Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
Infection Control Office, Yamanashi University Hospital, Yamanashi, Japan.
J Thromb Haemost. 2017 Mar;15(3):513-525. doi: 10.1111/jth.13604. Epub 2017 Feb 14.
Essentials The role of C-type lectin-like receptor-2 (CLEC-2) in cancer progression is unclear. CLEC-2-depleted mouse model is generated by using a rat anti-mouse CLEC-2 monoclonal antibody. CLEC-2 depletion inhibits hematogenous tumor metastasis of podoplanin-expressing B16F10 cells. CLEC-2 depletion prolongs cancer survival by suppressing thrombosis and inflammation.
Background C-type lectin-like receptor 2 (CLEC-2) is a platelet activation receptor of sialoglycoprotein podoplanin, which is expressed on the surface of certain types of tumor cells. CLEC-2-podoplanin interactions facilitate hematogenous tumor metastasis. However, direct evidence of the role of CLEC-2 in hematogenous metastasis and cancer progression is lacking. Objective and methods We generated immunological CLEC-2-depleted mice by using anti-mouse CLEC-2 monoclonal antibody 2A2B10 and investigated whether CLEC-2 promoted hematogenous tumor metastasis and tumor growth and exacerbated the prognosis of mice bearing podoplanin-expressing B16F10 melanoma cells. Results Our results showed that hematogenous metastasis was significantly inhibited in CLEC-2-depleted mice. B16F10 cells co-cultured with wild-type platelets, but not with CLEC-2-deficient platelets, showed increased proliferation. However, B16F10 cell proliferation was not inhibited in CLEC-2-depleted mice. Histological analysis showed that thrombus formation in tumor vessels was significantly inhibited and functional vessel density was significantly increased in CLEC-2-depleted mice. These data suggest that CLEC-2 deficiency may inhibit thrombus formation in tumor vessels and increase the density of functional vessels, thus improving oxygen and nutrient supply to tumors, indirectly promoting tumor proliferation. Furthermore, the overall survival of CLEC-2-depleted mice was significantly prolonged, which may be due to the suppression of thrombus formation in the lungs and subsequent inhibition of systemic inflammation and cachexia. Conclusions These data provide a rationale for the targeted inhibition of CLEC-2 as a new strategy for preventing hematogenous tumor metastasis and for inhibiting cancer-related thromboembolism.
要点 C 型凝集素样受体 2（CLEC-2）在癌症进展中的作用尚不清楚。使用抗鼠 CLEC-2 单克隆抗体 2A2B10 生成 CLEC-2 耗尽的小鼠模型。CLEC-2 耗竭抑制 podoplanin 表达的 B16F10 细胞的血行转移。CLEC-2 耗竭通过抑制血栓形成和炎症延长癌症的生存时间。
背景 C 型凝集素样受体 2（CLEC-2）是一种血小板激活受体，属于唾液酸化糖蛋白 podoplanin，表达于某些类型的肿瘤细胞表面。CLEC-2-podoplanin 相互作用促进血行转移肿瘤转移。然而，缺乏 CLEC-2 在血行转移和癌症进展中的直接作用的直接证据。目的和方法我们使用抗鼠 CLEC-2 单克隆抗体 2A2B10 生成免疫性 CLEC-2 耗竭小鼠，并研究 CLEC-2 是否促进血行转移和肿瘤生长，以及加剧表达 podoplanin 的 B16F10 黑色素瘤细胞荷瘤小鼠的预后。结果我们的结果表明，CLEC-2 耗竭小鼠的血行转移明显受到抑制。与野生型血小板共培养的 B16F10 细胞，但与 CLEC-2 缺陷型血小板共培养的 B16F10 细胞显示出增殖增加。然而，CLEC-2 耗竭小鼠的 B16F10 细胞增殖未受抑制。组织学分析表明，CLEC-2 耗竭小鼠肿瘤血管中的血栓形成明显抑制，功能性血管密度明显增加。这些数据表明，CLEC-2 缺失可能抑制肿瘤血管中的血栓形成，并增加功能性血管的密度，从而间接促进肿瘤增殖，改善肿瘤的氧气和营养供应。此外，CLEC-2 耗竭小鼠的总生存期明显延长，这可能是由于抑制了肺部的血栓形成，随后抑制了全身炎症和恶病质。结论这些数据为靶向抑制 CLEC-2 作为预防血行转移和抑制与癌症相关的血栓栓塞的新策略提供了依据。
