Neutrophils, Cancer and Thrombosis: The New Bermuda Triangle in Cancer Research.

Spontaneous venous thrombosis is often the first clinical sign of cancer, and it is linked to a worsened survival rate. Traditionally, tumor-cell induced platelet activation has been the main actor studied in cancer-associated-thrombosis. However, platelet involvement alone does not seem to be sufficient to explain this heightened pro-thrombotic state. Neutrophils are emerging as key players in both thrombus generation and cancer progression. Neutrophils can impact thrombosis through the release of pro-inflammatory cytokines and expression of molecules like P-selectin and Tissue Factor (TF) on their membrane and on neutrophil-derived microvesicles. Their role in cancer progression is evidenced by the fact that patients with high blood-neutrophil counts have a worsened prognosis. Tumors can attract neutrophils to the cancer site via pro-inflammatory cytokine secretions and induce a switch to pro-tumoral (or N2) neutrophils, which support metastatic spread and have an immunosuppressive role. They can also expel their nuclear contents to entrap pathogens forming Neutrophil Extracellular Traps (NETs) and can also capture coagulation factors, enhancing the thrombus formation. These NETs are also known to have pro-tumoral effects by supporting the metastatic process. Here, we strived to do a comprehensive literature review of the role of neutrophils as drivers of both cancer-associated thrombosis (CAT) and cancer progression.

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

The first cause of death in cancer patients, after tumoral progression itself, is thrombo-embolic disease. This cancer-associated hypercoagulability state is known as Trousseau's syndrome, and the risk for developing thrombotic events differs according to cancer type and stage, as well as within patients. Massive platelet activation by tumor cells is the key mediator of thrombus formation in Trousseau's syndrome. In this literature review, we aimed to compare the interactions between cancer cells and platelets in three different cancer types, with low, medium and high thrombotic risk. We chose oral squamous cell carcinoma for the low-thrombotic-risk, colorectal adenocarcinoma for the medium-thrombotic-risk, and pancreatic carcinoma for the high-thrombotic-risk cancer type. We showcase that understanding these interactions is of the highest importance to find new biomarkers and therapeutic targets for cancer-associated thrombosis.

P2RY12-Inhibitors Reduce Cancer-Associated Thrombosis and Tumor Growth in Pancreatic Cancers.

Platelet function can be modified by cancer cells to support tumor growth, causing alterations in the delicate hemostatic equilibrium. Cancer-cell and platelet interactions are one of the main pillars of Trousseau's syndrome: a paraneoplastic syndrome with recurring and migrating episodes of thrombophlebitis. Altogether, this leads to a four-fold risk of thrombotic events in cancer patients, which in turn, portend a poor prognosis. We previously demonstrated that anti-P2RY12 drugs inhibit cancer-associated-thrombosis and formation of tumor metastasis in pancreatic cancer models. Here, we aimed to (1) compare the effects of aspirin and clopidogrel on pancreatic cancer prevention, (2) characterize the effects of clopidogrel (platelet P2RY12 inhibitor) on cancer-associated thrombosis and cancer growth in vivo, (3) determine the effect of P2RY12 across different digestive-tract cancers in vitro, and (4) analyze the expression pattern of P2RY12 in two different cancer types affecting the digestive system. Clopidogrel treatment resulted in better survival rates with smaller primary tumors and less metastasis than aspirin treatment. Clopidogrel was also more effective than aspirin at dissolving spontaneous endogenous thrombi in our orthotopic advanced cancer mouse model. P2RY12 expression gives pancreatic adenocarcinomas proliferative advantages. In conclusion, we propose the hypothesis that clopidogrel should be further studied to target and prevent Trousseau's syndrome; as well as diminish cancer growth and spread. However, more studies are required to determine the implicated pathways and effects of these drugs on cancer development.

Cancer animal models in thrombosis research.

The cancer-thrombosis relationship has been established for decades, in both cancer biology and in the clinical signs and symptoms seen in cancer patients (thrombosis in cancer patients has been associated with a worse prognosis and survival). As the link between the pathologies becomes clearer, so does the need to develop models that enable researchers to study them simultaneously in vivo. Mouse models have often been used, and they have helped determine molecular pathways between cancer spread and thrombosis in humans. This review is a summary of the current literature that describes the use of cancer mouse models in thrombosis research. We included cancer models that are not yet used in thrombosis research, but that can positively impact this area of research in the near future. We describe the most commonly used techniques to generate thrombosis as well as the mouse strains and cancer cell types that are commonly used along with inoculation techniques. We endeavoured to create a compendium of the different mouse models that are beneficial for cancer-thrombosis research, as understanding these mechanisms is crucial for creating better and more effective treatments for thrombosis in cancer patients.

Platelets, Thrombo-Inflammation, and Cancer: Collaborating With the Enemy.

Platelets are small anucleate cells present in the blood stream, their typical role in primary hemostasis has been well-described. However, new evidence suggests that they have critically important roles in cancer progression and inflammation. Cancer cells can activate platelets, thus using them as physical shields from blood shear forces and natural killer (NK) cells. The activated platelets may also regulate hematopoietic and immune cell migration toward the tumor site; therefore, contributing to the cancer-associated inflammation. The activation of platelets by cancer cells may also contribute to metastasis and cancer progression by stimulating deep venous thrombosis and neutrophil extracellular trap formations (NETs) that "hide" cancer cells. We strived to review the current literature to dissect the role of platelets in cancer-associated thrombosis and tumor microenvironment inflammation.