Oral Squamous Cell Carcinoma Is Associated with a Low Thrombosis Risk Due to Storage Pool Deficiency in Platelets

Abstract

Venous thrombo-embolism (VTE) disease is the second most common cause of mortality in cancer patients, and evaluation and prevention of thrombosis risk is essential. VTE-associated risk varies according to the type of tumor disease. Oral cancer is the most frequent type of head and neck cancer, and it represents approximately 2.1% of all cancers worldwide. Most tumors are squamous cell carcinomas and are mainly due to tobacco and alcohol abuse. VTE risk associated with oral squamous cell carcinoma (OSCC) is low. However, many studies have shown that OSCC has the following biological features of cancers associated with a high thrombosis risk: modified thrombosis and fibrinolysis mechanisms; strong expression of procoagulant proteins; secretion of procoagulant microparticles; and production of procoagulant cytokines. Using an original mouse model of tongue squamous cell carcinoma, our study aimed to clarify this paradoxical situation. First, we showed that OSCC tumors have a pro-aggregatory phenotype and a high local thrombosis risk. Second, we found that tongue tumor mice do not have an elevated systemic thrombosis risk (the risk of an “at distance” thrombosis event such as lower extremity deep venous thrombosis or pulmonary embolism) and even show a reduction in risk. Third, we demonstrated that tongue tumor mice show a reduction in platelet reactivity, which explains the low systemic thrombosis risk. Finally, we found that tongue tumor mice present granule pool deficiency, thereby explaining the reduction in platelet reactivity and systemic thrombosis risk.

Platelet and Cancer-Cell Interactions Modulate Cancer-Associated Thrombosis Risk in Different Cancer Types

“…Authors found that, in vitro, OSCC cells induce platelet aggregation due to high TF activity; they confirmed this in vivo by detecting platelet aggregates and fibrin deposits in histological sections of primary mouse tongue tumors [62]. In orthotopic animal models, there was no significant difference in terms of blood cell counts or tail bleeding times between healthy and cancer-inoculated mice [62]. Using the same OSCC orthotopic mouse model, researchers studied platelet accumulation and fibrin generation in the cremasteric arteries after a laser induced injury.…”

“…Despite the fact that HNC is between the 8th and 10th most common cancer in the world, there is surprisingly little information available about the risk of developing thrombotic events in this disease [60][61][62]. In a worrisome manner, the incidence of oral cavity and pharyngeal cancer is on the rise at a rate of 0.6% per year in the last decade alone [63].…”

“…It is generally accepted that head and neck cancers have low thrombotic risk, and a clinical study review performed by P. Haen and collaborators in 2019 confirms this [61]. However, HNC and, more specifically, oral squamous cell carcinoma (OSCC) has multiple characteristics of cancers associated with high thrombotic risk, for example, modified thrombosis and fibrinolysis mechanisms, strong expression of procoagulant factors, and production of procoagulant cytokines and of procoagulant microparticles [62,[66][67][68][69][70][71]. Indeed, OSCC cells can express TF, podoplanin, and thromboxane A2 (TXA2) and secrete TNFα, interleukins IL1 and IL6, VEGF, and procoagulant microparticles into the tumoral microenvironment (Figure 2) [61].…”

“…Recently, evidence of this thrombotic paradox has been demonstrated: a study published in 2021 has shown for the first time, in an original mouse model of OSCC, that there is no elevated systemic thrombosis risk [62]. Authors found that, in vitro, OSCC cells induce platelet aggregation due to high TF activity; they confirmed this in vivo by detecting platelet aggregates and fibrin deposits in histological sections of primary mouse tongue tumors [62]. In orthotopic animal models, there was no significant difference in terms of blood cell counts or tail bleeding times between healthy and cancer-inoculated mice [62].…”

Oral Squamous Cell Carcinoma-Associated Thrombosis: What Evidence?

“…In a recent study, a potential mechanism that may explain this paradox was explained using a mouse model of tongue squamous cell carcinoma [ 26 ]. Surprisingly, platelet accumulation and fibrin generation in OSCC were highly inhibited in tumour-bearing mice versus healthy controls, suggesting a possible reduction in blood clot formation.…”