LAUSR

Decades of research have led to vast improvements in our understanding and management of malignancy. However, cancer remains a leading cause of death worldwide. A major obstacle in treating most solid tumor malignancies is not the elimination of the primary tumor, but the elimination of metastases. In fact, metastasis accounts for ~90% of cancer‐related deaths.1 These grim statistics speak to the critical need to better understand the metastatic process. Hematogenous metastasis is an inefficient process involving several sequential steps: (a) phenotypic changes within the cancer cell and formation of the premetastatic niche, (b) cancer cell detachment from the primary tumor and invasion of surrounding tissue, (c) intravasation, (d) intravascular survival, (e) adherence of the circulating cell in a distant vascular bed, (f) extravasation, and (g) proliferation in the distant host organ.2 Only a small fraction of cells that leave the original tumor survive and form a tumor at a distant site. Malignant cells require a specialized microenvironment consisting of non‐malignant stromal cells (eg, fibroblasts, macrophages, and other immune cells); a supportive vasculature; and a broad array of chemokines, cytokines, and growth factors.3 Leaving this highly nurturing microenvironment can lead to malignant cell death or destruction by a host of factors, including sheer stress within the vasculature, components of the host immune system, or a failure to find a suitable metastatic niche.4 Even if cancer cells implant into distant organs, many fail to proliferate in the new environment.4 Understanding the vulnerabilities of potentially metastatic tumor cells could lead to the development of treatments to eradicate and/or prevent metastasis. Metastatic tumor cells have been shown to possess strong procoagulant activity that appears to be largely driven by the expression of tissue factor (TF), the primary cell‐associated initiator of the hemostatic cascade.2,5‐7 The view that procoagulant functions driven by tumor cell‐associated TF promotes metastatic potential is supported by numerous studies of murine models, as well as epidemiological evidence showing that TF expression by tumor cells correlates with more advanced/aggressive disease.8-10 Given the apparent importance of tumor cell‐associated procoagulant function to metastatic potential, it is perhaps not surprising that platelet functions have been shown to play a major role in metastasis.2,11,12 The fact that we are now almost 60 years from the initial observation showing a role for platelets in metastasis,13 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/TXA2) pathway in platelets to metastatic potential.14 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. They went on to show that TXA2 is the prostanoid product of COX‐1 responsible for this prometastatic effect. Their data further suggest that the COX‐1/TXA2 pathway facilitates tumor cell adhesion to distant vascular endothelium, activates the endothelium leading to leukocyte‐endothelial interactions, and supports the recruitment of monocytes/macrophages that ultimately support metastasis. Notably the platelet COX‐1/TXA2 pathway was shown to play a role in these early steps in metastasis, but was not necessary for the longer term growth of the metastatic pulmonary foci. Lucotti et al performed studies in which the timing of COX‐1 inhibition was varied, demonstrating that mice treated during the “intravascular phase of metastasis,” had reduced levels of tumor dissemination and platelet aggregation but also decreased early retention of tumor cells in the lungs, indicating that the platelet COX‐1/TXA2 pathway is crucial during the early phases of metastatic colonization. Using an in vitro model to mimic intravascular shear stress, Lucotti et al showed that COX‐1 inhibition reduced tumor cell adhesion to endothelial cells and tumor cell association with platelets. Using fluorescently‐labeled monocytes and macrophages, this study found that COX‐1 (but not COX‐2) and TXA2 signaling inhibition Manuscript handled by: Ton Lisman