Podoplanin promotes tumor growth, platelet aggregation, and venous thrombosis in murine models of ovarian cancer.
Podoplanin promotes tumor growth, platelet aggregation, and venous thrombosis in murine models of ovarian cancer.
复制标题
DOI：
10.1111/jth.15544
复制
发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Afshar-Kharghan V
中科院分区：
文献类型：
--
作者：
Sasano T;Gonzalez-Delgado R;Muñoz NM;Carlos-Alcade W;Cho MS;Sheth RA;Sood AK;Afshar-Kharghan V
泊多普宁(PDPN)是一种唾液酸化的膜糖蛋白，与血小板上的C型凝集素样受体2(CLEC-2)结合，导致血小板活化。PDPN表达于淋巴管内皮细胞、血管周围成纤维细胞/周细胞、癌细胞、肿瘤相关成纤维细胞和肿瘤基质细胞。PDPN在恶性上皮细胞上的表达在肿瘤转移中起一定作用。此外，研究发现，PDPN在脑肿瘤(高级别胶质瘤)中的表达与静脉血栓形成的风险增加相关。我们研究了卵巢癌中PDPN的表达及其在肿瘤进展和静脉血栓形成中的作用。我们使用了卵巢癌和静脉血栓形成的小鼠模型。我们发现卵巢癌细胞表达PDPN并释放富含PDPN的胞外小泡(EVS)，顺铂和拓扑替康(卵巢癌常用的化疗药物)增加了癌细胞中泊多普宁的表达。我们还发现，在卵巢癌小鼠模型中，PDPN在卵巢癌细胞中的表达促进了肿瘤的生长，并且PDPN基因的表达下调导致了较小的原发肿瘤。表达PDPN的卵巢癌细胞及其EV均可引起血小板聚集。在静脉血栓形成的小鼠模型中，从HeyA8卵巢癌细胞释放的表达PDPN的EV比来自PDPN基因敲除的HeyA8细胞的PDPN阴性的EV更容易发生血栓形成。PDPN阳性EVS诱导的血栓比PDPN阴性EVS诱导的血栓含有更多的血小板。综上所述，我们的发现表明，卵巢癌细胞表达PDPN促进了小鼠肿瘤的生长和静脉血栓的形成。
Podoplanin (PDPN) is a sialylated membrane glycoprotein that binds to C-type lectin-like receptor 2 (CLEC-2) on platelets resulting in platelet activation. PDPN is expressed on lymphatic endothelial cells, perivascular fibroblasts/pericytes, cancer cells, cancer-associated fibroblasts, and tumor stromal cells. PDPN’s expression on malignant epithelial cells plays a role in metastasis. Furthermore, the expression of PDPN in brain tumors (high-grade gliomas) was found to correlate with an increased risk of venous thrombosis. We examined the expression of PDPN and its role in tumor progression and venous thrombosis in ovarian cancer. We used mouse models of ovarian cancer and venous thrombosis. We showed that ovarian cancer cells express PDPN and release PDPN-rich extracellular vesicles (EVs) and that cisplatin and topotecan (chemotherapies commonly used in ovarian cancer) increase the expression of podoplanin in cancer cells. We also show that expression of PDPN in ovarian cancer cells promotes tumor growth in a murine model of ovarian cancer and that knockdown of PDPN gene expression results in smaller primary tumors. Both PDPN-expressing ovarian cancer cells and their EVs cause platelet aggregation. In a mouse model of venous thrombosis, PDPN-expressing EVs released from HeyA8 ovarian cancer cells produce more frequent thrombosis than PDPN-negative EVs derived from PDPN-knockdown HeyA8 cells. Blood clots induced by PDPN-positive EVs contain more platelets than those in blood clots induced by PDPN-negative EVs. In summary, our findings demonstrate that the expression of PDPN by ovarian cancer cells promotes tumor growth and venous thrombosis in mice.
登录
查看更多内容
影响因子：
5.5
作者：
Lee, Hsing-Ying;Yu, Ni-Yen;Tseng, Ching-Ping
通讯作者：
Tseng, Ching-Ping
影响因子：
7.3
作者：
Astarita JL;Acton SE;Turley SJ
通讯作者：
Turley SJ
平铺 3D 显微图像采集的全局最佳拼接。
DOI：
10.1093/bioinformatics/btp184
发表时间：
2009-06-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Preibisch S;Saalfeld S;Tomancak P
通讯作者：
Tomancak P
影响因子：
6.2
作者：
Khorana, AA;Francis, CW;Lyman, GH
通讯作者：
Lyman, GH
影响因子：
20.3
作者：
Finney, Brenda A.;Schweighoffer, Edina;Watson, Steve P.
通讯作者：
Watson, Steve P.