The involvement of platelets in
tumor progression is well recognized. The depletion of circulating platelets or pharmacologic inhibitors of platelet activation decreases the metastatic potential of
circulating tumor cells in
metastasis mouse models. The platelet
ADP receptor P2Y12 amplifies the initial
hemostatic responses activated by a variety of platelet agonists and stabilizes platelet aggregation, playing a crucial role in granule secretion,
integrin activation and
thrombus formation. However, the relationship between P2Y12 and
tumor progression is not clear. In our study, the
Lewis Lung Carcinoma (LLC) spontaneous metastatic mouse model was used to evaluate the role of P2Y12 in
metastasis. The results demonstrated that P2Y12 deficiency significantly reduced pulmonary
metastasis. Further studies indicated that P2Y12 deficiency diminished the ability of LLC cells to induce platelet shape change and release of active TGFβ1 by a non-contact dependent mechanism resulting in a diminished, platelet-induced EMT-like transformation of the LLC cells, and that transformation probably is a prerequisite of LLC cell
metastasis. Immunohistochemical analyses indicated an obvious P2Y12 deficiency related attenuation of recruitment of VEGFR1+ bone marrow derived cell clusters, and extracellular matrix
fibronectin deposition in lungs, which presumably are required for pre-metastatic niche formation. In contrast to the LLC cells, non-epithelial
melanoma B16 cells induced platelet aggregation in a cell number and P2Y12-dependent manner. Also, a platelet induced EMT-like transformation of B16 cells is dependent on P2Y12. In agreement with the LLC cell model, platelet P2Y12 deficiency also results in significantly less lung
metastasis in the
B16 melanoma experimental
metastasis model. These results demonstrate that P2Y12 is a safe
drug target for anti-thrombotic
therapy, and that P2Y12 may serve as a new target for inhibition of
tumor metastasis.