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

Abstract

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.

Prognostic value of the pretreatment systemic immune-inflammation index in patients with prostate cancer: a systematic review and meta-analysis

“…Platelets mainly regulate blood coagulation and hemostasis. The asymmetric status of platelets contributes to cancer promotion and progression, directly causing thrombocytosis in patients with cancer [ 55 ]. Present cell research has already indicated that platelets enhance the invasion of androgen receptor-negative PCa cells via increased matrix metalloproteinase expression [ 56 ].…”

“…Platelets mainly regulate blood coagulation and hemostasis. The asymmetric status of platelets contributes to cancer promotion and progression, directly causing thrombocytosis in patients with cancer [55].…”

m6A/ m1A /m5C/m7G-related methylation modification patterns and immune characterization in prostate cancer

“…Additionally, the CIBERSORT algorithm was used to calculate the scores of 22 different human immune cell types for each PCa sample ( Hao et al, 2019 ). We used single-sample Gene Set Enrichment Analysis (ssGSEA) to explore the levels of immune cell infiltration ( Hwang et al, 2021 ). DEG identification and functional annotation of DEGs with the “limma” package in R, DEGs were discovered with a p -value of 0.…”

A narrative review for platelets and their RNAs in cancers: New concepts and clinical perspectives

“…[ 49 ] Podoplanin is a cell-surface mucin-like glycoprotein that is overexpressed in several tumor cells, as well as in the tumor stroma, inducing platelet aggregation by binding to platelet receptor C-type lectin-like receptor 2 and modulating signal transductions that enhance malignant progression. [ 50 , 51 ] Furthermore, aberrant expression of the podoplanin gene in promyelocytes is the most distinctive transcript of promyelocytic leukemia, and is associated with thrombocytopenia and prolonged bleeding time in a xenograft model. [ 52 ] In preclinical models, platelets binding to CD97 overexpressed on tumor cells can autonomously initiate αIIbβ3-dependent platelet activation to release ATP and LPA, and stimulate tumor cell CD97/LPA receptor-dependent Rho activation, resulting in endothelial junction destruction, vascular extravasation and metastasis.…”