TY - JOUR
T1 - Podoplanin promotes tumor growth, platelet aggregation, and venous thrombosis in murine models of ovarian cancer
AU - Sasano, Tomoyuki
AU - Gonzalez-Delgado, Ricardo
AU - Muñoz, Nina M.
AU - Carlos-Alcade, Wendolyn
AU - Cho, Min Soon
AU - Sheth, Rahul A.
AU - Sood, Anil K.
AU - Afshar-Kharghan, Vahid
N1 - Publisher Copyright:
© 2021 International Society on Thrombosis and Haemostasis
PY - 2022/1
Y1 - 2022/1
N2 - Background: Podoplanin (PDPN) is a sialylated membrane glycoprotein that binds to C-type lectin-like receptor 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. Objective: We examined the expression of PDPN and its role in tumor progression and venous thrombosis in ovarian cancer. Methods: We used mouse models of ovarian cancer and venous thrombosis. Results: Ovarian cancer cells express PDPN and release PDPN-rich extracellular vesicles (EVs), and cisplatin and topotecan (chemotherapies commonly used in ovarian cancer) increase the expression of podoplanin in cancer cells. The 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. Conclusions: In summary, our findings demonstrate that the expression of PDPN by ovarian cancer cells promotes tumor growth and venous thrombosis in mice.
AB - Background: Podoplanin (PDPN) is a sialylated membrane glycoprotein that binds to C-type lectin-like receptor 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. Objective: We examined the expression of PDPN and its role in tumor progression and venous thrombosis in ovarian cancer. Methods: We used mouse models of ovarian cancer and venous thrombosis. Results: Ovarian cancer cells express PDPN and release PDPN-rich extracellular vesicles (EVs), and cisplatin and topotecan (chemotherapies commonly used in ovarian cancer) increase the expression of podoplanin in cancer cells. The 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. Conclusions: In summary, our findings demonstrate that the expression of PDPN by ovarian cancer cells promotes tumor growth and venous thrombosis in mice.
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U2 - 10.1111/jth.15544
DO - 10.1111/jth.15544
M3 - Article
C2 - 34608736
AN - SCOPUS:85117061811
SN - 1538-7933
VL - 20
SP - 104
EP - 114
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 1
ER -