Angiogenesis inhibitors overcome tumor induced endothelial cell anergy

Damen, Cora A.; Mayo, Kevin H.; Barendsz-Janson, A.F.; Martinotti, Stefano; Blijham, Geert H.; Groenewegen, Gerard

doi:10.1002/(sici)1097-0215(19990118)80:2<315::aid-ijc23>3.0.co;2-l

Cited by 76 publications

(62 citation statements)

References 20 publications

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“…In recent years, ECs have been the target cell of some angiogenesis inhibitors that have been undergoing clinical trials. These inhibitors can selectively affect diverse EC functions that are related to angiogenesis, including activation, proliferation, migration, invasion and survival [25,26] . It has been reported that particles of realgar (As 2 S 2 ) with an average diameter of 100-150 nm can induce EVCV-304 cell apoptosis [27] .…”

Section: Discussionmentioning

confidence: 99%

Effect of arsenic trioxide on vascular endothelial cell proliferation and expression of vascular endothelial growth factor receptors Flt-1 and KDR in gastric cancer in nude mice

Xiao¹

2007

WJG

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AIM:To investigate the effect of arsenic trioxide (As2O3) on expression of vascular endothelial growth factor receptor-1 (VEGFR-1, Flt-1) and VEGFR-2 (KDR) in human gastric tumor cells and proliferation of vascular endothelial cells. METHODS:The solid tumor model was formed in nude mice with the gastric cancer cell line SGC-7901. The animals were treated with As2O3. Microvessel density (MVD) and expression of Flt-1 and KDR were detected by immunofluorescence laser confocal microscopy. SGC-7901 cells were treated respectively by exogenous recombinant human VEGF165 or VEGF165 + As2O3. Cell viability was measured by MTT assay. Cell viability of ECV304 cells was measured by MTT assay, and cell cycle and apoptosis were analyzed using flow cytometry. RESULTS:The tumor growth inhibition was 30.33% and 50.85%, respectively, in mice treated with As2O3 2.5 and 5 mg/kg. MVD was significantly lower in arsenic-treated mice than in the control group. The fluorescence intensity levels of Flt-1 and KDR were significantly less in the arsenic-treated mice than in the control group. VEGF165 may accelerate growth of SGC7901 cells, but As2O3 may disturb the stimulating effect of VEGF165. ECV304 cell growth was suppressed by 76.51%, 71.09% and 61.49% after 48 h treatment with As2O3 at 0.5, 2.5 and 5 μmol/L, respectively. Early apoptosis in the As2O3-treated mice was 2.88-5.1 times higher than that in the controls, and late apoptosis was 1.17-1.67 times higher than that in the controls. CONCLUSION:Our results showed that As2O3 delays tumor growth, inhibits MVD, down-regulates Flt-1 and KDR expression, and disturbs the stimulating effect of VEGF165 on the growth of SGC7901 cells. These results suggest that As2O3 might delay growth of gastric tumors through inhibiting the paracrine and autocrine pathways of VEGF/VEGFRs.

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Section: Discussionmentioning

confidence: 99%

Effect of arsenic trioxide on vascular endothelial cell proliferation and expression of vascular endothelial growth factor receptors Flt-1 and KDR in gastric cancer in nude mice

Xiao¹

2007

WJG

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“…32 Reciprocally, ICAM-1 expression in melanoma cells and primary vascular endothelial cells could be completely suppressed and significantly overexpressed (59-fold and 135-fold, respectively). This is of particular importance, since ICAM-1 is specifically down-regulated in tumor endothelial cells during tumor angio-genesis 33 and de novo expression of ICAM-1 in melanoma correlates with increased risk of metastasis. 34 Therefore, our library and affinity maturation approach provide powerful TF ZF s to study ICAM-1 regulation and function by imposed regulation.…”

Section: Discussionmentioning

confidence: 99%

“…12 Comparative analysis of ICAM-1 flow cytometric data, mean fluorescence intensities (MFI), was determined using CELLQuest software (Becton Dickinson) as described. 33 For each sample analyzed, the MFI was corrected for background by subtraction of the autofluorescence of cells incubated with the secondary antibody only and normalized to the value of cells infected with the unselected 6ZFlibrary and presented as fold activation or percentage remaining ICAM-1. For ICAM-1 induction studies, 20 ng/ml IL-1b (Sigma) and 10 ng/ml TNF-a (Sigma) were added to the cells 12 hours before the FACS analysis.…”

Section: Retroviral Gene Delivery and Facsmentioning

confidence: 99%

In Vivo Selection of Combinatorial Libraries and Designed Affinity Maturation of Polydactyl Zinc Finger Transcription Factors for ICAM-1 Provides New Insights into Gene Regulation

Magnenat

Blancafort

Barbas

2004

Journal of Molecular Biology

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Zinc finger DNA-binding domains can be combined to create new proteins of desired DNA-binding specificity. By shuffling our repertoire of modified zinc finger domains to create randomly generated polydactyl zinc finger proteins with transcriptional regulatory domains, we developed large combinatorial libraries of zinc finger transcription factors (TF ZF s). Millions of TF ZF s can then be simultaneously screened in mammalian cells. Here, we successfully isolated specific TF ZF s that significantly positively and negatively modulate the transcription of the ICAM-1 gene in primary and cancer cells, which are relevant to ICAM-1 biology and tumor development. We show that TF ZF s can work in a general and in a cell-type specific manner depending on the regulatory domain and the zinc finger protein. We show that a TF ZF that interacts directly with the ICAM-1 promoter at an overlapping NF-kB binding enhancer can overcome or synergistically cooperate with NF-kB induction of ICAM-1. For this TF ZF , rational design was used to optimize the binding of the zinc finger protein to its DNA element and the resulting TF ZF demonstrated a direct correlation between increased affinity and efficiency of target gene regulation. Thus, combining library and affinity maturation approaches generated superior TF ZF s that may find further applications in therapeutic research and in ICAM-1 biology, and also provided novel mechanistic insights into the biology of transcription factors. Transcription factor libraries provide genome-wide approaches that can be applied towards the development of TF ZF s specific for virtually any gene or desired phenotype and may lead to the discovery of new genetic functions and pathways.

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“…Angiostatin, when bound to integrins, 35 may alter trafficking of lymphocytes, while the expression of hypoxic-induced proangiogenic factors in tumors can alter the expression of cell adhesion molecules involved in systemic cell trafficking. 36,37 Hence, this alteration by angiostatin in the trafficking of cells that have receptors for IL-2 may affect how IL-2 is distributed throughout the host. The significantly higher level of sFvIL-2 in the circulation and in the tumor may account for the improved efficacy of the coencapsulation protocol compared to the single IL-2 treatment (Fig 3b).…”

Section: Discussionmentioning

confidence: 99%