Aspirin affects early phases of metastasis through the inhibition of COX-1-thromboxane A2 axis
<p>Metastasis is the major cause of cancer related mortality, due to a poor understanding of the metastatic process and a subsequent lack of effective anti-metastatic therapies. Evidence from experimental studies and clinical trials has shown that aspirin reduces the incidence of distant metas...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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2016
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| _version_ | 1826273980511682560 |
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| author | Lucotti, S |
| author2 | Muschel, R |
| author_facet | Muschel, R Lucotti, S |
| author_sort | Lucotti, S |
| collection | OXFORD |
| description | <p>Metastasis is the major cause of cancer related mortality, due to a poor understanding of the metastatic process and a subsequent lack of effective anti-metastatic therapies. Evidence from experimental studies and clinical trials has shown that aspirin reduces the incidence of distant metastases. It is well established that aspirin inhibits cyclooxygenase (COX)-1 and COX-2, triggering anti-thrombotic and anti-inflammatory effects, respectively. However, the mechanisms underlying the anti-metastatic effect of aspirin are still largely unknown. </p> <p>By using an experimental model of pulmonary metastasis, we have found that the anti-metastatic effect of aspirin is associated with the inhibition of COX-1. In support of this, metastasis establishment was impaired in COX-1 deficient mice, suggesting a pivotal role of this isoform in the metastatic process. Looking in more detail into the metastatic cascade, we found that COX-1 contributes to the intravascular phase of metastasis and promotes the early persistence of tumour cells in the lung vasculature. In particular, COX-1 inhibition decreased the interaction of platelets with tumour cells and was associated with the reduction of endothelial activation, of tumour cell adhesion to the endothelium, of recruitment of metastasis-promoting monocytes/macrophages and of transendothelial migration. We have identified platelet-derived thromboxane A<sub>2</sub> (TXA<sub>2</sub>) as the main product of COX-1 responsible for its permissive effect on metastasis. Indeed, TXA<sub>2</sub> delivered to mice in combination with aspirin was able to abrogate the anti-metastatic effect of aspirin.</p> <p>Taken together, our data suggest that the inhibition of COX-1:TXA<sub>2</sub> axis by aspirin is sufficient to exert an anti-metastatic effect. In particular, the inhibition of platelet-derived TXA<sub>2</sub> seems to affect multiple early steps of the haematogenous transit of tumour cells. In this perspective, TXA<sub>2</sub> might represent a more selective therapeutic target for the prevention of metastasis.</p> |
| first_indexed | 2024-03-06T22:36:29Z |
| format | Thesis |
| id | oxford-uuid:5a12480c-6b8a-4f46-b38a-4b59122e9280 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:36:29Z |
| publishDate | 2016 |
| record_format | dspace |
| spelling | oxford-uuid:5a12480c-6b8a-4f46-b38a-4b59122e92802022-03-26T17:13:35ZAspirin affects early phases of metastasis through the inhibition of COX-1-thromboxane A2 axisThesishttp://purl.org/coar/resource_type/c_db06uuid:5a12480c-6b8a-4f46-b38a-4b59122e9280EnglishORA Deposit2016Lucotti, SMuschel, R<p>Metastasis is the major cause of cancer related mortality, due to a poor understanding of the metastatic process and a subsequent lack of effective anti-metastatic therapies. Evidence from experimental studies and clinical trials has shown that aspirin reduces the incidence of distant metastases. It is well established that aspirin inhibits cyclooxygenase (COX)-1 and COX-2, triggering anti-thrombotic and anti-inflammatory effects, respectively. However, the mechanisms underlying the anti-metastatic effect of aspirin are still largely unknown. </p> <p>By using an experimental model of pulmonary metastasis, we have found that the anti-metastatic effect of aspirin is associated with the inhibition of COX-1. In support of this, metastasis establishment was impaired in COX-1 deficient mice, suggesting a pivotal role of this isoform in the metastatic process. Looking in more detail into the metastatic cascade, we found that COX-1 contributes to the intravascular phase of metastasis and promotes the early persistence of tumour cells in the lung vasculature. In particular, COX-1 inhibition decreased the interaction of platelets with tumour cells and was associated with the reduction of endothelial activation, of tumour cell adhesion to the endothelium, of recruitment of metastasis-promoting monocytes/macrophages and of transendothelial migration. We have identified platelet-derived thromboxane A<sub>2</sub> (TXA<sub>2</sub>) as the main product of COX-1 responsible for its permissive effect on metastasis. Indeed, TXA<sub>2</sub> delivered to mice in combination with aspirin was able to abrogate the anti-metastatic effect of aspirin.</p> <p>Taken together, our data suggest that the inhibition of COX-1:TXA<sub>2</sub> axis by aspirin is sufficient to exert an anti-metastatic effect. In particular, the inhibition of platelet-derived TXA<sub>2</sub> seems to affect multiple early steps of the haematogenous transit of tumour cells. In this perspective, TXA<sub>2</sub> might represent a more selective therapeutic target for the prevention of metastasis.</p> |
| spellingShingle | Lucotti, S Aspirin affects early phases of metastasis through the inhibition of COX-1-thromboxane A2 axis |
| title | Aspirin affects early phases of metastasis through the inhibition of COX-1-thromboxane A2 axis |
| title_full | Aspirin affects early phases of metastasis through the inhibition of COX-1-thromboxane A2 axis |
| title_fullStr | Aspirin affects early phases of metastasis through the inhibition of COX-1-thromboxane A2 axis |
| title_full_unstemmed | Aspirin affects early phases of metastasis through the inhibition of COX-1-thromboxane A2 axis |
| title_short | Aspirin affects early phases of metastasis through the inhibition of COX-1-thromboxane A2 axis |
| title_sort | aspirin affects early phases of metastasis through the inhibition of cox 1 thromboxane a2 axis |
| work_keys_str_mv | AT lucottis aspirinaffectsearlyphasesofmetastasisthroughtheinhibitionofcox1thromboxanea2axis |