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  • 1
    Keywords: RECEPTOR ; SPECTRA ; ANGIOGENESIS ; CANCER ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; proliferation ; SURVIVAL ; tumor ; ADVANCED SOLID TUMORS ; AGENTS ; ANGIOSTATIN ; BLOOD ; carcinoma ; CELL ; CELL LUNG-CANCER ; CELL-PROLIFERATION ; CLINICAL-TRIAL ; COMBINATION ; DOPPLER ; ENDOTHELIAL GROWTH-FACTOR ; evaluation ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; LUNG ; MICROSCOPY ; MICROVESSEL DENSITY ; MODEL ; MODELS ; neoplasms ; PATHWAY ; PATHWAYS ; PERFUSION ; PHASE-I ; PROSTATE ; RECOMBINANT HUMAN ENDOSTATIN ; THERAPY ; TOXICITY ; tumor growth ; TYROSINE KINASE ; VITRO ; VIVO
    Abstract: The multifaceted nature of the angiogenic process in malignant neoplasms suggests that protocols that combine antiangiogenic agents may be more effective than single-agent therapies. However it is unclear which combination of agents would be most efficacious and will have the highest degree of synergistic activity while maintaining low overall toxicity. Here we investigate the concept of combining a "direct" angiogenesis inhibitor (endostatin) with an "indirect" antiangiogenic compound [SU5416, a vascular endothelial growth factor receptor 2 (VEGFR2) receptor tyrosine kinase (RTK) inhibitor]. These angiogenic agents were more effective in combination than when used alone in vitro (endothelial cell proliferation, survival, migration/invasion, and tube formation tests) and in vivo. The combination of SU5416 and low-dose endostatin further reduced tumor growth versus monotherapy in human prostate (M), lung (A459), and glioma (U87) xenograft models, and reduced functional microvessel density, tumor microcirculation, and blood perfusion as detected by intravital microscopy and contrast-enhanced Doppler ultrasound. One plausible explanation for the efficacious combination could be that, whereas SU5416 specifically inhibits vascular endothelial growth factor signaling, low-dose endostatin is able to inhibit a broader spectrum of diverse angiogenic pathways directly in the endothelium. The direct antiangiogenic agent might be able to suppress alternative angiogenic pathways up-regulated by the tumor in response to the indirect, specific pathway inhibition. For future clinical evaluation of the concept, a variety of agents with similar mechanistic properties could be tested
    Type of Publication: Journal article published
    PubMed ID: 14695206
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  • 2
    Keywords: ENVIRONMENT ; RECEPTOR ; ANGIOGENESIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; INHIBITOR ; tumor ; AGENTS ; CELL ; Germany ; human ; NETWORK ; RISK ; GENE ; GENES ; PROTEIN ; PROTEINS ; DRUG ; COMPONENTS ; MICE ; PATIENT ; knockout ; STAGE ; PROGRESSION ; DESIGN ; INDUCED APOPTOSIS ; METASTASIS ; COLORECTAL-CANCER ; COMPONENT ; cancer risk ; RECURRENCE ; COLON-CANCER ; CANCER-PATIENTS ; STRATEGIES ; REVEALS ; systems biology ; CANCER PATIENTS ; pancreatic cancer ; pancreatic carcinoma ; chronic pancreatitis ; ACQUIRED-RESISTANCE ; INHIBITORS ; signaling ; AGENT ; RE ; PANCREATIC-CANCER ; PATTERN ; TUMOR-GROWTH ; cancer therapy ; PANCREATITIS ; regulation ; antiangiogenic therapy ; LEVEL ; pancreatic ; USA ; DRUGS ; INCREASED RISK ; CANCER-RISK ; ENDOTHELIAL-CELL ; HOMEOSTASIS ; SPECIMENS ; peroxisome ; EGFR INHIBITORS ; GLUCOSYLCERAMIDE SYNTHASE ; homeostatic balance ; PPAR-DELTA
    Abstract: A shift of the angiogenic balance to the proangiogenic state, termed the "angiogenic switch," is a hallmark of cancer progression. Here we devise a strategy for identifying genetic participants of the angiogenic switch based on inverse regulation of genes in human endothelial cells in response to key endogenous pro- and antiangiogenic proteins. This approach reveals a global network pattern for vascular homeostasis connecting known angiogenesis-related genes with previously unknown signaling components. We also demonstrate that the angiogenic switch is governed by simultaneous regulations of multiple genes organized as transcriptional circuitries. In pancreatic cancer patients, we validate the transcriptome-derived switch of the identified "angiogenic network:" The angiogenic state in chronic pancreatitis specimens is intermediate between the normal (angiogenesis off) and neoplastic (angiogenesis on) condition, suggesting that aberrant proangiogenic environment contributes to the increased cancer risk in patients with chronic pancreatitis. In knockout experiments in mice, we show that the targeted removal of a hub node (peroxisome proliferative-activated receptor delta) of the angiogenic network markedly impairs angiogenesis and tumor growth. Further, in tumor patients, we show that peroxisome proliferative-activated receptor 8 expression levels are correlated with advanced pathological tumor stage, increased risk for tumor recurrence, and distant metastasis. Our results therefore also may contribute to the rational design of antiangiogenic cancer agents; whereas "narrow" targeted cancer drugs may fail to shift the robust angiogenic regulatory network toward antiangiogenesis, the network may be more vulnerable to multiple or broad-spectrum inhibitors or to the targeted removal of the identified angiogenic "hub" nodes
    Type of Publication: Journal article published
    PubMed ID: 17652168
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