Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2

Abstract

Because metastasis is associated with the majority of cancer-related deaths, its prevention is a clinical aspiration. Prostanoids are a large family of bioactive lipids derived from the activity of cyclooxygenase-1 (COX-1) and COX-2. Aspirin impairs the biosynthesis of all prostanoids through the irreversible inhibition of both COX isoforms. Long-term administration of aspirin leads to reduced distant metastases in murine models and clinical trials, but the COX isoform, downstream prostanoid, and cell compartment responsible for this effect are yet to be determined. Here, we have shown that aspirin dramatically reduced lung metastasis through inhibition of COX-1 while the cancer cells remained intravascular and that inhibition of platelet COX-1 alone was sufficient to impair metastasis. Thromboxane A 2 (TXA 2 ) was the prostanoid product of COX-1 responsible for this antimetastatic effect. Inhibition of the COX-1/TXA 2 pathway in platelets decreased aggregation of platelets on tumor cells, endothelial activation, tumor cell adhesion to the endothelium, and recruitment of metastasis-promoting monocytes/macrophages, and diminished the formation of a premetastatic niche. Thus, platelet-derived TXA 2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and identifies COX-1/TXA 2 signaling as a target for the prevention of metastasis.

New insights into cancer's exploitation of platelets

“…While the mechanisms by which platelets impede NK‐mediated clearance of newly adherent metastatic tumor cells in the lungs remain an active area of study, it is notable that previous studies demonstrated that in the absence of functioning NK cells, platelet function was no longer a determinant of early tumor cell survival . Notably, the timeframe whereby platelet/NK cell interactions impacted metastatic potential closely paralleled that observed for the COX‐1/TXA 2 pathway . Specifically, platelet functions were dispensable for the initial adhesion of embolic tumor cells in the pulmonary vasculature, but platelet‐mediated inhibition of NK cell functions were important in the first hours to days after the tumor cells arrived in the lungs .…”

“…17 Notably, the timeframe whereby platelet/NK cell interactions impacted metastatic potential closely paralleled that observed for the COX-1/TXA 2 pathway. 14,17 Specifically, platelet functions were dispensable for the initial adhesion of embolic tumor cells in the pulmonary vasculature, but platelet-mediated inhibition of NK cell functions were important in the first hours to days after the tumor cells arrived in the lungs. 17 Platelet functions were also shown to be entirely dispensable for the robust growth of established metastatic foci.…”

“…The fact that we are now almost 60 years from the initial observation showing a role for platelets in metastasis, and we are still elucidating the mechanisms coupling platelets to metastasis, speaks to both the complexity of the metastatic process and the complexity of platelet biology. In a recent paper published in the Journal of Clinical Investigation, Lucotti et al used a combination of in vitro and in vivo experimental systems to provide strong evidence directly linking activation of the cyclooxygenase/thromboxane A2 (COX‐1/TXA 2 ) pathway in platelets to metastatic potential . They showed that pharmacological inhibition of COX‐1 or genetic elimination of COX‐1 in the host significantly impaired metastasis, demonstrating that COX‐1 activity in the host cells rather than the tumor cells promotes metastasis.…”

“…While the elegant studies by Lucotti et al shed significant light on the specific role of the platelet COX‐1/TXA 2 pathway in metastasis, these studies also raise interesting and important questions. Previous studies showed that platelets promote metastasis through a mechanism that involves impedance of natural killer (NK) cell‐mediated clearance of micrometastases .…”

“…While the elegant studies by Lucotti et al14 shed significant light on the specific role of the platelet COX-1/TXA 2 pathway in metastasis, these studies also raise interesting and important questions.…”