prevention of thrombosis for more than 50 years, has been shown to have anticancer effects. We hypothesized that the molecular mechanism underlying its antitumor activity is unrelated to its effect on coagulation, but is due to inhibition of the Axl receptor tyrosine kinase on tumor cells. Activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. Here, we show that inhibiting Gas6-dependent Axl activation with low-dose warfarin, or with other tumor-specific Axl-targeting agents, blocks the progression and spread of pancreatic cancer. Warfarin also inhibited Axl-dependent tumor cell migration, invasiveness, and proliferation while increasing apoptosis and sensitivity to chemotherapy. We conclude that Gas6-induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low-dose warfarin or other Axl-targeting agents may improve outcome in patients with Axl-expressing tumors.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Kirane A,Ludwig KF,Sorrelle N,Haaland G,Sandal T,Ranaweera R,Toombs JE,Wang M,Dineen SP,Micklem D,Dellinger MT,Lorens JB,Brekken RAdoi
10.1158/0008-5472.CAN-14-2887-Tsubject
Has Abstractpub_date
2015-09-15 00:00:00pages
3699-705issue
18eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-14-2887-Tjournal_volume
75pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract::The treatment of K562 human myeloblastic leukemia cells and YAC-1 murine lymphoma cells with cadeguomycin at concentrations over 0.6 microM significantly enhanced the cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C). The degree of potentiation depended upon the antibiotic concentration. The treatment with 75 ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1987-02-01 00:00:00
abstract::Two murine monoclonal antibodies, 2H6G5 (IgM) and 4A9E10 (IgG3), were obtained by using either cultured human hepatocellular carcinoma cells (PLC/PRF/5) or the acidic glycolipid mixture prepared from the same cells as immunogens. The antigen in PLC/PRF/5 cell membranes recognized by both antibodies was identified as a...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1988-12-01 00:00:00
abstract::A series of nitrofuran-based compounds were identified as inhibitors of estrogen signaling in a cell-based, high-throughput screen of a diverse library of small molecules. These highly related compounds were subsequently found to inhibit topoisomerase II in vitro at concentrations similar to that required for the inhi...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-0393
更新日期:2007-05-01 00:00:00
abstract::The molecular pathways driving mesenchymal glioblastoma (GBM) are still not well understood. We report here that truncated glioma-associated oncogene homolog 1 (tGLI1) is a tumor-specific transcription factor that facilitates GBM growth, is enriched in the mesenchymal subtype of GBM and glioma stem cells (GSC), and pr...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-17-2933
更新日期:2018-05-15 00:00:00
abstract::Lipid peroxidation is considered a unifying mechanistic pathway through which known risk factors induce renal cell carcinoma (RCC). We hypothesized that genes selected a priori for their role in lipid peroxidation would modify cancer risk. We genotyped 635 single nucleotide polymorphisms (SNP) in 38candidate genes in ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-09-1734
更新日期:2009-10-15 00:00:00
abstract::Prior studies of fluorescence anisotropy (polarization) with diphenylhexatriene in normal and malignant cell populations have shown differences which have been attributed to an altered membrane lipid composition in cancer. We studied fresh tumor cells from patients with diverse lymphoid neoplasms and found a discrete ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1981-02-01 00:00:00
abstract::Activin, a member of the transforming growth factor beta (TGFbeta) superfamily, regulates diverse processes, such as cellular growth and differentiation. There is increasing evidence that TGFbeta and its signaling effectors are key determinants of tumor cell behavior. Loss of sensitivity to TGFbeta-induced growth arre...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-0805
更新日期:2007-08-01 00:00:00
abstract::Chronic exposure to UV radiation (UVR), especially in the UVA (315-400 nm) and UVB (280-315 nm) spectrum of sunlight, is the major risk factor for the development of nonmelanoma skin cancer. UVR is a complete carcinogen, which both initiates and promotes carcinogenesis. We found that protein kinase C epsilon (PKCepsil...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-1881
更新日期:2004-11-01 00:00:00
abstract::UV radiation has been shown to play a role in the initiation of human cutaneous melanoma, but its role in the development of malignant melanoma to the metastatic state is not very well defined. Although previous studies have concentrated on the effect of UV-B on the host immune response, the effect of UV-B on the tumo...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1995-08-15 00:00:00
abstract::Since gamma-interferon (IFN-gamma) is a potent immunomodulator and patients receiving certain antineoplastic agents are at risk of unusual infections, we have determined the effect of certain antineoplastic agents on IFN-gamma production. Induction of peripheral blood mononuclear cells from normal donors in the presen...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1984-11-01 00:00:00
abstract::The specific binding of labeled porcine insulin, human prolactin, and human growth hormone was studied in 63 human breast tumors and 15 nonmalignant breast tissues. Most (90%) of the tumors demonstrated significant binding of insulin, as did 80% of nonmalignant tissues. Autoradiographic studies indicated that insulin ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1977-07-01 00:00:00
abstract::To determine whether the toxic effects and changes in many cell functions caused by antitumor 1-nitroacridines are related to their enzymatically mediated covalent interstrand DNA cross-linking (J. Konopa, J. W. Pawlak, and K. Pawlak. Chem.-Biol. Interact., 43: 175-197, 1983), the cross-linking potency of the derivati...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1984-10-01 00:00:00
abstract::Multiple tobacco smoke-related premalignant and malignant lesions develop synchronously or metachronously in various organ sites, including the oral cavity. Both field cancerization and clonal migration seem to contribute to the occurrence of multiple tumors. Although the importance of endogenous factors (e.g., oncoge...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-1388
更新日期:2007-09-15 00:00:00
abstract::The prodrug of 9-beta-D-arabinosylguanine (ara-G), nelarabine, demonstrated efficacy against T-cell acute lymphoblastic leukemia, and its effectiveness correlated with the accumulation of the triphosphate form (ara-GTP). Although in vitro investigations using purified deoxycytidine kinase (dCK) or deoxyguanosine kinas...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2002-06-01 00:00:00
abstract::We examined the therapeutic effect of lipopolysaccharide (LPS), a differentiation inducer, in combination with daunomycin, an antileukemia drug possessing differentiation-inducing potential, on a rat myelomonocytic leukemia (c-WRT-7). c-WRT-7 cells were found to differentiate into macrophage-like cells and to lose the...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1987-03-15 00:00:00
abstract::In vitro analysis of the mitosis from 3-day lymphocyte cultures from two normal males and two normal females treated with bromodeoxyuridine and stained with acridine orange after addition of vincristine during different times demonstrated that vincristine inhibits the progression of the second division. When the secon...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1976-08-01 00:00:00
abstract::Carcinoembryonic antigen (CEA)-related cell adhesion molecule 1 (CEACAM1) is a member of the CEA family of immunoglobulin-like adhesion molecules with two major splice variants, CEACAM1(a)-4L and CEACAM1(b)-4S, differing in the length of their COOH-terminal cytoplasmic tail. Both forms are down-regulated in prostate a...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-2841
更新日期:2005-12-01 00:00:00
abstract::Clinical response of liver metastases treated by high-dose intraarterial chemotherapy (HDIAC) delivered via the hepatic artery was predicted by a modification of the human tumor colony-forming assay (HTCFA) originally described by Hamburger and Salmon [Science (Wash. DC), 197:461-463, 1977. In a first set of experimen...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-09-01 00:00:00
abstract::The invasive transformation of A-459 lung epithelial carcinoma cells has been linked to the autocrine regulation of malignant phenotypic changes by transforming growth factor beta (TGF-beta). Here we demonstrate, using stable 13C glucose isotopes, that the transformed phenotype is characterized by decreased CO2 produc...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2000-03-01 00:00:00
abstract::The local growth rate of Morris Hepatoma 44 (generation time, 6 months) was inhibited by 66 to 87%, and host survival was prolonged by 36 to 78% after the induction of hypothyroidism within 2 weeks of tumor implantation by propylthiouracil (0.1% in Purina chow), 131I(1 mCi/100 g body weight i.p.), or surgical thyroide...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1981-08-01 00:00:00
abstract::Natural killer (NK) cells safeguard against early tumor formation by destroying transformed target cells in a process referred to as NK immune surveillance. However, the immune escape mechanisms used by malignant brain tumors to subvert this innate type of immune surveillance remain unclear. Here we show that malignan...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-14-1203
更新日期:2014-09-15 00:00:00
abstract::Carcinoma cells can transition from an epithelial-to-mesenchymal differentiation state through a process known as epithelial-mesenchymal transition (EMT). The process of EMT is characterized by alterations in the pattern of gene expression and is associated with a loss of cell polarity, an increase in invasiveness, an...
journal_title:Cancer research
pub_type: 杂志文章,评审
doi:10.1158/0008-5472.CAN-14-2824
更新日期:2015-01-01 00:00:00
abstract::After 10 years of clinical trials in patients with advanced cancer, monoclonal antibodies (mAbs) against cell surface antigens have not lived up to their initial promise. One such cell surface antigen is the ganglioside GD2. GD2 is richly expressed at the cell surfaces of human neuroblastomas, sarcomas, and melanomas....
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1998-07-01 00:00:00
abstract::The migration of three human prostate tumor epithelial cell lines (TSU-pr1, PC-3, DU-145) in response to secreted protein from a human prostate stromal cell line was investigated by using the modified blind-well Boyden chamber assay. Migrated cells were quantified by spectrophotometrically measuring the concentration ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1993-03-15 00:00:00
abstract::Thirty-seven endometrial cancers were subjected to an allelotype analysis in an attempt to identify chromosomal regions that are lost in a significant portion of tumors and to identify tumors characterized by replication errors. Thirty-nine highly polymorphic microsatellite markers representing all chromosomal arms, e...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1995-05-01 00:00:00
abstract::Previously, we have shown that the expression of Wnt-1-induced signaling protein-2 (WISP-2), also known as CCN5, can be regulated by multiple stimulants in estrogen receptor (ER)-positive breast tumor cells to exert their mitogenic action in these cells. Here, we show that insulin-like growth factor-1 (IGF-1), a stron...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-3753
更新日期:2007-02-15 00:00:00
abstract::The human leukemia cell lines HL-60, KG-1, KLM-2, ML-3, THP-1, and U-937 were treated with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). TPA partially or completely inhibited the proliferative activity of the cell cultures. The number of cells with the ability to reduce nitroblue tetrazolium increased ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-12-01 00:00:00
abstract::4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is activated to DNA alkylating species via two different alpha-hydroxylation pathways. Methylene hydroxylation leads to DNA methylation, whereas methyl hydroxylation yields DNA pyridyloxobutylation. We have developed a high-pressure liquid chromatography assay utili...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1991-10-15 00:00:00
abstract::Peripheral blood monocytes were isolated from normal human donors by separation on a continuous Percoll gradient and adherence to yield preparations of blood monocytes with a high degree of purity (greater than 99%). The monocytes were incubated in vitro with medium alone or with multilamellar liposomes that contained...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1983-05-01 00:00:00
abstract::Seventy-nine esophageal carcinoma patients were studied for genetic abnormalities in the p53 and Rb tumor suppressor genes. Single-strand conformation polymorphism analysis and DNA sequencing were used to detect p53 point mutations, Northern blotting was used to examine abnormal expression of p53 and Rb, and polymeras...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1993-04-15 00:00:00