Podoplanin promotes cancer-associated thrombosis and contributes to the unfavorable overall survival in an ectopic xenograft mouse model of oral cancer
Podoplanin promotes cancer-associated thrombosis and contributes to the unfavorable overall survival in an ectopic xenograft mouse model of oral cancer
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DOI：
10.1016/j.bj.2019.07.001
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发表时间：
2020-04-01
影响因子：
5.5
通讯作者：
Tseng, Ching-Ping
中科院分区：
文献类型：
--
作者：
Lee, Hsing-Ying;Yu, Ni-Yen;Tseng, Ching-Ping
背景：平足蛋白（PDPN）是一种跨膜糖蛋白，在不同癌症类型中介导肿瘤细胞诱导的血小板聚集。新数据表明，PDPN 是人类口腔鳞状细胞癌 (OSCC) 预后不良的标志物。然而，PDPN对OSCC癌症形成和疾病进展的功能影响仍有待阐明。方法：建立PDPN敲低或过表达的OECM-1口腔癌细胞亚系。分析了这些细胞系的细胞特征和诱导血小板聚集的能力。通过将癌细胞接种到裸鼠颈前区建立异种异种移植动物模型，研究PDPN对OSCC疾病进展和癌相关血栓形成的功能影响。结果：PDPN促进OSCC细胞迁移和侵袭，但对体外细胞增殖和体内肿瘤生长没有影响。 PDPN 阳性 (PDPNthorn) OSCC 细胞与血小板共孵育可诱导血小板活化和聚集。尽管没有肉眼可见的远处转移，但携带 PDPN+ 肿瘤的小鼠的总体存活率有所下降。 PDPN+肿瘤切片中定义了血小板标记物mCD41的斑点免疫荧光染色模式，并且强度大于PDPN-低或阴性肿瘤切片中的强度。 mCD41和内皮细胞标记物mCD31对肿瘤切片进行免疫荧光联合染色，进一步证明血小板聚集体位于血管腔内，并且在携带PDPN+肿瘤的小鼠中也分布在瘤内。结论：这些数据表明癌细胞中PDPN的表达与血栓形成的高风险相关，导致小鼠的总体生存不利。这项研究为 PDPN 在癌症相关血栓形成和 OSCC 病理生理学中的功能提供了新的见解。
Background: Podoplanin (PDPN) is a transmembrane glycoprotein that mediates tumor cell-induced platelets aggregation in different cancer types. Emerging data indicate that PDPN is a marker for poor prognosis of human oral squamous cell carcinoma (OSCC). However, the functional impacts of PDPN on cancer formation and disease progression of OSCC remain to be elucidated.Methods: The sublines of the OECM-1 oral cancer cells with PDPN knockdown or overexpression were established. The cellular characteristics and the ability to induce platelet aggregation of these cells lines were analyzed. An ectopic xenograft animal model by inoculating cancer cells into the anterior neck region of nude mice was established to investigate the functional impact of PDPN on disease progression and cancer-associated thrombosis of OSCC.Results: PDPN promoted OSCC cell migration and invasion, but had no effect on cell proliferation in vitro and tumor growth in vivo. Co-incubation of PDPN-positive (PDPNthorn) OSCC cells with platelets induced platelet activation and aggregation. The mice bearing PDPN+ tumor had a decrease in overall survival despite that there was no gross appearance of distant metastasis. A speckled immunofluorescence staining pattern of platelet marker mCD41 was defined in the PDPN+ tumor sections and the intensity was greater than in the PDPN-low or negative tumor sections. Co-immunofluorescence staining of the tumor sections with mCD41 and the endothelial cell marker mCD31 further demonstrated that platelet aggregates were located in the lumen of blood vessel and were also distributed intratumorally in the mice bearing PDPN+ tumors.Conclusions: These data demonstrated that PDPN expression in the cancer cells is associated with high risk of thrombosis, leading to unfavorable overall survival of the mice. This study provides new insights into the functions of PDPN in cancer-associated thrombosis and in the pathophysiology of OSCC.