A relationship between coagulation and cancer has been known since the 19th century, when Armand Trousseau first described a clinical association between active cancer and elevated thromboembolic disorders and hypercoagulability. Thromboembolic events have been observed in many patients with various cancers, and they are the leading cause of non-cancer-related death in patients with cancer . Patients with a known history of thrombosis have an increased risk for cancer-associated thrombosis, and hypercoagulability can increase the cancer progression in these patients [2, 3]. In addition, thrombosis can be the first sign of malignant disease, preceding the clinical detection of cancer by months or even years .
Thrombotic events are a complication of both solid tumors and hematological malignancies. Hemorrhages and uncompensated disseminated intravascular coagulation further complicate the spectrum of hemostatic complications in malignancy and can be fatal. Cancer activates blood coagulation, inducing a hypercoagulable state or chronic disseminated intravascular coagulation. Laboratory tests showed that malignancy development is parallel to fibrin formation and fibrinolysis .
Blood coagulation pathogenesis in cancer is multifactorial and involves clinical and biological factors.
Clinical factors include patient-related characteristics, cancer-related features, and anti-cancer therapies. It is known that advanced age, prolonged immobility, and a prior history of thrombosis can increase the risk of thrombosis in cancer patients. Furthermore, in many studies, the highest venous thromboembolism (VTE) risk has been correlated with specific cancers, such as malignant brain tumors, hematological malignancies, and adenocarcinoma of the pancreas, stomach, ovary, uterus, lungs, and kidneys. Moreover, advanced, metastatic cancers are associated with an increased risk of VTE compared with localized tumors. Finally, chemotherapy, hormonal therapy, antiangiogenic agents, combination regimens and surgery have a pro-thrombotic effect. Many chemotherapeutic agents cause the increase of procoagulant tissue factor (TF) expression and the release of circulating microparticles (MPs) after treatment.
Cancer cells can activate a series of biological factors that lead to the expression of procoagulant proteins, exposure of procoagulant lipids, release of inflammatory cytokines and MPs, and adhesion to host vascular cells. By releasing procoagulant TFs, cancer procoagulant and MPs, tumor cells directly activate the coagulation cascade. Cancer cells can also promote MP formation by platelets. TF and phosphatidylserine (PS) expression on the surfaces of both platelet- and tumor-derived MPs are involved in the activation of blood clotting and thrombus formation.
Tumor cells and platelets maintain such a complex, bidirectional interaction in the blood and tumor microenvironment that recently the concept of “tumor-educated platelets” was proposed to group the series of mechanism that allows tumor cells to change platelet behaviors. Tumor cells release platelet agonists and express procoagulant proteins, such as TF, which induce platelet activation and aggregation in the bloodstream inducing thrombosis. However, platelets also support tumor growth and metastasis. Platelets facilitate cancer to sustain proliferative signaling, resist cell death and induce tumor angiogenesis. They also induce an invasive epithelial–mesenchymal transition phenotype of tumor cells and promote cell survival in blood circulation .
Therefore, platelets are key players in tumor hemostasis and thrombosis. On the one hand, low platelet counts in blood, such as immune-mediated and chemotherapy-induced thrombocytopenias, may cause excessive bleeding. On the other hand, improper platelet activation and aggregation may result in thrombosis, leading to CVD.
Molecular basis of thrombosis
Numerous studies have investigated the molecular basis in mediating thrombosis. Fibrinogen has been documented to be required for platelet aggregation, but platelet aggregation can occur in a fibrinogen-independent manner as well. In this pathway, platelet αIIbβ3 integrin is essential, and fibronectin, thrombospondin-1, and counter-receptor cadherin 6 may be involved as αIIbβ3 ligands. These molecules also likely contribute to platelet–tumor interactions, metastasis and cancer-associated thrombosis.
To complicate even more this scenario, platelet activation may induce different effects in tumor behavior and metastasis depending on the type of cancer. A study reported that inhibition of platelets decreases tumor growth and metastasis in pancreatic cancer .
A more recent study that investigated the effect of platelet interactions with colorectal tumor cells found that platelets extravasated into the tumor microenvironment played an important role in reducing tumor growth by generating MPs and recruiting tumoricidal macrophages. Platelets in the tumor microenvironment interacted with tumors through the expression of cadherin 6. The interaction of platelets with cancer cells induced the generation of MPs that recruited monocytes through RANTES, MIF, CCL2, and CXCL12 chemo-attractants. Macrophages were activated through IFN-g and IL-4, leading to cell cycle arrest of tumor cells in a p21-dependent manner.
However, the same study found a different behavior of platelet when released in the bloodstream. Platelets and MPs that are released in the bloodstream during cancer progression facilitates the interactions between tumor cells and the endothelium, inducing epithelial–mesenchymal transition and promoting metastasis. Depending on the environment, local or bloodstream, the consequences of the interactions between platelets and a tumor may promote or prevent cancer progression. A deep characterization of the role played by platelets depending on the type of cancer and its stage is needed before using antiplatelet drugs in the management of cancer and cancer-associated thrombosis .
A recent study analyzed the unfolded protein response (UPR) signaling functions in pancreatic cancer cells’ prothrombotic transformation. UPR is an integrated intracellular signaling pathway that is initiated by three endoplasmic reticulum receptors in response to accumulation of unfolded and misfolded protein in the endoplasmic reticulum lumen. UPR is associated with malignant transformation in pancreatic cancer but its link with cancer thrombosis has not been evaluated yet. The study highlighted that after UPR induction, pancreatic cancer cells release prothrombotic vesicles. These vesicles increase thrombin generation. In addition, upon UPR induction, more prothrombotic proteins, such as TF, are present on the surface of pancreatic cancer cells.
To evaluate the possibility of an association between the UPR and cancer thrombosis in the clinical setting, they collected plasma from pancreatic cancer patients who were monitored prospectively for the development of VTE. After proteomic analysis, they discovered that patients that are prone to develop VTE increase UPR marker in their plasma. These findings support the hypothesis that UPR response promote cat in pancreatic cells .
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