The role of podoplanin in tumor-associated thrombosis
https://doi.org/10.18705/2782-3806-2023-3-4-44-51
Abstract
Venous thromboembolism (VTE) is highly consequential for patients with cancer, it is the second leading cause of death in these patients. The literature describes several mechanisms leading to these complications. One of these is the interaction of podoplanin (PDPN), which is the subject of this article, with its receptor on platelets CLEC-2 (C-type lectin-like type II transmembrane receptor). This interaction leads to platelet activation and promotes hematogenous metastasis and thrombosis associated with cancer. Podoplanin is expressed in gliomas, squamous cell carcinoma, osteosarcoma by cancer cells, and it is also normally expressed in podocytes and lymphatic endothelial cells, but not in vascular endothelium. Thrombus inflammation initiates ectopic expression of podoplanin in vascular endothelial cells, which promotes thrombosis. It has been shown that podoplanin expression correlates with the incidence of VTE, as well as with cancer metastasis. Violation of the PDPN-CLEC-2 interaction may become a new direction in the development of drugs for the prevention of thrombosis for patients with cancer.
About the Authors
A. V. Savelyeva
Almazov National Medical Research Centre, World-Class Research Centre for Personalized Medicine
Russian Federation
Russian Federation
Savelyeva Anna V - Resident, in Clinical Laboratory Diagnostics
Akkuratova str., 2, Saint Petersburg, 197341
K. A. Pishchulov
Almazov National Medical Research Centre, World-Class Research Centre for Personalized Medicine
Russian Federation
Russian Federation
Pishchulov Konstantin A. - Junior Researcher, Research Group of Cardio-Oncology
Akkuratova str., 2, Saint Petersburg, 197341
References
1. Low S, et al. Isocitrate dehydrogenase mutation and risk of venous thromboembolism in glioma: A systematic review and meta-analysis. Thrombosis Research. 2022; 45: 175–198.
2. Horsted F, West J, Grainge M. Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Med. 2012. 9: 1–19.
3. Davila M, et al. Tissue factor-bearing microparticles derived from tumor cells: impact on coagulation activation. Journal of thrombosis and haemostasis. 2008; 9: 1517–1524.
4. Geddings J, Mackman M. Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood. 2013; 122: 1873–1880.
5. Hisada Y, et al. Human pancreatic tumors grown in mice release tissue factor-positive microvesicles that increase venous clot size. Journal of Thrombosis and Haemostasis. 2017; 11: 208–2217.
6. Astarita J, Acton E, Turley J. Podoplanin: emerging functions in development, the immune system, and cancer. Frontiers in immunology. 2012; 3: 283–287.
7. Ugorski M, Dziegiel P, Suchanski J. Podoplanin-a small glycoprotein with many faces. American journal of cancer research. 2016; 2: 370.
8. Renart J, et al. New insights into the role of podoplanin in epithelial–mesenchymal transition.International review of cell and molecular biology. 2015; 317: 185–239.
9. Suzuki-Inoue K. Platelets and cancer-associated thrombosis: focusing on the platelet activation receptor CLEC-2 and podoplanin. the American Society of Hematology Education Program Book. 2019; 1: 175–181.
10. Navarro-Núñez L, et al. The physiological and pathophysiological roles of platelet CLEC-2. Thrombosis and haemostasis. 2013; 109: 991–998.
11. Astarita J, et al. The CLEC-2–podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture. Nature immunology. 2015; 16: 75–84.
12. Martín-Villar E, et al. Podoplanin mediates ECM degradation by squamous carcinoma cells through control of invadopodia stability. Oncogene. 2015; 34: 4531–4544.
13. Kato Y, et al. Molecular analysis of the pathophysiological binding of the platelet aggregation- inducing factor podoplanin to the C-type lectin-like receptor CLEC-2. Cancer science. 2008; 99: 54–61.
14. Nagae M, et al. A platform of C-type lectin-like receptor CLEC-2 for binding O-glycosylated podoplanin and nonglycosylated rhodocytin. Structure. 2014; 22: 1711–1721.
15. Suzuki-Inoue K, Osada M, Ozaki Y. Physiologic and pathophysiologic roles of interaction between C- type lectin-like receptor 2 and podoplanin: partners from in utero to adulthood. Journal of Thrombosis and Haemostasis. 2017; 15: 219–229.
16. Tammela T, Alitalo K. Lymphangiogenesis: molecular mechanisms and future promise. Cell. 2010; 140: 460–476.
17. Peterziel H, et al. Expression of podoplanin in human astrocytic brain tumors is controlled by the PI3K-AKT-AP-1 signaling pathway and promoter methylation. Neuro-oncology. 2012; 14: 426–439.
18. Durchdewald M, et al. Podoplanin is a novel fos target gene in skin carcinogenesis. Cancer Research. 2008; 68: 6877–6883.
19. Kunita A, et al. Podoplanin is regulated by AP-1 and promotes platelet aggregation and cell migration in osteosarcoma. The American journal of pathology. 2011; 179: 1041–1049.
20. Kato Y, Kaneko M. A cancer-specific monoclonal antibody recognizes the aberrantly glycosylated podoplanin. Sci. Rep. 2014.; 4:5924.
21. Shirai T, et al. C-type lectin-like receptor 2 promotes hematogenous tumor metastasis and prothrombotic state in tumor-bearing mice. Journal of Thrombosis and Haemostasis. 2017; 15: 513–525.
22. Lee H, et al. Podoplanin promotes cancer-associated thrombosis and contributes to the unfavorable overall survival in an ectopic xenograft mouse model of oral cancer. Biomedical journal. 2020; 43: 146–162.
23. Wang X, et al. Blocking podoplanin inhibits platelet activation and decreases cancer-associated venous thrombosis. Thrombosis Research. 2021; 200: 72–80.
24. Payne H, et al. Mice with a deficiency in CLEC-2 are protected against deep vein thrombosis. Blood, The Journal of the American Society of Hematology. 2017; 129: 2013–2020.
25. Hitchcock J, et al. Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets. The Journal of clinical investigation. 2015; 125: 4429–4446.
26. Riedl J, et al. Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism. Blood, The Journal of the American Society of Hematology. 2017; 129: 1831– 1839.
27. Khorana A, et al. Cancer-associated venous thromboembolism. Nature Reviews Disease Primers. 2022; 8: 1337–1347.
28. Seyed N, et al. Combination of isocitrate dehydrogenase 1 (IDH 1) mutation and podoplanin expression in brain tumors identifies patients at high or low risk of venous thromboembolism. Journal of Thrombosis and Haemostasis. 2008; 6: 1121–1127.
29. Gharahkhani R, Pourhadi M, Mirdamadi N, et al. Effect of Anti-Podoplanin on Malignant Glioma Cell Viability, Invasion and Tumor Cell-Induced Platelet Aggregation. Arch Med Res. 2022; 53: 461–468.
30. Gi T, et al. Histopathological features of cancer-associated venous thromboembolism: presence of intrathrombus cancer cells and prothrombotic factors. Arteriosclerosis, Thrombosis, and Vascular Biology. 2023; 43: 146–159.
31. Schacht V, et al. Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. The American journal of pathology. 2005; 166: 913–921.
32. Takagi S, et al. Expression of Aggrus/podoplanin in bladder cancer and its role in pulmonary metastasis. International journal of cancer. 2014; 134: 2605–2614.
33. Hisakane K, et al. Unique intravascular tumor microenvironment predicting recurrence of lung squamous cell carcinoma.Journal of cancer research and clinical oncology. 2016; 142: 593–600.
34. Mishima K, et al. Podoplanin expression in primary central nervous system germ cell tumors: a useful histological marker for the diagnosis of germinoma. Acta neuropathologica. 2006; 111: 563–568.
35. Sankiewicz A, et al. Podoplanin serum and urine concentration in transitional bladder cancer. Cancer Biomarkers. 2016; 16: 343–350.
36. Zhao X, et al. Plasma soluble podoplanin is a novel marker for the diagnosis of tumor occurrence and metastasis. Cancer science. 2018; 109: 403–411.
37. Pan Y, et al. Podoplanin requires sialylated O-glycans for stable expression on lymphatic endothelial cells and for interaction with platelets. Blood, The Journal of the American Society of Hematology. 2014; 124: 3656–3665.
38. Carrasco-Ramírez P, et al. Podoplanin is a component of extracellular vesicles that reprograms cell-derived exosomal proteins and modulates lymphatic vessel formation. Oncotarget. 2016; 7: 16070.
39. Falanga A, et al. Mechanisms and risk factors of thrombosis in cancer. Critical reviews in oncology/ hematology. 2017; 118: 79–83.
40. Mege D, et al. The origin and concentration of circulating microparticles differ according to cancer type and evolution: A prospective single-center study. International journal of cancer. 2016; 138: 939–948.
41. Melnichnikova O, et al. Circulating Small Extracellular Vesicles Profiling and Thrombin Generation as Potential Markers of Thrombotic Risk in Glioma Patients. Frontiers in Cardiovascular Medicine. 2022; 9.
Review
For citations:
Savelyeva A.V., Pishchulov K.A. The role of podoplanin in tumor-associated thrombosis. Russian Journal for Personalized Medicine. 2023;3(4):44-51. (In Russ.) https://doi.org/10.18705/2782-3806-2023-3-4-44-51
Views:
248
Email this article 