Regression of Human Breast Carcinoma in Nude Mice after Ad<i>sflt</i> Gene Therapy Is Mediated by Tumor Vascular Endothelial Cell Apoptosis
Two vascular endothelial growth factor (VEGF) receptors, FLT-1 and KDR, are expressed preferentially in proliferating endothelium. There is increasing evidence that recombinant, soluble VEGF receptor domains interfering with VEGF signaling may inhibit in vivo neoangiogenesis, tumor growth and metast...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/24/6175 |
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| author | Angelina Felici Donald P. Bottaro Antonella Mangoni Petra Reusch Dieter Marmé Imre Kovesdi Dinuka M. De Silva Young H. Lee Maurizio C. Capogrossi Judith Mühlhauser |
| author_facet | Angelina Felici Donald P. Bottaro Antonella Mangoni Petra Reusch Dieter Marmé Imre Kovesdi Dinuka M. De Silva Young H. Lee Maurizio C. Capogrossi Judith Mühlhauser |
| author_sort | Angelina Felici |
| collection | DOAJ |
| description | Two vascular endothelial growth factor (VEGF) receptors, FLT-1 and KDR, are expressed preferentially in proliferating endothelium. There is increasing evidence that recombinant, soluble VEGF receptor domains interfering with VEGF signaling may inhibit in vivo neoangiogenesis, tumor growth and metastatic spread. We hypothesized that a soluble form of FLT-1 receptor (sFLT-1) could inhibit the growth of pre-established tumors via an anti-angiogenic mechanism. A replication-deficient adenovirus (Ad) vector carrying the sflt-1 cDNA (Ad<i>sflt</i>) was used to overexpress the sFLT-1 receptor in a breast cancer animal model. MCF-7 cells, which produce VEGF, were used to establish solid tumors in the mammary fat pads of female nude mice. After six weeks, tumors were injected either with Ad<i>sflt</i> or a negative control virus (AdCMV.βgal). After six months, average tumor volume in the Ad<i>sflt</i>-infected group (33 ± 22 mm<sup>3</sup>) decreased by 91% relative to that of the negative control group (388 ± 94 mm<sup>3</sup>; <i>p</i> < 0.05). Moreover, 10 of 15 Ad<i>sflt</i>-infected tumors exhibited complete regression. The vascular density of Ad<i>sflt</i>-infected tumors was reduced by 50% relative to that of negative controls (<i>p</i> < 0.05), which is consistent with sFLT-1-mediated tumor regression through an anti-angiogenic mechanism. Moreover, cell necrosis and fibrosis associated with long-term regression of Ad<i>sflt</i>–infected tumors were preceded by apoptosis of tumor vascular endothelial cells. Mice treated with Ad<i>sflt</i> intratumorally showed no delay in the healing of cutaneous wounds, providing preliminary evidence that Ad-mediated sFLT-1 overexpression may be an effective anti-angiogenic therapy for cancer without the risk of systemic anti-angiogenic effects. |
| first_indexed | 2024-03-09T17:14:52Z |
| format | Article |
| id | doaj.art-f8e996d040894787aff0f3f3ce50fd7b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T17:14:52Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-f8e996d040894787aff0f3f3ce50fd7b2023-11-24T13:47:28ZengMDPI AGCancers2072-66942022-12-011424617510.3390/cancers14246175Regression of Human Breast Carcinoma in Nude Mice after Ad<i>sflt</i> Gene Therapy Is Mediated by Tumor Vascular Endothelial Cell ApoptosisAngelina Felici0Donald P. Bottaro1Antonella Mangoni2Petra Reusch3Dieter Marmé4Imre Kovesdi5Dinuka M. De Silva6Young H. Lee7Maurizio C. Capogrossi8Judith Mühlhauser9Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, 00167 Rome, ItalyLaboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USALaboratorio di Patologia Vascolare, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, 00167 Rome, ItalyInstitute of Molecular Medicine, Tumor Biology Center, D-79106 Freiburg, GermanyInstitute of Molecular Medicine, Tumor Biology Center, D-79106 Freiburg, GermanyUnleash Immuno-Oncolytics, Inc., St. Louis, MO 63110-1110, USAUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USAUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USALaboratorio di Patologia Vascolare, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, 00167 Rome, ItalyLaboratorio di Patologia Vascolare, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, 00167 Rome, ItalyTwo vascular endothelial growth factor (VEGF) receptors, FLT-1 and KDR, are expressed preferentially in proliferating endothelium. There is increasing evidence that recombinant, soluble VEGF receptor domains interfering with VEGF signaling may inhibit in vivo neoangiogenesis, tumor growth and metastatic spread. We hypothesized that a soluble form of FLT-1 receptor (sFLT-1) could inhibit the growth of pre-established tumors via an anti-angiogenic mechanism. A replication-deficient adenovirus (Ad) vector carrying the sflt-1 cDNA (Ad<i>sflt</i>) was used to overexpress the sFLT-1 receptor in a breast cancer animal model. MCF-7 cells, which produce VEGF, were used to establish solid tumors in the mammary fat pads of female nude mice. After six weeks, tumors were injected either with Ad<i>sflt</i> or a negative control virus (AdCMV.βgal). After six months, average tumor volume in the Ad<i>sflt</i>-infected group (33 ± 22 mm<sup>3</sup>) decreased by 91% relative to that of the negative control group (388 ± 94 mm<sup>3</sup>; <i>p</i> < 0.05). Moreover, 10 of 15 Ad<i>sflt</i>-infected tumors exhibited complete regression. The vascular density of Ad<i>sflt</i>-infected tumors was reduced by 50% relative to that of negative controls (<i>p</i> < 0.05), which is consistent with sFLT-1-mediated tumor regression through an anti-angiogenic mechanism. Moreover, cell necrosis and fibrosis associated with long-term regression of Ad<i>sflt</i>–infected tumors were preceded by apoptosis of tumor vascular endothelial cells. Mice treated with Ad<i>sflt</i> intratumorally showed no delay in the healing of cutaneous wounds, providing preliminary evidence that Ad-mediated sFLT-1 overexpression may be an effective anti-angiogenic therapy for cancer without the risk of systemic anti-angiogenic effects.https://www.mdpi.com/2072-6694/14/24/6175soluble FLT-1breast carcinomavessel regressionadenovirusgene therapy |
| spellingShingle | Angelina Felici Donald P. Bottaro Antonella Mangoni Petra Reusch Dieter Marmé Imre Kovesdi Dinuka M. De Silva Young H. Lee Maurizio C. Capogrossi Judith Mühlhauser Regression of Human Breast Carcinoma in Nude Mice after Ad<i>sflt</i> Gene Therapy Is Mediated by Tumor Vascular Endothelial Cell Apoptosis Cancers soluble FLT-1 breast carcinoma vessel regression adenovirus gene therapy |
| title | Regression of Human Breast Carcinoma in Nude Mice after Ad<i>sflt</i> Gene Therapy Is Mediated by Tumor Vascular Endothelial Cell Apoptosis |
| title_full | Regression of Human Breast Carcinoma in Nude Mice after Ad<i>sflt</i> Gene Therapy Is Mediated by Tumor Vascular Endothelial Cell Apoptosis |
| title_fullStr | Regression of Human Breast Carcinoma in Nude Mice after Ad<i>sflt</i> Gene Therapy Is Mediated by Tumor Vascular Endothelial Cell Apoptosis |
| title_full_unstemmed | Regression of Human Breast Carcinoma in Nude Mice after Ad<i>sflt</i> Gene Therapy Is Mediated by Tumor Vascular Endothelial Cell Apoptosis |
| title_short | Regression of Human Breast Carcinoma in Nude Mice after Ad<i>sflt</i> Gene Therapy Is Mediated by Tumor Vascular Endothelial Cell Apoptosis |
| title_sort | regression of human breast carcinoma in nude mice after ad i sflt i gene therapy is mediated by tumor vascular endothelial cell apoptosis |
| topic | soluble FLT-1 breast carcinoma vessel regression adenovirus gene therapy |
| url | https://www.mdpi.com/2072-6694/14/24/6175 |
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