Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic Response
Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted therapies predominantly affect nascent, immature tumor vessels. Since platelet-derived growth factor receptor (PDGFR) blockade inhibits vessel maturation and thus increases the amount of immature tumor vessels, we evaluated whe...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-11-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558617300404 |
| _version_ | 1828386942311464960 |
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| author | Sara Zafarnia Jessica Bzyl-Ibach Igor Spivak Yongping Li Susanne Koletnik Dennis Doleschel Anne Rix Sibylle Pochon Isabelle Tardy Seena Koyadan Marc van Zandvoort Moritz Palmowski Fabian Kiessling Wiltrud Lederle |
| author_facet | Sara Zafarnia Jessica Bzyl-Ibach Igor Spivak Yongping Li Susanne Koletnik Dennis Doleschel Anne Rix Sibylle Pochon Isabelle Tardy Seena Koyadan Marc van Zandvoort Moritz Palmowski Fabian Kiessling Wiltrud Lederle |
| author_sort | Sara Zafarnia |
| collection | DOAJ |
| description | Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted therapies predominantly affect nascent, immature tumor vessels. Since platelet-derived growth factor receptor (PDGFR) blockade inhibits vessel maturation and thus increases the amount of immature tumor vessels, we evaluated whether the combined PDGFR inhibition by nilotinib and VEGFR2 blockade by DC101 has synergistic therapy effects in a desmoplastic breast cancer xenograft model. In this context, besides immunohistological evaluation, molecular ultrasound imaging with BR55, the clinically used VEGFR2-targeted microbubbles, was applied to monitor VEGFR2-positive vessels noninvasively and to assess the therapy effects on tumor angiogenesis. DC101 treatment alone inhibited tumor angiogenesis, resulting in lower tumor growth and in significantly lower vessel density than in the control group after 14 days of therapy. In contrast, nilotinib inhibited vessel maturation but enhanced VEGFR2 expression, leading to markedly increased tumor volumes and a significantly higher vessel density. The combination of both drugs led to an almost similar tumor growth as in the DC101 treatment group, but VEGFR2 expression and microvessel density were higher and comparable to the controls. Further analyses revealed significantly higher levels of tumor cell–derived VEGF in nilotinib-treated tumors. In line with this, nilotinib, especially in low doses, induced an upregulation of VEGF and IL-6 mRNA in the tumor cells in vitro, thus providing an explanation for the enhanced angiogenesis observed in nilotinib-treated tumors in vivo. These findings suggest that nilotinib inhibits vessel maturation but counteracts the effects of antiangiogenic co-therapy by enhancing VEGF expression by the tumor cells and stimulating tumor angiogenesis. |
| first_indexed | 2024-12-10T05:47:15Z |
| format | Article |
| id | doaj.art-0bfad39e91c6449da9f7b6358df61396 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-10T05:47:15Z |
| publishDate | 2017-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-0bfad39e91c6449da9f7b6358df613962022-12-22T02:00:08ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022017-11-01191189690710.1016/j.neo.2017.08.009Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic ResponseSara Zafarnia0Jessica Bzyl-Ibach1Igor Spivak2Yongping Li3Susanne Koletnik4Dennis Doleschel5Anne Rix6Sibylle Pochon7Isabelle Tardy8Seena Koyadan9Marc van Zandvoort10Moritz Palmowski11Fabian Kiessling12Wiltrud Lederle13Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, GermanyInstitute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, GermanyInstitute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, GermanyInstitute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, GermanyInstitute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, GermanyInstitute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, GermanyInstitute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, GermanyBracco Suisse SA, Geneva, SwitzerlandBracco Suisse SA, Geneva, SwitzerlandCore Facility Two-Photon Imaging, Interdisciplinary Center for Clinical Research Aachen, GermanyInstitute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University Clinic, Aachen, GermanyAcademic Radiology Baden-Baden, Diagnostic and Interventional Radiology, University Medical Center Heidelberg, GermanyInstitute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, GermanyInstitute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, GermanyVascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted therapies predominantly affect nascent, immature tumor vessels. Since platelet-derived growth factor receptor (PDGFR) blockade inhibits vessel maturation and thus increases the amount of immature tumor vessels, we evaluated whether the combined PDGFR inhibition by nilotinib and VEGFR2 blockade by DC101 has synergistic therapy effects in a desmoplastic breast cancer xenograft model. In this context, besides immunohistological evaluation, molecular ultrasound imaging with BR55, the clinically used VEGFR2-targeted microbubbles, was applied to monitor VEGFR2-positive vessels noninvasively and to assess the therapy effects on tumor angiogenesis. DC101 treatment alone inhibited tumor angiogenesis, resulting in lower tumor growth and in significantly lower vessel density than in the control group after 14 days of therapy. In contrast, nilotinib inhibited vessel maturation but enhanced VEGFR2 expression, leading to markedly increased tumor volumes and a significantly higher vessel density. The combination of both drugs led to an almost similar tumor growth as in the DC101 treatment group, but VEGFR2 expression and microvessel density were higher and comparable to the controls. Further analyses revealed significantly higher levels of tumor cell–derived VEGF in nilotinib-treated tumors. In line with this, nilotinib, especially in low doses, induced an upregulation of VEGF and IL-6 mRNA in the tumor cells in vitro, thus providing an explanation for the enhanced angiogenesis observed in nilotinib-treated tumors in vivo. These findings suggest that nilotinib inhibits vessel maturation but counteracts the effects of antiangiogenic co-therapy by enhancing VEGF expression by the tumor cells and stimulating tumor angiogenesis.http://www.sciencedirect.com/science/article/pii/S1476558617300404 |
| spellingShingle | Sara Zafarnia Jessica Bzyl-Ibach Igor Spivak Yongping Li Susanne Koletnik Dennis Doleschel Anne Rix Sibylle Pochon Isabelle Tardy Seena Koyadan Marc van Zandvoort Moritz Palmowski Fabian Kiessling Wiltrud Lederle Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic Response Neoplasia: An International Journal for Oncology Research |
| title | Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic Response |
| title_full | Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic Response |
| title_fullStr | Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic Response |
| title_full_unstemmed | Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic Response |
| title_short | Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic Response |
| title_sort | nilotinib enhances tumor angiogenesis and counteracts vegfr2 blockade in an orthotopic breast cancer xenograft model with desmoplastic response |
| url | http://www.sciencedirect.com/science/article/pii/S1476558617300404 |
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