Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesis
Thrombosis can cause localized ischemia and tissue hypoxia, and both of these are linked to cancer metastasis. Vascular micro-occlusion can occur as a result of arrest of circulating tumour cells in small capillaries, giving rise to microthrombotic events that affect flow, creating localized hypoxic...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2017-05-01
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| Series: | Biology Open |
| Subjects: | |
| Online Access: | http://bio.biologists.org/content/6/5/688 |
| _version_ | 1819004343068655616 |
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| author | Colin E. Evans Asis Palazon Jingwei Sim Petros A. Tyrakis Alice Prodger Xiao Lu Saria Chan Pär-Ola Bendahl Mattias Belting Love Von Euler Helene Rundqvist Randall S. Johnson Cristina Branco |
| author_facet | Colin E. Evans Asis Palazon Jingwei Sim Petros A. Tyrakis Alice Prodger Xiao Lu Saria Chan Pär-Ola Bendahl Mattias Belting Love Von Euler Helene Rundqvist Randall S. Johnson Cristina Branco |
| author_sort | Colin E. Evans |
| collection | DOAJ |
| description | Thrombosis can cause localized ischemia and tissue hypoxia, and both of these are linked to cancer metastasis. Vascular micro-occlusion can occur as a result of arrest of circulating tumour cells in small capillaries, giving rise to microthrombotic events that affect flow, creating localized hypoxic regions. To better understand the association between metastasis and thrombotic events, we generated an experimental strategy whereby we modelled the effect of microvascular occlusion in metastatic efficiency by using inert microbeads to obstruct lung microvasculature before, during and after intravenous tumour cell injection. We found that controlled induction of a specific number of these microthrombotic insults in the lungs caused an increase in expression of the hypoxia-inducible transcription factors (HIFs), a pro-angiogenic and pro-tumorigenic environment, as well as an increase in myeloid cell infiltration. Induction of pulmonary microthrombosis prior to introduction of tumour cells to the lungs had no effect on tumorigenic success, but thrombosis at the time of tumour cell seeding increased number and size of tumours in the lung, and this effect was strikingly more pronounced when the micro-occlusion occurred on the day following introduction of tumour cells. The tumorigenic effect of microbead treatment was seen even when thrombosis was induced five days after tumour cell injection. We also found positive correlations between thrombotic factors and expression of HIF2α in human tumours. The model system described here demonstrates the importance of thrombotic insult in metastatic success and can be used to improve understanding of thrombosis-associated tumorigenesis and its treatment. |
| first_indexed | 2024-12-20T23:35:23Z |
| format | Article |
| id | doaj.art-4bb30084d1524fcabf20b1feeab2ac4f |
| institution | Directory Open Access Journal |
| issn | 2046-6390 |
| language | English |
| last_indexed | 2024-12-20T23:35:23Z |
| publishDate | 2017-05-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Biology Open |
| spelling | doaj.art-4bb30084d1524fcabf20b1feeab2ac4f2022-12-21T19:23:13ZengThe Company of BiologistsBiology Open2046-63902017-05-016568869710.1242/bio.024653024653Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesisColin E. Evans0Asis Palazon1Jingwei Sim2Petros A. Tyrakis3Alice Prodger4Xiao Lu5Saria Chan6Pär-Ola Bendahl7Mattias Belting8Love Von Euler9Helene Rundqvist10Randall S. Johnson11Cristina Branco12 Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK Department of Clinical Sciences, Lund University, Lund, SE-221 00, Sweden Department of Clinical Sciences, Lund University, Lund, SE-221 00, Sweden Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm SE-171 77, Sweden Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm SE-171 77, Sweden Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK Thrombosis can cause localized ischemia and tissue hypoxia, and both of these are linked to cancer metastasis. Vascular micro-occlusion can occur as a result of arrest of circulating tumour cells in small capillaries, giving rise to microthrombotic events that affect flow, creating localized hypoxic regions. To better understand the association between metastasis and thrombotic events, we generated an experimental strategy whereby we modelled the effect of microvascular occlusion in metastatic efficiency by using inert microbeads to obstruct lung microvasculature before, during and after intravenous tumour cell injection. We found that controlled induction of a specific number of these microthrombotic insults in the lungs caused an increase in expression of the hypoxia-inducible transcription factors (HIFs), a pro-angiogenic and pro-tumorigenic environment, as well as an increase in myeloid cell infiltration. Induction of pulmonary microthrombosis prior to introduction of tumour cells to the lungs had no effect on tumorigenic success, but thrombosis at the time of tumour cell seeding increased number and size of tumours in the lung, and this effect was strikingly more pronounced when the micro-occlusion occurred on the day following introduction of tumour cells. The tumorigenic effect of microbead treatment was seen even when thrombosis was induced five days after tumour cell injection. We also found positive correlations between thrombotic factors and expression of HIF2α in human tumours. The model system described here demonstrates the importance of thrombotic insult in metastatic success and can be used to improve understanding of thrombosis-associated tumorigenesis and its treatment.http://bio.biologists.org/content/6/5/688HIFHypoxiaThrombosisMetastasisMicrovascular |
| spellingShingle | Colin E. Evans Asis Palazon Jingwei Sim Petros A. Tyrakis Alice Prodger Xiao Lu Saria Chan Pär-Ola Bendahl Mattias Belting Love Von Euler Helene Rundqvist Randall S. Johnson Cristina Branco Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesis Biology Open HIF Hypoxia Thrombosis Metastasis Microvascular |
| title | Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesis |
| title_full | Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesis |
| title_fullStr | Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesis |
| title_full_unstemmed | Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesis |
| title_short | Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesis |
| title_sort | modelling pulmonary microthrombosis coupled to metastasis distinct effects of thrombogenesis on tumorigenesis |
| topic | HIF Hypoxia Thrombosis Metastasis Microvascular |
| url | http://bio.biologists.org/content/6/5/688 |
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