Vascular Endothelial Growth Factor: A Therapeutic Target for Tumors of the Ewing's Sarcoma Family

Dalal, Sharvari; Berry, Andrea M.; Cullinane, Catherine; Mangham, D. C.; Grimer, R. J.; Lewis, Ian; Johnston, C.; Laurence, Valérie; Burchill, Susan A.

doi:10.1158/1078-0432.ccr-04-1201

Cited by 109 publications

(86 citation statements)

References 59 publications

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“…Microvessel density was determined as described previously. 17 Briefly, 4 or 5 fields per tumor were scored for tumor microvessel elements at 4003 magnification and tumor microvessel densities (i.e., number of microvessel elements/field) were calculated.…”

Section: Immunohistochemistry (Ihc) Analysismentioning

confidence: 99%

E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition

Matsui¹,

Yamamoto²,

Funahashi³

et al. 2007

Intl Journal of Cancer

483

315

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E7080 is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. In this study, we show the inhibitory activity of E7080 against SCF-induced angiogenesis in vitro and tumor growth of SCF-producing human small cell lung carcinoma H146 cells in vivo. E7080 inhibits SCF-driven tube formation of HUVEC, which express SCF receptor, KIT at the IC 50 value of 5.2 nM and it was almost identical for VEGFdriven one (IC 50 5 5.1 nM). To assess the role of SCF/KIT signaling in tumor angiogenesis, we evaluated the effect of imatinib, a selective KIT kinase inhibitor, on tumor growth of H146 cells in nude mice. Imatinib did not show the potent antitumor activity in vitro (IC 50 5 2,200 nM), because H146 cells did not express KIT. However, oral administration of imatinib at 160 mg/kg clearly slowed tumor growth of H146 cells in nude mice, accompanied by decreased microvessel density. Oral administration of E7080 inhibited tumor growth of H146 cells at doses of 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg. While anti-VEGF antibody also slowed tumor growth, it did not cause tumor regression. These results indicate that KIT signaling has a role in tumor angiogenesis of SCF-producing H146 cells, and E7080 causes regression of H146 tumors as a result of antiangiogenic activity mediated by inhibition of both KIT and VEGF receptor signaling. E7080 may provide therapeutic benefits in the treatment of SCF-producing tumors. ' 2007 Wiley-Liss, Inc.

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Section: Immunohistochemistry (Ihc) Analysismentioning

confidence: 99%

E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition

Matsui¹,

Yamamoto²,

Funahashi³

et al. 2007

Intl Journal of Cancer

483

315

View full text Add to dashboard Cite

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“…VEGF is one of the well-studied angiogenic factors; it is produced and secreted by Angiogenesis in GIST M Imamura et al tumor cells and is associated with tumor neovascularization in various kind of malignant tumors. 14,33,34 Likewise, VEGF expressed by GIST cells may function via a paracrine mechanism in angiogenesis in GIST.…”

Section: Factorsmentioning

confidence: 99%

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

et al. 2007

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Angiogenesis is important in the growth and metastasis of various kinds of solid tumors. To investigate the potential role of angiogenesis in gastrointestinal stromal tumor (GIST), an immunohistochemical analysis was performed in 95 cases of GISTs for microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression. MVD was evaluated with immunohistochemical staining for CD31. A high level of MVD was significantly correlated with overexpression of VEGF, tumor location (intestine4stomach), tumor size (Z5 cm), tumor grade (high4intermediate4low grade) (P ¼ o0.0001, 0.0422, 0.0006, 0.0359, respectively). Of the 70 GISTs analyzed, KIT exon 11 mutations were detected in 45 cases (64.3%) and KIT exon 9 mutations in two cases (2.9%). No mutations were found in KIT exons 13 and 17, and platelet-derived growth factor receptor-alpha exons 12 and 18. Interestingly, VEGF expression level was significantly higher in the non-KIT exon 11 mutant group than in the KIT exon 11 mutant group (P ¼ 0.0266). In univariate analysis, tumor grade (high grade), tumor size (Z5 cm), mitotic count (Z5/50 high-power fields), Ki-67 labeling index (Z4.6%), MVD (Z7.0/0.95 mm 2 ) and VEGF expression (high) were significantly associated with a shorter period of disease-free survival (P ¼ o0.0001, 0.0199, 0.0055 0.0027, 0.0028 and 0.0302, respectively). In multivariate analysis, tumor grade and MVD were identified as independent worse prognostic factors (P ¼ 0.0007, 0.0152, respectively). In conclusion, our results suggest that the evaluation of MVD and VEGF expression is useful for predicting the aggressive biologic behavior of GIST, and that angiogenesis associated with VEGF may play an important role, at least in part, in the progression of GIST. Modern Pathology (2007) 20, 529-537.

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“…Both the presence of active IGF-IR and the autocrine production of IGF-I have been observed in EWS cells 12 and, although several other growth factor circuits are involved in deregulated EWS tumor cell growth, [13][14][15] the contribution of the IGF-I/IGF-IR circuit to the malignant behavior of EWS cells has been clearly identified to be of major importance. IGF-IR is implicated in the autocrine and paracrine control of EWS growth and appears to be particularly relevant for the pathogenesis of this tumor.…”

mentioning

confidence: 99%

Insulin‐like growth factor binding protein 3 as an anticancer molecule in Ewing's sarcoma

Benini

Zuntini

Manara

et al. 2006

Intl Journal of Cancer

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The IGF/IGF‐IR system plays a major role in the pathogenesis and progression of Ewing's sarcoma. In this article, the authors evaluated whether the insulin‐like growth factor binding protein‐3 (IGFBP‐3), a molecule with growth‐inhibitory and proapoptotic activities, may be exploited for therapeutic applications in the treatment of Ewing's sarcoma (EWS). Expression of IGFBP‐3 was analyzed in a panel of EWS cell lines and clinical samples. Parameters related to malignancy (growth in anchorage‐independent conditions, migration, invasion and angiogenesis properties) were studied to establish the potential in vitro anticancer effects of exogenous IGFBP‐3. The activity of the molecule against metastasis was analyzed by taking advantage of selected clones in which IGFBP‐3 endogenous production was induced by gene transfection. The authors observed a generally low expression of IGFBP‐3 either in a panel of EWS cell lines or clinical samples. Exogenous IGFBP‐3 remarkably inhibits EWS growth, both in monolayer and anchorage‐independent conditions, and significantly reduces cell motility. Forced expression of IGFBP‐3 in TC‐71 EWS cells confirms the growth and migratory effects observed with the exogenous protein, decreases the production or activity of the matrixmetalloprotease MMP‐9 and vascular endothelial factor (VEGF)‐A and abrogates EWS metastasis ability. IGFBP‐3 acts mainly through IGF‐dependent mechanisms and the protein may therefore represent an alternative strategy to inhibit IGF‐IR functions. The data indicate IGFBP‐3 as a molecule of therapeutic potential in EWS. © 2006 Wiley‐Liss, Inc.

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Vascular Endothelial Growth Factor: A Therapeutic Target for Tumors of the Ewing's Sarcoma Family

Cited by 109 publications

References 59 publications

E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition

E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

Insulin‐like growth factor binding protein 3 as an anticancer molecule in Ewing's sarcoma

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