Patients with cancer have an increased risk of thromboembolism, which is the second leading cause of death in these patients. Several mechanisms of the prothrombotic state in these patients have been proposed. Among them are a platelet activation receptor, C-type lectin-like receptor 2 (CLEC-2), and its endogenous ligand podoplanin, which are the focus of this review. CLEC-2 is almost specifically expressed in platelets/megakaryocytes in humans. A membrane protein, podoplanin is expressed in certain types of cancer cells, including squamous cell carcinoma, brain tumor, and osteosarcoma, in addition to several normal tissues, including kidney podocytes and lymphatic endothelial cells but not vascular endothelial cells. In the bloodstream, podoplanin induces platelet activation by binding to CLEC-2 and facilitates hematogenous cancer metastasis and cancer-associated thrombosis. In an experimental lung metastasis model, the pharmacological depletion of CLEC-2 from platelets in mice resulted in a marked reduction of lung metastasis of podoplanin-expressing B16F10 cells. Control mice with B16F10 orthotopically inoculated in the back skin showed massive thrombus formation in the lungs, but the cancer-associated thrombus formation in CLEC-2-depleted mice was significantly inhibited, suggesting that CLEC-2-podoplanin interaction stimulates cancer-associated thrombosis. Thromboinflammation induced ectopic podoplanin expression in vascular endothelial cells or macrophages, which may also contribute to cancer-associated thrombosis. CLEC-2 depletion in cancer-bearing mice resulted in not only reduced cancer-associated thrombosis but also reduced levels of plasma inflammatory cytokines, anemia, and sarcopenia, suggesting that cancer-associated thrombosis may cause thromboinflammation and cancer cachexia. Blocking CLEC-2-podoplanin interaction may be a novel therapeutic strategy in patients with podoplanin-expressing cancer.

中文翻译：

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血小板和癌症相关血栓形成：关注血小板激活受体 CLEC-2 和 podoplanin

癌症患者血栓栓塞的风险增加，这是这些患者的第二大死亡原因。已经提出了这些患者血栓形成前状态的几种机制。其中包括血小板活化受体、C 型凝集素样受体 2 (CLEC-2) 及其内源性配体 podoplanin，这是本综述的重点。CLEC-2 几乎在人类的血小板/巨核细胞中特异性表达。一种膜蛋白，podoplanin 在某些类型的癌细胞中表达，包括鳞状细胞癌、脑肿瘤和骨肉瘤，以及几种正常组织，包括肾足细胞和淋巴管内皮细胞，但不表达血管内皮细胞。在血液中，podoplanin 通过与 CLEC-2 结合诱导血小板活化，并促进血源性癌症转移和癌症相关血栓形成。在实验性肺转移模型中，小鼠血小板中 CLEC-2 的药理学耗竭导致表达 podoplanin 的 B16F10 细胞的肺转移显着减少。在背部皮肤原位接种 B16F10 的对照小鼠在肺部显示出大量血栓形成，但 CLEC-2 耗尽小鼠中与癌症相关的血栓形成受到显着抑制，表明 CLEC-2-podoplanin 相互作用会刺激与癌症相关的血栓形成。血栓炎症在血管内皮细胞或巨噬细胞中诱导异位足蛋白表达，这也可能导致癌症相关血栓形成。携带癌症的小鼠体内 CLEC-2 的消耗不仅导致癌症相关血栓形成减少，而且血浆炎症细胞因子、贫血和肌肉减少症的水平降低，这表明癌症相关血栓形成可能导致血栓炎症和癌症恶病质。阻断 CLEC-2-podoplanin 相互作用可能是表达 podoplanin 的癌症患者的一种新治疗策略。