Platelet P2Y12 is involved in murine pulmonary metastasis.
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.
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yanhua
Y
Wang
Yueping
Y
Sun
Ding
D
Li
Lin
L
Zhang
Kemin
K
Wang
Yong
Y
Zuo
T Kent
TK
Gartner
Junling
J
Liu
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D010974:Platelet Aggregation; D058925:Receptors, Purinergic P2Y12 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000235:genetics
D058925:Receptors, Purinergic P2Y12; D053773:Transforming Growth Factor beta1