Dataset Information

Morpholino-Mediated Isoform Modulation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) Reduces Colon Cancer Xenograft Growth.

ABSTRACT: Angiogenesis plays a key role in tumor growth. Vascular endothelial growth factor (VEGF) is a pro-angiogenic that is involved in tumor angiogenesis. When VEGF binds to membrane-bound vascular endothelial growth factor receptor 2 (mVEGFR2), it promotes angiogenesis. Through alternative polyadenylation, VEGFR2 is also expressed in a soluble form (sVEGFR2). sVEGFR2 sequesters VEGF and is therefore anti-angiogenic. The aim of this study was to show that treatment with a previously developed and reported antisense morpholino oligomer that shifts expression from mVEGFR2 to sVEGFR2 would lead to reduced tumor vascularization and growth in a murine colon cancer xenograft model. Xenografts were generated by implanting human HCT-116 colon cancer cells into the flanks of NMRI nu/nu mice. Treatment with the therapeutic morpholino reduced both tumor growth and tumor vascularization. Because the HCT-116 cells used for the experiments did not express VEGFR2 and because the treatment morpholino targeted mouse rather than human VEGFR2, it is likely that treatment morpholino was acting on the mouse endothelial cells rather than directly on the tumor cells.

SUBMITTER: Stagg BC

PROVIDER: S-EPMC4276969 | biostudies-other | 2014 Nov

REPOSITORIES: biostudies-other

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Morpholino-Mediated Isoform Modulation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) Reduces Colon Cancer Xenograft Growth.

Stagg Brian C BC Uehara Hironori H Lambert Nathan N Rai Ruju R Gupta Isha I Radmall Bryce B Bates Taylor T Ambati Balamurali K BK

Cancers 20141126 4

Angiogenesis plays a key role in tumor growth. Vascular endothelial growth factor (VEGF) is a pro-angiogenic that is involved in tumor angiogenesis. When VEGF binds to membrane-bound vascular endothelial growth factor receptor 2 (mVEGFR2), it promotes angiogenesis. Through alternative polyadenylation, VEGFR2 is also expressed in a soluble form (sVEGFR2). sVEGFR2 sequesters VEGF and is therefore anti-angiogenic. The aim of this study was to show that treatment with a previously developed and repo ...[more]

PMID: 25534570

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Project description:PurposeA previously published study demonstrated a pharmacogenetic association between the minor alleles of 2 VEGFR2 single nucleotide polymorphisms (SNPs) and greater improvement in visual acuity (VA) to treatment with ranibizumab, an anti-vascular endothelial growth factor (VEGF) drug, in patients with neovascular age-related macular degeneration (AMD). We evaluated whether this association was replicated among patients who participated in the Comparison of AMD Treatments Trials (CATT) or the Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation (IVAN) trial.DesignCohort studies within randomized clinical trials.ParticipantsEight hundred thirty-five patients participating in CATT and 512 patients participating in IVAN.MethodsEach patient was genotyped for the SNPs rs4576072 and rs6828477 in the VEGFR2 gene.Main outcomes measuresMean change in VA from baseline to 1 year after initiation of treatment with ranibizumab or bevacizumab. Differences in VA response between the patient group homozygous for the minor allele of each SNP and the other genotype groups were evaluated with analysis of variance. Differences in VA response by the number of minor alleles present for either SNP or both combined were evaluated with tests of linear trend. Analyses were conducted separately for CATT and IVAN participants and with both the studies combined.ResultsNo statistically significant difference in mean change in VA was identified between genotypes of either SNP (P ≥ 0.05). Furthermore, a stepwise analysis failed to show a significant interaction for either SNP based on the number of minor alleles present. The lack of association was similar in both the CATT and IVAN cohorts and whether the analysis combined patients treated with either ranibizumab or bevacizumab or when restricted to patients treated with ranibizumab only.ConclusionsThe CATT and IVAN data do not support a pharmacogenetic association between the 2 VEGFR2 SNPs, rs4576072 and rs6828477, and change in VA in response to anti-VEGF therapy in patients with neovascular AMD.

Dataset Information

Morpholino-Mediated Isoform Modulation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) Reduces Colon Cancer Xenograft Growth.

Publications

Morpholino-Mediated Isoform Modulation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) Reduces Colon Cancer Xenograft Growth.

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