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. 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. 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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:729984 |
| Date | January 2016 |
| Creators | Lucotti, Serena |
| Contributors | Muschel, Ruth J. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://ora.ox.ac.uk/objects/uuid:5a12480c-6b8a-4f46-b38a-4b59122e9280 |
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