title: Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein.
abstract: Increasing evidence suggests that TLR4 expression by tumour cells promotes tumour progression, but it is unclear whether TLR4 is involved in metastasis. Here we show that TLR4 deficiency significantly diminishes experimental lung metastasis without affecting primary tumour growth. Bone marrow transplantation experiment and application of antiplatelet agents in mice demonstrate that TLR4 on platelets plays an important role in metastasis. TLR4 is critical for platelet-tumour cell interaction in vitro. Furthermore, high-mobility group box1 (HMGB1) neutralization attenuates platelet-tumour cell interaction in vitro and metastasis in vivo in a TLR4-dependent manner, indicating that tumour cell-released HMGB1 is the key factor that interacts with TLR4 on platelets and mediates platelet-tumour cell interaction, which promotes metastasis. These findings demonstrate a mechanism by which platelets promote tumour cell metastasis and suggest TLR4, and its endogenous ligand HMGB1 as targets for antimetastatic therapies.
authors.affiliation: 1] National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China [2] The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Le-Xing
authors.initials: LX
authors.lastname: Yu
authors.affiliation: 1] National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China [2] The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yan
authors.affiliation: 1] National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China [2] The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.affiliation: 1] National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China [2] The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Fu-Quan
authors.initials: FQ
authors.lastname: Wu
authors.affiliation: 1] National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China [2] The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ling
authors.affiliation: 1] National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China [2] The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Shu-Zhen
authors.initials: SZ
authors.lastname: Chen
authors.affiliation: 1] National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China [2] The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.affiliation: 1] National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China [2] The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Ye-Xiong
authors.initials: YX
authors.lastname: Tan
authors.affiliation: 1] National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China [2] The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Cao
authors.affiliation: 1] National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China [2] The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Wu
authors.affiliation: 1] National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China [2] The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China.
authors.forename: He-Xin
authors.initials: HX
authors.lastname: Yan
authors.affiliation: 1] National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China [2] The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China [3] State Key Laboratory of Oncogenes and Related Genes, Cancer Institute of Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai 200032, China.
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D018827:Carcinoma, Lewis Lung / Q000473:pathology*; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000378:metabolism*; D006410:Hematopoiesis / Q000187:drug effects; D008297:Male; D008546:Melanoma, Experimental / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D010973:Platelet Adhesiveness / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D024243:HMGB1 Protein; D010975:Platelet Aggregation Inhibitors; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4