Abstract
Thrombotic complications are the second leading cause of death among oncology patients worldwide. Enhanced thrombogenesis has multiple origins and may result from a deregulation of megakaryocyte platelet production in the bone marrow, the synthesis of coagulation factors in the liver, and coagulation factor signaling upon cancer and the tumor microenvironment (TME). While a hypercoagulable state has been attributed to factors such as thrombocytosis, enhanced platelet aggregation and Tissue Factor (TF) expression on cancer cells, further reports have suggested that coagulation factors can enhance metastasis through increased endothelial-cancer cell adhesion and enhanced endothelial cell activation. Autophagy is highly associated with cancer survival as a double-edged sword, as can both inhibit and promote cancer progression. In this review, we shall dissect the crosstalk between the coagulation cascade and autophagic pathway and its possible role in metastasis and cancer-associated thrombosis formation. The signaling of the coagulation cascade through the autophagic pathway within the hematopoietic stem cells, the endothelial cell and the cancer cell are discussed. Relevant to the coagulation cascade, we also examine the role of autophagy-related pathways in cancer treatment. In this review, we aim to bring to light possible new areas of cancer investigation and elucidate strategies for future therapeutic intervention.
Highlights
While the precise role of the extrinsic coagulation cascade in the pathophysiology of cancer progression is still largely unknown, a hypercoagulable state has been intimately linked to cancer progression for more than a century [1]
The aforementioned data suggest that activation of PAR2 by Tissue Factor (TF)-FVII-Xa suppresses the autophagic pathway in a Phosphatidylinositol 3-Kinase (PI3K)/AKT/mTOR-dependent manner [184], contributing to the generation of an inflammatory microenvironment that may lead to increased cancer cell migration and invasiveness
Given that macrophage-specific deletion of factor X (FX) prevented in vitro macrophage polarization, these observations suggest that coagulation factors contribute to cancer progression by promoting the formation of Tumor-Associated Macrophage (TAM)-like cells
Summary
While the precise role of the extrinsic coagulation cascade in the pathophysiology of cancer progression is still largely unknown, a hypercoagulable state has been intimately linked to cancer progression for more than a century [1]. AMPK, AMP-activated protein kinase; ATG, autophagy-related proteins; BafA1, bafilomycin A1; BECN1, Beclin-1; BCL-2, B Cell Lymphoma 2; CQ, chloroquine; ER, endoplasmic reticulum; FIP200, focal adhesion kinase family interacting protein of 200 kDa; JNK1, c-Jun N-terminal kinase 1; LC3, microtubule-associated protein 1A/1B-light chain 3; mTORC1, mammalian target of rapamycin complex 1; PE, phosphatidylethanolamine; PI3K, phosphatidylinositol 3-kinase; SNAREs, soluble N-ethylmaleimidesensitive factor attachment protein receptors; ULK1, unc-51-like kinase; VPS, vacuolar protein sorting; vWF, von Willebrand factor; 3-MA, 3-methyladenine. The secretory autophagy pathway plays a key role in the progression of several diseases, including cancer [102, 103] It is involved in the secretion of cytokines such as IL-6, IL-8, and IL-1b, damage response mediators such as High mobility group box 1 protein (HMGB1) or ATP, and granule content such as von Willebrand factor (vWF) [104,105,106,107]. AUTOPHAGY REGULATES THROMBUS FORMATION THROUGH MEGAKARYOCYTE DIFFERENTIATION, PLATELET PRODUCTION, AND PLATELET ACTIVATION
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