Blocking podoplanin inhibits platelet activation and decreases cancer-associated venous thrombosis

Wang, Xia; Liu, Biao; Xu, Mingxin; Jiang, Yuan; Jun, Zhou; Yang, Jun; Gu, Haidi; Ruan, Changgeng; Wu, Jinchang; Zhao, Yiming

doi:10.1016/j.thromres.2021.01.008

Cited by 26 publications

(17 citation statements)

References 26 publications

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“…Tumors 34 In addition, the use of blocking antibodies to PDPN reduced intratumor thrombosis in metastatic melanoma lesions in lungs, 35 and blocking CLEC-2 reduced venous thrombosis induced by PDPN-expressing melanoma cells in a murine model of IVC ligation. 20 In patients with high-grade gliomas, high expression of PDPN was found to be associated with a higher risk of venous thrombosis. 23 The mechanism by which PDPN on cancer cells induces thrombosis is not known.…”

Section: Discussionmentioning

confidence: 99%

“…22 In a recent study, mixing melanoma cells with anti-PDPN antibodies before subcutaneous injection reduced venous thrombosis induced by IVC ligation in mice. 20 This study aimed to investigate the impact of PDPN on tumor progression and venous thrombosis in a murine model of ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

“…CLEC‐2 deficiency reduced Salmonella‐induced thrombosis in hepatic vasculature 18,19 . There is evidence that PDPN is also involved in cancer‐induced thrombosis 13,20–22 . In a study on brain tumors from patients with high‐grade gliomas, increased expression of PDPN was associated with low platelet counts and an increased risk of venous thrombosis (hazard ratio for high vs. no PDPN expression: 5.71; 95% confidence interval, 1.52–21.26; p = 010) 23 .…”

Section: Introductionmentioning

confidence: 99%

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Podoplanin promotes tumor growth, platelet aggregation, and venous thrombosis in murine models of ovarian cancer

Sasano¹,

Gonzalez-Delgado²,

Muñoz³

et al. 2022

Journal of Thrombosis and Haemostasis

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Podoplanin promotes tumor growth, platelet aggregation, and venous thrombosis in murine models of ovarian cancer

Sasano¹,

Gonzalez-Delgado²,

Muñoz³

et al. 2022

Journal of Thrombosis and Haemostasis

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“…In addition, cancer cells could induce platelet aggregation and thrombus by directly binding via their cell surface podoplanin (PDPN) to C-type lectin receptor type 2 (CLEC-2) on the platelets (120)(121)(122). In breast cancer and melanoma, direct interaction between cancer cells and platelets induced platelet activation, modulated the VEGF release, and regulated CXCL5 and CXCL7 discharge from platelet granules (123), which were required for granulocytes recruitment and "early metastatic niches" formation (124).…”

Section: Platelet Activationmentioning

confidence: 99%

Bidirectional Interaction Between Cancer Cells and Platelets Provides Potential Strategies for Cancer Therapies

Guo

Chang

et al. 2021

Front. Oncol.

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Platelets are essential components in the tumor microenvironment. For decades, clinical data have demonstrated that cancer patients have a high risk of thrombosis that is associated with adverse prognosis and decreased survival, indicating the involvement of platelets in cancer progression. Increasing evidence confirms that cancer cells are able to induce production and activation of platelets. Once activated, platelets serve as allies of cancer cells in tumor growth and metastasis. They can protect circulating tumor cells (CTCs) against the immune system and detachment-induced apoptosis while facilitating angiogenesis and tumor cell adhesion and invasion. Therefore, antiplatelet agents and platelet-based therapies should be developed for cancer treatment. Here, we discuss the mechanisms underlying the bidirectional cancer-platelet crosstalk and platelet-based therapeutic approaches.

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“…These PDPN mAbs specifically inhibited PDPN-mediated platelet aggregation and cancer metastasis in the murine experimental models ( 128 , 192 , 193 ). Moreover, anti-PDPN antibody SZ-168 reduced the incidence of VTE in mice ( 194 ). Similar to PDPN mAbs, anti-CLEC2 antibody 2A2B10 suppressed intratumoral thrombus formation as well as metastasis in mice ( 68 , 127 ).…”

Section: Targeting Platelet-tumor Interaction For Chemotherapymentioning

confidence: 99%

Platelet CLEC2-Podoplanin Axis as a Promising Target for Oral Cancer Treatment

et al. 2021

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Cancer tissues are not just simple masses of malignant cells, but rather complex and heterogeneous collections of cellular and even non-cellular components, such as endothelial cells, stromal cells, immune cells, and collagens, referred to as tumor microenvironment (TME). These multiple players in the TME develop dynamic interactions with each other, which determines the characteristics of the tumor. Platelets are the smallest cells in the bloodstream and primarily regulate blood coagulation and hemostasis. Notably, cancer patients often show thrombocytosis, a status of an increased platelet number in the bloodstream, as well as the platelet infiltration into the tumor stroma, which contributes to cancer promotion and progression. Thus, platelets function as one of the important stromal components in the TME, emerging as a promising chemotherapeutic target. However, the use of traditional antiplatelet agents, such as aspirin, has limitations mainly due to increased bleeding complications. This requires to implement new strategies to target platelets for anti-cancer effects. In oral squamous cell carcinoma (OSCC) patients, both high platelet counts and low tumor-stromal ratio (high stroma) are strongly correlated with increased metastasis and poor prognosis. OSCC tends to invade adjacent tissues and bones and spread to the lymph nodes for distant metastasis, which is a huge hurdle for OSCC treatment in spite of relatively easy access for visual examination of precancerous lesions in the oral cavity. Therefore, locoregional control of the primary tumor is crucial for OSCC treatment. Similar to thrombocytosis, higher expression of podoplanin (PDPN) has been suggested as a predictive marker for higher frequency of lymph node metastasis of OSCC. Cumulative evidence supports that platelets can directly interact with PDPN-expressing cancer cells via C-type lectin-like receptor 2 (CLEC2), contributing to cancer cell invasion and metastasis. Thus, the platelet CLEC2-PDPN axis could be a pinpoint target to inhibit interaction between platelets and OSCC, avoiding undesirable side effects. Here, we will review the role of platelets in cancer, particularly focusing on CLEC2-PDPN interaction, and will assess their potentials as therapeutic targets for OSCC treatment.

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Blocking podoplanin inhibits platelet activation and decreases cancer-associated venous thrombosis

Cited by 26 publications

References 26 publications

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

Bidirectional Interaction Between Cancer Cells and Platelets Provides Potential Strategies for Cancer Therapies

Platelet CLEC2-Podoplanin Axis as a Promising Target for Oral Cancer Treatment

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