Megakaryocytes Mediate Hyperglycemia-Induced Tumor Metastasis

被引:19
|
作者
Wu, Biying [1 ]
Ye, Ying [2 ,3 ]
Xie, Sisi [1 ]
Li, Yintao [4 ]
Sun, Xiaoting [5 ]
Lv, Mengyuan [1 ]
Yang, Ling [1 ]
Cui, Nan [6 ]
Chen, Qiying [7 ]
Jensen, Lasse D. [8 ]
Cui, Dongmei [9 ]
Huang, Guichun [10 ]
Zuo, Ji [1 ]
Zhang, Shaochong [9 ]
Liu, Wen [1 ]
Yang, Yunlong [1 ]
机构
[1] Fudan Univ, Sch Basic Med Sci, Dept Cellular & Genet Med, Shanghai 200030, Peoples R China
[2] Tongji Univ, Dept Oral Implantol, Sch & Hosp Stomatol, Shanghai, Peoples R China
[3] Shanghai Engn Res Ctr Tooth Restorat & Regenerat, Shanghai, Peoples R China
[4] Shandong First Med Univ & Shandong Acad Med Sci, Phase I Clin Ctr, Jinan, Peoples R China
[5] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Med Oncol, Shanghai, Peoples R China
[6] Xi An Jiao Tong Univ, Dept Reprod Med, Affiliated Hosp 1, Xian, Peoples R China
[7] Fudan Univ, Dept Cardiol, Huashan Hosp, Shanghai 200040, Peoples R China
[8] Linkoping Univ, Div Diagnost & Specialist Med, Unit Cardiovasc Med, Dept Med Hlth & Caring Sci, Linkoping, Sweden
[9] Jinan Univ, Affiliated Shenzhen Eye Hosp, Shenzhen Eye Hosp, Shenzhen Key Lab Ophthalmol, Shenzhen, Peoples R China
[10] Nanjing Univ, Dept Med Oncol, Sch Med, Jinling Hosp, Nanjing, Peoples R China
基金
中国国家自然科学基金;
关键词
CANCER-CELLS; ENDOPLASMIC-RETICULUM; PLATELET ACTIVATION; GLUCOSE-METABOLISM; GLYCEMIC CONTROL; CLEARANCE; MORTALIN; ROLES;
D O I
10.1158/0008-5472.CAN-21-1180
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
High blood glucose has long been established as a risk factor for tumor metastasis, yet the molecular mechanisms underlying this association have not been elucidated. Here we describe that hyperglycemia promotes tumor metastasis via increased platelet activity. Administration of glucose, but not fructose, reprogrammed the metabolism of megakaryocytes to indirectly prime platelets into a prometastatic phenotype with increased adherence to tumor cells. In megakaryocytes, a glucose metabolism-related gene array identified the mitochondrial molecular chaperone glucose-regulated protein 75 (GRP75) as a trigger for platelet activation and aggregation by stimulating the Ca2+-PKC alpha pathway. Genetic depletion of Glut1 in megakaryocytes blocked MYC-induced GRP75 expression. Pharmacologic blockade of platelet GRP75 compromised tumor-induced platelet activation and reduced metastasis. Moreover, in a pilot clinical study, drinking a 5% glucose solution elevated platelet GRP75 expression and activated platelets in healthy volunteers. Platelets from these volunteers promoted tumor metastasis in a plateletadoptive transfer mouse model. Together, under hyperglycemic conditions, MYC-induced upregulation of GRP75 in megakaryocytes increases platelet activation via the Ca2+-PKC alpha pathway to promote cancer metastasis, providing a potential new therapeutic target for preventing metastasis. Significance: This study provides mechanistic insights into a glucose-megakaryocyte-platelet axis that promotes metastasis and proposes an antimetastatic therapeutic approach by targeting the mitochondrial protein GRP75.
引用
收藏
页码:5506 / 5522
页数:17
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