Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signalling
Introduction: Surgery and radiotherapy are key cancer treatments and the leading causes of damage to the lymphatics, a vascular network critical to fluid homeostasis and immunity. The clinical manifestation of this damage constitutes a devastating side-effect of cancer treatment, known as lymphoedem...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1152314/full |
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| author | Vinochani Pillay Lipi Shukla Lipi Shukla Lipi Shukla Lipi Shukla Prad Herle Simon Maciburko Nadeeka Bandara Isabella Reid Steven Morgan Yinan Yuan Jennii Luu Karla J. Cowley Susanne Ramm Susanne Ramm Kaylene J. Simpson Kaylene J. Simpson Kaylene J. Simpson Marc G. Achen Steven A. Stacker Steven A. Stacker Ramin Shayan Ramin Shayan Ramin Shayan Ramin Shayan Tara Karnezis Tara Karnezis |
| author_facet | Vinochani Pillay Lipi Shukla Lipi Shukla Lipi Shukla Lipi Shukla Prad Herle Simon Maciburko Nadeeka Bandara Isabella Reid Steven Morgan Yinan Yuan Jennii Luu Karla J. Cowley Susanne Ramm Susanne Ramm Kaylene J. Simpson Kaylene J. Simpson Kaylene J. Simpson Marc G. Achen Steven A. Stacker Steven A. Stacker Ramin Shayan Ramin Shayan Ramin Shayan Ramin Shayan Tara Karnezis Tara Karnezis |
| author_sort | Vinochani Pillay |
| collection | DOAJ |
| description | Introduction: Surgery and radiotherapy are key cancer treatments and the leading causes of damage to the lymphatics, a vascular network critical to fluid homeostasis and immunity. The clinical manifestation of this damage constitutes a devastating side-effect of cancer treatment, known as lymphoedema. Lymphoedema is a chronic condition evolving from the accumulation of interstitial fluid due to impaired drainage via the lymphatics and is recognised to contribute significant morbidity to patients who survive their cancer. Nevertheless, the molecular mechanisms underlying the damage inflicted on lymphatic vessels, and particularly the lymphatic endothelial cells (LEC) that constitute them, by these treatment modalities, remain poorly understood.Methods: We used a combination of cell based assays, biochemistry and animal models of lymphatic injury to examine the molecular mechanisms behind LEC injury and the subsequent effects on lymphatic vessels, particularly the role of the VEGF-C/VEGF-D/VEGFR-3 lymphangiogenic signalling pathway, in lymphatic injury underpinning the development of lymphoedema.Results: We demonstrate that radiotherapy selectively impairs key LEC functions needed for new lymphatic vessel growth (lymphangiogenesis). This effect is mediated by attenuation of VEGFR-3 signalling and downstream signalling cascades. VEGFR-3 protein levels were downregulated in LEC that were exposed to radiation, and LEC were therefore selectively less responsive to VEGF-C and VEGF-D. These findings were validated in our animal models of radiation and surgical injury.Discussion: Our data provide mechanistic insight into injury sustained by LEC and lymphatics during surgical and radiotherapy cancer treatments and underscore the need for alternative non-VEGF-C/VEGFR-3-based therapies to treat lymphoedema. |
| first_indexed | 2024-04-09T15:31:10Z |
| format | Article |
| id | doaj.art-606001842ee84fea84121c90aaec3c6e |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-09T15:31:10Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-606001842ee84fea84121c90aaec3c6e2023-04-28T07:38:57ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-04-011410.3389/fphar.2023.11523141152314Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signallingVinochani Pillay0Lipi Shukla1Lipi Shukla2Lipi Shukla3Lipi Shukla4Prad Herle5Simon Maciburko6Nadeeka Bandara7Isabella Reid8Steven Morgan9Yinan Yuan10Jennii Luu11Karla J. Cowley12Susanne Ramm13Susanne Ramm14Kaylene J. Simpson15Kaylene J. Simpson16Kaylene J. Simpson17Marc G. Achen18Steven A. Stacker19Steven A. Stacker20Ramin Shayan21Ramin Shayan22Ramin Shayan23Ramin Shayan24Tara Karnezis25Tara Karnezis26O’Brien Institute Department, St Vincent’s Institute for Medical Research, Fitzroy, VIC, AustraliaO’Brien Institute Department, St Vincent’s Institute for Medical Research, Fitzroy, VIC, AustraliaDepartment of Plastic Surgery, St. Vincent’s Hospital, Fitzroy, VIC, AustraliaFaculty of Health Sciences, ACU, AORTEC; Australian Catholic University, Fitzroy, VIC, AustraliaDepartment of Plastic Surgery, Alfred Health, Melbourne, VIC, AustraliaO’Brien Institute Department, St Vincent’s Institute for Medical Research, Fitzroy, VIC, AustraliaO’Brien Institute Department, St Vincent’s Institute for Medical Research, Fitzroy, VIC, AustraliaO’Brien Institute Department, St Vincent’s Institute for Medical Research, Fitzroy, VIC, AustraliaO’Brien Institute Department, St Vincent’s Institute for Medical Research, Fitzroy, VIC, AustraliaO’Brien Institute Department, St Vincent’s Institute for Medical Research, Fitzroy, VIC, AustraliaO’Brien Institute Department, St Vincent’s Institute for Medical Research, Fitzroy, VIC, AustraliaVictorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC, AustraliaVictorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC, AustraliaVictorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC, AustraliaDepartment of Biochemistry and Pharmacology, University of Melbourne, Parkville, VIC, AustraliaVictorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC, AustraliaDepartment of Biochemistry and Pharmacology, University of Melbourne, Parkville, VIC, AustraliaDepartment of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, VIC, AustraliaO’Brien Institute Department, St Vincent’s Institute for Medical Research, Fitzroy, VIC, AustraliaTumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, AustraliaDepartment of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, AustraliaO’Brien Institute Department, St Vincent’s Institute for Medical Research, Fitzroy, VIC, AustraliaDepartment of Plastic Surgery, St. Vincent’s Hospital, Fitzroy, VIC, AustraliaDepartment of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, AustraliaDepartment of Plastic Surgery, Alfred Health, Melbourne, VIC, AustraliaO’Brien Institute Department, St Vincent’s Institute for Medical Research, Fitzroy, VIC, AustraliaDepartment of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, VIC, AustraliaIntroduction: Surgery and radiotherapy are key cancer treatments and the leading causes of damage to the lymphatics, a vascular network critical to fluid homeostasis and immunity. The clinical manifestation of this damage constitutes a devastating side-effect of cancer treatment, known as lymphoedema. Lymphoedema is a chronic condition evolving from the accumulation of interstitial fluid due to impaired drainage via the lymphatics and is recognised to contribute significant morbidity to patients who survive their cancer. Nevertheless, the molecular mechanisms underlying the damage inflicted on lymphatic vessels, and particularly the lymphatic endothelial cells (LEC) that constitute them, by these treatment modalities, remain poorly understood.Methods: We used a combination of cell based assays, biochemistry and animal models of lymphatic injury to examine the molecular mechanisms behind LEC injury and the subsequent effects on lymphatic vessels, particularly the role of the VEGF-C/VEGF-D/VEGFR-3 lymphangiogenic signalling pathway, in lymphatic injury underpinning the development of lymphoedema.Results: We demonstrate that radiotherapy selectively impairs key LEC functions needed for new lymphatic vessel growth (lymphangiogenesis). This effect is mediated by attenuation of VEGFR-3 signalling and downstream signalling cascades. VEGFR-3 protein levels were downregulated in LEC that were exposed to radiation, and LEC were therefore selectively less responsive to VEGF-C and VEGF-D. These findings were validated in our animal models of radiation and surgical injury.Discussion: Our data provide mechanistic insight into injury sustained by LEC and lymphatics during surgical and radiotherapy cancer treatments and underscore the need for alternative non-VEGF-C/VEGFR-3-based therapies to treat lymphoedema.https://www.frontiersin.org/articles/10.3389/fphar.2023.1152314/fullradiotherapyVEGFR-3VEGF-Clymphoedemaradiation-injuryLEC |
| spellingShingle | Vinochani Pillay Lipi Shukla Lipi Shukla Lipi Shukla Lipi Shukla Prad Herle Simon Maciburko Nadeeka Bandara Isabella Reid Steven Morgan Yinan Yuan Jennii Luu Karla J. Cowley Susanne Ramm Susanne Ramm Kaylene J. Simpson Kaylene J. Simpson Kaylene J. Simpson Marc G. Achen Steven A. Stacker Steven A. Stacker Ramin Shayan Ramin Shayan Ramin Shayan Ramin Shayan Tara Karnezis Tara Karnezis Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signalling Frontiers in Pharmacology radiotherapy VEGFR-3 VEGF-C lymphoedema radiation-injury LEC |
| title | Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signalling |
| title_full | Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signalling |
| title_fullStr | Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signalling |
| title_full_unstemmed | Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signalling |
| title_short | Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signalling |
| title_sort | radiation therapy attenuates lymphatic vessel repair by reducing vegfr 3 signalling |
| topic | radiotherapy VEGFR-3 VEGF-C lymphoedema radiation-injury LEC |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1152314/full |
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