Abstract：
:The vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. However, clinical trials targeting the VEGF pathway are often ineffective, suggesting that other factors/pathways are also important in tumor angiogenesis. We have previously shown that the Notch ligand Delta-like 4 (DLL4) is up-regulated in tumor vasculature. Here, we show that DLL4, when expressed in tumor cells, functions as a negative regulator of tumor angiogenesis by reducing the number of blood vessels in all five types of xenografts, but acts as a positive driver for tumor growth in two of them (human glioblastoma and prostate cancer). The growth of in vivo models was not related to the effects on growth in vitro. DLL4 expressed in the tumor cells activated Notch signaling in host stromal/endothelial cells, increased blood vessel size, and improved vascular function within tumors. The promotion of tumor growth was, to some extent, due to a reduction of tumor hypoxia and apoptosis. DLL4-expressing tumor cells responded to anti-VEGF therapy with bevacizumab. A soluble form of DLL4 (D4ECD-Fc) blocked tumor growth in both bevacizumab-sensitive and bevacizumab-resistant tumors by disrupting vascular function despite increased tumor vessel density. In addition, we show that DLL4 is up-regulated in tumor cells and tumor endothelial cells of human glioblastoma. Our findings provide a rational basis for the development of novel antiangiogenic strategies via blockade of DLL4/Notch signaling and suggest that combined approaches for interrupting both DLL4 and VEGF pathways may improve antiangiogenic therapy.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Li JL,Sainson RC,Shi W,Leek R,Harrington LS,Preusser M,Biswas S,Turley H,Heikamp E,Hainfellner JA,Harris ALdoi
10.1158/0008-5472.CAN-07-0969subject
Has Abstractpub_date
2007-12-01 00:00:00pages
11244-53issue
23eissn
0008-5472issn
1538-7445pii
67/23/11244journal_volume
67pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract：:The pharmacology of high-dose 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) has been studied by radiochemical and chromatographic techniques in eight patients. Plasma disappearance of FT was exponential, with a half-life of 8.8 hr. Plasma concentrations of 5-fluorouracil (FUra) were sustained at 12.8 nmol/ml (1.7 micro...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1978-11-01 00:00:00
abstract：:A nationwide study of all 3183 female patients with breast cancer in Israel diagnosed over a 7-year period (1960 to 1966) was conducted. Monthly series analysis showed a clear seasonal pattern in the symptomatology of the disease most pronounced in patients younger than 55 years, in all ethnic groups, mainly confined ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1983-02-01 00:00:00
abstract：:Degradation and invasion of basement membrane by tumor cells involves the cooperative hydrolysis of proteoglycans, collagens, and glycoproteins mediated by a number of enzymes including proteases, collagenases, and glycosidases. In order to study these processes in vitro, a tissue culture system was developed in which...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1989-10-15 00:00:00
abstract：:Crude tissue or tumor extracts either do not contain sufficient inosine 5'-monophosphate dehydrogenase (IMPD) activity to be measured spectrophotometrically, or interfering enzyme activities prevent the use of a more sensitive radiochemical assay. A modified assay system which incorporates alpha, beta-methylene adenos...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1983-04-01 00:00:00
abstract：:Hypoxia is a common feature of solid tumors. Prolyl hydroxylase enzymes (PHD1-3) are molecular oxygen sensors that regulate hypoxia-inducible factor activity, but their functions in metastatic disease remain unclear. Here, we assessed the significance of PHD enzymes during the metastatic spread of colorectal cancer. P...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-15-1474
更新日期：2016-04-15 00:00:00
abstract：:Groups of 120 male and 120 female rats were exposed by inhalation to 0, 2, 6, or 15 ppm formaldehyde vapor 6 hr/day, 5 days/week, for 18 months of a 24-month study. The present communication describes interim findings based on data available after 18 months of exposure. Squamous cell carcinomas occurred in the nasal c...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1980-09-01 00:00:00
abstract：:Pemetrexed is a novel antifolate effective in the treatment of mesothelioma. Studies were undertaken to characterize the transport of this antifolate in this tumor. We report the presence of a novel, concentrative high-affinity transport activity in three human mesothelioma cell lines, characterized in detail in the N...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2002-11-15 00:00:00
abstract：:We report here the use of viral fusogenic membrane glycoproteins (FMGs) as a new class of therapeutic genes for the control of tumor growth. FMGs kill cells by fusing them into large multinucleated syncytia, which die by sequestration of cell nuclei and subsequent nuclear fusion by a mechanism that is nonapoptotic, as...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2000-03-15 00:00:00
abstract：:The Rb/E2F pathway is deregulated in most human brain tumors, and the finding that loss of E2F1 reduced pituitary tumorigenesis in Rb(+/-) mice suggests that loss of pRb induces brain tumors by activating E2F1. We therefore investigated the role of E2F1 in the development and maintenance of brain cancer using a transg...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-06-2973
更新日期：2007-05-01 00:00:00
abstract：:We have constructed a DNA plasmid encoding the full length complementary DNA for human carcinoembryonic antigen (CEA) driven by the cytomegalovirus early promoter/enhancer (plasmid DNA encoding human CEA) and demonstrated that this plasmid can function as a polynucleotide vaccine. This polynucleotide vaccine induced h...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1994-03-01 00:00:00
abstract：:Prostate cancer biology varies from locally confined tumors with low risk for relapse to tumors with high risk for progression even after radical prostatectomy. Currently, there are no reliable biomarkers to predict tumor relapse and poor clinical outcome. In this study, we correlated expression patterns of the androg...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-06-1570
更新日期：2006-12-01 00:00:00
abstract：:The most deadly phase in cancer progression is attributed to the inappropriate acquisition of molecular machinery leading to metastatic transformation and spread of disease to distant organs. Although it is appreciated that metastasis involves epithelial-mesenchymal interplay, the underlying mechanism defining this pr...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-10-3223
更新日期：2011-02-15 00:00:00
abstract：:Primary prostate cancer can have extensive microheterogeneity, but its contribution to the later emergence of metastatic castration-resistant prostate cancer (mCRPC) remains unclear. In this study, we microdissected residual prostate cancer foci in radical prostatectomies from 18 men treated with neoadjuvant-intensive...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-18-0610
更新日期：2018-08-15 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：:DIS3-like 3'-5' exoribonuclease 2 (DIS3L2) degrades aberrant RNAs, however, its function in tumorigenesis remains largely unexplored. Here, aberrant DIS3L2 expression promoted human hepatocellular carcinoma (HCC) progression via heterogeneous nuclear ribonucleoproteins (hnRNP) U-mediated alternative splicing. DIS3L2 d...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-19-0376
更新日期：2019-10-01 00:00:00
abstract：:Oncogenic transformation has been induced in vitro in the C3H/10T1/2 clone 8 line of mouse cells by exposure to 5-fluoro-2'-deoxyuridine (FUdR) or 5-fluorouracil. This transformation is both dose and time dependent and can be markedly decreased by simultaneous exposure of the cells to thymidine. The transformation ind...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1976-01-01 00:00:00
abstract：:In order to explain the heterogeneity of Ca antigen (Ca) expression observed previously on human malignant cells, a relationship of antigen content with events in the cell cycle was studied by multiparameter flow cytometry on four continuous human cell lines, HeLaS3, C4l, HT29, and T24, grown exponentially in culture....
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1984-10-01 00:00:00
abstract：:The capacity for tumor cells to metastasize efficiently is directly linked to their ability to colonize secondary sites. Here we identify Six2, a developmental transcription factor, as a critical regulator of a breast cancer stem cell program that enables metastatic colonization. In several triple-negative breast canc...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-18-1791
更新日期：2019-02-15 00:00:00
abstract：:Several studies have suggested that calmodulin (CAM) levels increase in cells as a consequence of transformation by RNA tumor viruses. This study examines factors affecting CAM levels in normal and transformed chick embryo fibroblasts. Significant differences in CAM levels of normal and transformed cells were observed...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1984-08-01 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：:Recent technologic advances have permitted higher resolution and more rapid analysis of individual cancer genomes at the single-nucleotide level. Such advances have shown bewildering intertumor heterogeneity with limited somatic alterations shared between tumors of the same histopathologic subtype. Exacerbating such c...
journal_title：Cancer research
pub_type： 杂志文章,评审
doi：10.1158/0008-5472.CAN-12-2217
更新日期：2012-10-01 00:00:00
abstract：:Extracellular signal-regulated kinases (ERK) regulate cellular functions in response to a variety of external signals. However, the specific functions of individual ERK isoforms are largely unknown. Hence, we have investigated the specific function of ERK1 in skin homeostasis and tumorigenesis in ERK1 knockout mice. T...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-05-3129
更新日期：2006-03-01 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：:Combination of chemotherapy and immunotherapy to increase the effectiveness of an antitumor immune response is currently regarded as an attractive antitumor strategy. In a pilot clinical trial, we have recently documented an increase of melanoma antigen A (Melan-A)-specific, tumor-reactive, long-lasting effector-memor...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-10-1326
更新日期：2010-09-15 00:00:00
abstract：:SMYD3 methyltransferase is nearly undetectable in normal human tissues but highly expressed in several cancers, including breast cancer, although its contributions to pathogenesis in this setting are unclear. Here we report that histone H2A.Z.1 is a substrate of SMYD3 that supports malignancy. SMYD3-mediated dimethyla...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-16-0500
更新日期：2016-10-15 00:00:00
abstract：:Retinoids have chemopreventive activity for epithelial tumors in a variety of systems, including the two-stage tumorigenesis system of mouse skin in which only the promotion stage is inhibited. We asked whether dietary vitamin A deficiency could affect the skin tumorigenic response, prior to major changes in body weig...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1989-10-01 00:00:00
abstract：:Glioblastoma multiforme (GBM) is the most frequent and incurable type of brain tumor of adults. Hypoxia has been shown to direct GBM toward a more aggressive and malignant state. Here we show that hypoxia increases Notch1 activation, which in turn induces the expression of transient receptor potential 6 (TRPC6) in pri...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-09-2654
更新日期：2010-01-01 00:00:00
abstract：:Human polynucleotide phosphorylase (hPNPase(old-35)) is a type I IFN-inducible 3',5' exoribonuclease that mediates mRNA degradation. In melanoma cells, slow and sustained overexpression of hPNPase(old-35) induces G(1) cell cycle arrest ultimately culminating in apoptosis, whereas rapid overexpression of hPNPase(old-35...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-07-0872
更新日期：2007-09-01 00:00:00
abstract：:A family of cell surface glycoproteins with a molecular weight of 96,000 (gp96) has recently been implicated in the individually distinct immunogenicity of chemically induced sarcomas of inbred mice. Rabbit antiserum to murine gp96 detects an antigenically related Mr 96,000 cell surface glycoprotein on two cultured hu...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1989-03-15 00:00:00
abstract：:The use of rat testicular seminiferous tubular basement membrane (STBM) segments as a model substratum for the in vitro maintenance of tumor cells dissociated from a transplantable pancreatic acinar rat carcinoma (J. K. Reddy and M. S. Rao, Science (Wash. DC), 198: 78-80, 1977) is described. Ultrastructurally pure, ho...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1984-11-01 00:00:00
