Abstract
Platelets are critical to hemostatic and immunological function, and are key players in cancer progression, metastasis, and cancer-related thrombosis. Platelets interact with immune cells to stimulate anti-tumor responses and can be activated by immune cells and tumor cells. Platelet activation can lead to complex interactions between platelets and tumor cells. Platelets facilitate cancer progression and metastasis by: (1) forming aggregates with tumor cells; (2) inducing tumor growth, epithelial-mesenchymal transition, and invasion; (3) shielding circulating tumor cells from immune surveillance and killing; (4) facilitating tethering and arrest of circulating tumor cells; and (5) promoting angiogenesis and tumor cell establishment at distant sites. Tumor cell-activated platelets also predispose cancer patients to thrombotic events. Tumor cells and tumor-derived microparticles lead to thrombosis by secreting procoagulant factors, resulting in platelet activation and clotting. Platelets play a critical role in cancer progression and thrombosis, and markers of platelet-tumor cell interaction are candidates as biomarkers for cancer progression and thrombosis risk.
Introduction
Platelets were first described as an independent cell type present in the blood in 1881 by Giulio Bizzozero (reviewed in Mazzarello et al., 2001). They were named after their morphology in the non-activated state, small discoid cells resembling “small plates.” Bizzozero was also the first to describe the morphological changes in platelets attributed to platelet activation and their important role in thrombus formation (Bizzozero, 1881). Subsequently, James Homer Wright described platelets as originating from megakaryocytes in the bone marrow (Wright, 1910). Many bleeding disorders and diseases attributed to defects in platelet function were described during this period.
Platelets are produced by hematopoietic stem cells in the liver during fetal development and can be seen in fetal circulation as early as 8–9 weeks (Palis and Segel, 2016). Platelets quickly reach adult quantities, and neonatal thrombocytopenia is defined by the same criteria as adult thrombocytopenia (<150 × 109/L) (Sola-Visner, 2012). Late in gestation through adulthood, platelet production shifts to megakaryocytes (MKs) in the bone marrow. Once mature, MKs migrate to the vascular bed and release proplatelets into the circulation, eventually leading to the dissolution of the entire MK (Machlus and Italiano, 2013). Once in circulation, proplatelets break apart and form mature platelets that travel through the circulation for 7–10 days before being cleared by resident phagocytes in the liver and spleen (Sørensen et al., 2009).
Platelet composition
Platelets possess and display a variety of functional immunoreceptors that respond to a broad spectrum of agonists including those associated with tissue injury and infection (Kasirer-Friede et al., 2007; Cox et al., 2011). Platelets have glycoproteins (GPs) that sense vascular and sub-endothelial structures such as collagen and other exposed proteins, which enable platelets to respond to injury. GPIbα and GPVI are involved in thrombus formation (Gardiner and Andrews, 2014), and GPIIb/IIIa, also known as integrin αIIbβ3, is critical for platelet aggregation, adhesion to ECM, and clot retraction (Kasirer-Friede et al., 2007). Platelets also express pattern recognition receptors (PRRs) including toll-like receptors (TLRs), NOD-like receptors (Zhang S. et al., 2015), and C-type lectin receptors (Polgar et al., 1997). TLR expression enables activated platelets to bind and capture bacteria (Cognasse et al., 2005; Aslam et al., 2006). Other important surface receptors including P-selectin (Furie et al., 2001), integrins (Kasirer-Friede et al., 2007; Bennett et al., 2009), and FcγRIIa (Berlacher et al., 2013) also increase upon platelet activation, facilitating interactions between activated platelets and leukocytes.
Platelets are continually exposed to all components of plasma through their open canalicular system, which provides a conduit for release of granule contents, and facilitates platelet shape change in response to stimuli (Escolar et al., 1989; Escolar and White, 1991; Jurk and Kehrel, 2005). Mature platelets possess three distinct types of cytoplasmic storage compartments: alpha (α-) granules, dense (δ-) granules, and lysosomal (λ-) granules. These granules contain vast array of bioactive molecules with hemostatic and host defense properties that can be released into the circulation or translocated to the platelet surface upon platelet activation. α-granules are the most abundant type and contain bioactive mediators including adhesion molecules, coagulation factors, growth factors, cytokines and chemokines, and microbicidal proteins. δ-granules store bioactive amines (histamine and serotonin), ions (calcium and phosphate), and nucleotides (ADP and ATP) (Yeaman, 2014). The list of proteins housed in each type of granules is summarized in our previous report (Ali et al., 2015).
Platelets are anucleate, but they contain thousands of unique RNA transcripts (Zimmerman and Weyrich, 2008), including long-lived mRNA that can act as a template for protein translation throughout the platelet lifespan (Booyse and Rafelson, 1967) and unspliced pre-mRNA that can be processed by megakaryocyte-derived spliceosome (Denis et al., 2005). In addition to translation mechanisms common to many cell types, platelet activation influences translation via mTOR signaling (Weyrich et al., 1998). The 5′ and especially 3′ untranslated regions of platelet mRNA contribute to differential translation and transcript half-life (Zimmerman and Weyrich, 2008), and activated-platelet protein-1 expressed during platelet activation binds poly A sequences in the 3′ region to regulate translation (Houng et al., 1997). Notably, platelet activation stimulates translation of multiple proteins (Denis et al., 2005) including Bcl-3 (Weyrich et al., 1998), tissue factor (Schwertz et al., 2006), and IL-1β (Lindemann et al., 2001), among many others.
In addition to mRNA, platelets also contain microRNAs (miRNAs). miRNAs are small non-coding RNAs shown to play important roles in gene regulation, and act as biomarkers and regulators of disease states (Ardekani and Naeini, 2010; Li and Kowdley, 2012; McManus and Freedman, 2015). Platelets possess the machinery necessary for processing pre-miRNA to functional miRNA (Landry et al., 2009). Platelets contain a distinct miRNA profile and changes to miRNA within the platelet can lead to dysfunctional platelet activity (Plé et al., 2012; Rowley et al., 2016). Platelet miRNA can also exert effects on surrounding tissues, leading to decreased expression of intercellular adhesion molecule-1 (ICAM-1) on the endothelium during myocardial infarction (Gidlöf et al., 2013). As they are abundant in the circulation and are able to secrete bioactive miRNA that can affect surrounding cells and tissues, platelets' role in regulation of health and disease can be significant.
Platelet function
Platelets play a critical role in hemostasis and immunity, and are among the first cells to detect endothelial injury and microbial pathogens invading the bloodstream and tissues (Al Dieri et al., 2012; Gardiner and Andrews, 2013). Platelets circulate in a quiescent state without forming stable adhesions with the endothelial cells. Vascular injury causes platelet glycoproteins GPVI and GPIbα to interact with exposed collagen and von Willebrand Factor (VWF), respectively, in the subendothelial matrix. These receptor-ligand interactions mediate platelets' stable adhesion to the endothelial cells and initiate a cascade of intracellular responses that results in amplification of activation signals through the release of platelet agonists like ADP and thrombin. In response to activation, platelets change their shape, degranulate, and upregulate surface receptor expression. Collectively, this leads to further platelet aggregation and recruitment to the sites of tissue damage or infection (Semple et al., 2011). In addition to activation by classic platelet agonists, platelets can also be partially activated or “primed” by the presence of atypical agonists such as IgG (Antczak et al., 2010). Human platelets possess the Fcγ receptor IIa that is actively able to bind and internalize IgG complexes (Worth et al., 2006; Antczak et al., 2011). Pre-stimulation with IgG complexes leads to increased activation in response to lower levels of agonists causing a state of “platelet hypersensitivity” (Berlacher et al., 2013). We have shown this phenomenon in systemic lupus erythematosus (SLE), an inflammatory condition that is known to have circulating IgG complexes.
Platelet interaction with immune cells with respect to cancer
Platelets play a role in inflammation by binding to immune cells to modulate immune function. Binding of activated platelets to leukocytes stimulates cytokine release, oxidative burst, phagocytosis, and formation of neutrophil extracellular traps (NETs), which are composed of DNA, histones, and antimicrobial proteins (Kral et al., 2016). Platelets also recruit and activate macrophages and neutrophils in tumor tissue, stimulating TGF-β release and platelet-tumor cell aggregation (Kim and Bae, 2016). Macrophages infiltrate tumors and release cytolytic factors including tumor necrosis factor α (TNF-α) to destroy the tumor (Larrick and Wright, 1990), and it was found that platelets reduced macrophage-mediated cytotoxicity in fibrosarcoma by inhibiting the effects of TNF-α (Philippe et al., 1993). Immune cells may also stimulate platelets. For example, neutrophil release of myeloperoxidase partially activates platelets (Kolarova et al., 2013). Moreover, NETs stimulate the intrinsic pathway of the coagulation cascade, ultimately generating thrombin and activating platelets (Gould et al., 2014).
Platelet-immune cell interactions have applications in cancer treatment. For example, elevated PLR correlated with elevated CA 19-9, the current biomarker used of diagnosis of pancreatic cancer (Miglani et al., 2013). Similar changes in PLR have also been reported in patients at risk of lung cancer (Sanchez-Salcedo et al., 2016). Therefore, changes in PLR are most likely not cancer-specific and may not be able to differentiate specific cancer types based solely on PLR levels. However, elevated PLR is reported as a prognostic tool (Zhou et al., 2014; Cummings et al., 2015; Messager et al., 2015; Zhang Y. et al., 2015; Wang et al., 2016) and staging and follow up tool (Emir et al., 2015; Jia et al., 2015), often in conjunction with neutrophil/lymphocyte ratio (NLR). Furthermore, PLR has been found to be an independent predictor of venous thromboembolism in cancer patients (Ferroni et al., 2015). COmbination of Platelet count and Neutrophil to Lymphocyte Ratio (COP-NLR) (Ishizuka et al., 2013, 2014; Feng et al., 2014a; Zhang H. et al., 2015; Nakahira et al., 2016) and Neutrophil-Platelet Score (NPS) (Watt et al., 2015) are predictors of survival for several types of cancer. Notably, some scoring systems that include evaluation of platelet count or function have higher predictive value in certain cancers than tools not analyzing platelets (Feng et al., 2014b; Ferroni et al., 2015; Sanchez-Salcedo et al., 2016), indicating that platelets may play a key role in cancer development and have prognostic value.
Platelets and cancer progression
Platelet-tumor cell interaction
Platelets play an integral role in the development and metastasis of cancer; high platelet counts have been linked to increased metastasis (Buergy et al., 2012) and poorer outcomes in multiple types of cancer (Kim et al., 2014, 2015; Moschini et al., 2014; Voutsadakis, 2014; Chadha et al., 2015; Ji et al., 2015). Tumor cells interact with platelets through a number of receptors and signaling molecules. For example, tumor cells release soluble molecules that activate platelets, including ADP and thrombin (Zucchella et al., 1989; Boukerche et al., 1994; Bambace and Holmes, 2011) while direct contact of platelets with tumor cells also results in activation (Suzuki-Inoue et al., 2006; Erpenbeck and Schon, 2010; Lal et al., 2013; Menter et al., 2014; Li, 2016). Platelet-tumor cell aggregates form through binding of platelet integrin αIIbβ3 to tumor cell integrin αvβ3 via RGD-containing proteins including fibrinogen, von Willebrand factor, and fibronectin (Kitagawa et al., 1989; Felding-Habermann et al., 1996), a process known as tumor cell-induced platelet aggregation (TCIPA) (Jurasz et al., 2004; Goubran et al., 2013). electins expressed on platelets, leukocytes, and endothelium may also bind tumor cells to form platelet-tumor-leukocyte aggregates (Laubli and Borsig, 2010). Specifically, P-selectin expressed on the surface of activated platelets binds to many types of human cancer cells (Chen and Geng, 2006). Activated platelets were observed to interact with small cell lung cancer and neuroblastoma cell lines, and this interaction was blocked with inhibitory anti-P-selectin antibodies (Stone and Wagner, 1993), indicating that P-selectin is a key mediator of platelet-tumor interaction (Borsig, 2008). L-selectin on leukocytes acts synergistically with P-selectin, facilitating platelet-tumor interaction (Borsig et al., 2002). Podocalyxin-like protein 1 (PCLP1) binds E- and L-selectin in pancreatic cancer (Dallas et al., 2012), and is overexpressed in many cancers and on activated platelets (Amo et al., 2014). Once activated, platelets can then bind to tumor cells via P-selectin (Chen and Geng, 2006; Coupland et al., 2012; Qi et al., 2015) and glycoproteins (Lonsdorf et al., 2012; Goubran et al., 2013) and directly induce tumor growth and metastasis by releasing pro-tumor angiogenic and growth factors.
Platelet-derived microparticles (PDMPs) also promote metastasis and angiogenesis by producing matrix metalloproteinase 2 (MMP-2), angiogenic platelet-derived growth factors and tissue factor (Dashevsky et al., 2009; Martinez and Andriantsitohaina, 2011; Falanga et al., 2012; Varon et al., 2012). These pathways create a loop of activation as tumor cells activate platelets, which in turn support growth, invasion, and metastasis of tumor cells (Goubran et al., 2013).
Tumor cells transfer RNA into platelets via microvesicles, resulting in tumor educated platelets (TEPs) (Nilsson et al., 2011). Importantly, this observation was applied to cancer diagnostics using mRNA sequencing of TEPs. Sequencing of TEPs was 96% accurate in distinguishing cancer patients from individuals without cancer, and was able to provide information about the location of some cancers (Best et al., 2015). Platelet mRNA profiles showed downregulation of numerous genes, including many associated with translation, IL-signaling, protein synthesis, and immunity, and upregulation of cancer-associated, metabolic, cytoskeletal, and platelet-related genes (Best et al., 2015). EML4-ALK rearrangements in non-small-cell lung cancer were detectable by RT-PCR in platelets, and this correlated with poor prognosis (Nilsson et al., 2015), suggesting TEP may be a promising source for liquid biopsy (Feller and Lewitzky, 2016; Perez-Callejo et al., 2016).
Platelet effect on tumor invasion and intravasation
Activated platelets play multiple roles in the progression of tumor metastasis, including facilitation of tumor cell epithelial-mesenchymal transition (EMT), degradation of surrounding extracellular matrix (ECM), increasing vascular permeability, and aiding in the establishment of malignancies in distant tissues (Miyashita et al., 2015; Pang et al., 2015; Guillem-Llobat et al., 2016) through interactions with tumor cells through selectins and glycoproteins (Kohler et al., 2010; Laubli and Borsig, 2010; Gay and Felding-Habermann, 2011; Bendas and Borsig, 2012; Pang et al., 2015). Activated platelets promote metastasis by secreting lysophosphatidic acid (LPA), a lipid that has growth factor-like properties, which has been found to be involved in the progression of multiple cancers (Mills and Moolenaar, 2003; Leblanc and Peyruchaud, 2015; Lou et al., 2015). LPA plays a role in many cellular processes including cell proliferation, survival, migration, tumor cell invasion, and reversal of differentiation through multiple G protein-coupled receptor (LPA1-6) cascades, and is a potential target for cancer therapy (summarized in Mills and Moolenaar, 2003). Activated platelets also secrete transforming growth factor β (TGF-β) (Assoian and Sporn, 1986) and platelet-derived growth factor (PDGF) (Kong et al., 2008) from α-granules in response to tumor cell stimulation, inducing EMT (Assoian and Sporn, 1983; Radisky and LaBarge, 2008; Labelle et al., 2011; Yu et al., 2013; Leblanc and Peyruchaud, 2016). By releasing TGF-β and PGE2, platelets strongly activate genes promoting EMT, ECM remodeling, and metastasis in tumor cells (Labelle et al., 2011; Guillem-Llobat et al., 2016). Tumor cell expression of the EMT-associated transcription factor Snail1 correlated with platelet localization on the leading edge of tumor cells as indicated by CD42b (Miyashita et al., 2015). This is an important area of investigation that may yield important results.
Platelets also influence tumor metastasis by enhancing tumor cell expression of tissue factor, a primary initiator of the coagulation cascade (Orellana et al., 2015). Tissue factor is constitutively present on the surface of malignant tumors which activates platelets (Callander et al., 1992; Date et al., 2013), and is shed on tumor microvesicles (Yu and Rak, 2004). Tissue factor generates thrombin, which has been shown to induce platelet-tumor cell interactions in vitro, and administration of thrombin increases pulmonary metastases in murine models of colon cancer (summarized in Gay and Felding-Habermann, 2011). Tissue factor also drives growth of primary tumors, stimulates angiogenesis, and is associated with EMT and cancer stem cell behavior (Versteeg, 2015), and was found to be an indicator of metastasis and prognosis in numerous types of cancer (summarized in van den Berg et al., 2012).
Once tumor cells undergo EMT, the next step in metastasis is to invade local tissues and enter the bloodstream (Hunter et al., 2008). Tumor cells activate platelets through a number of mechanisms, including release of platelet-activating soluble factors like ADP and thrombin and ligation of TLR-4 (Grignani et al., 1989; Li, 2016). Activated platelets then release serotonin, ATP and histamine increasing vascular permeability, and MMPs that degrade ECM (Deryugina and Quigley, 2006; Li, 2016). Platelet-derived LPA also up-regulates matrix metalloproteinase (MMP) activity (Lou et al., 2015). The weakened extracellular matrix and endothelial barrier allow tumor cells to enter circulation and metastasize (Stegner et al., 2014).
Tumor shielding
Tumor cells free in circulation are susceptible to immune surveillance and killing. Natural killer (NK) cells are the primary killers of metastasizing tumor cells (Talmadge et al., 1980; Wiltrout et al., 1985). Platelets shield tumor cells from NK cell lysis by forming aggregates on the tumor cell surface (Nieswandt et al., 1999). Platelets interfere with NK cell binding to tumor cells both sterically and by inhibiting NK cell cytolytic function (Philippe et al., 1993; Shau et al., 1993). Specifically, activated platelets release soluble factors (e.g., TGF-β) that down-regulate NK cell immunoreceptors and inhibit NK cell functions including IFN-γ production, cytotoxicity, and granule mobilization (Kopp et al., 2009).
Platelets also may facilitate tumor escape from NK cell lysis by modulating expression of major histone compatibility complex (MHC) class I. MHC class I is an antigen that host cells express to identify them as “self” or to present antigen fragments to CD8+ T cells if the host cell is infected or abnormal. Many types of malignancies have been shown to express abnormal MHC class I, including MHC class I with structurally altered heavy chains, mutated β2-microglobulin and TAP1, or dysregulated antigen processing machinery, leading to reduced or absent MHC class I expression (Seliger, 2008, 2014). This dysregulation makes tumor cells susceptible to killing by NK cells, which target cells lacking MHC class I (Seliger, 2008). Platelets can transfer MHC class I antigens to tumor cells, protecting them from T-cell mediated immunity without inducing NK cell cytotoxicity and IFN-γ production (Placke et al., 2011, 2012), and direct platelet inhibition of tumor cell lysis by NK cells can also occur in an MHC-independent manner (Nieswandt et al., 1999). In mice, thrombocytopenia inhibits metastasis but this effect is reversed if NK cells are depleted, indicating platelets' key role in metastasis is shielding tumor cells from NK cell killing (Kopp et al., 2009). Platelets and platelet-derived microparticles adhere to tumor cells through interactions with integrins and selectins (Kitagawa et al., 1989; Felding-Habermann et al., 1996; Gay and Felding-Habermann, 2011). Additionally, fibronectin and other adhesive molecules may act as a bridge between platelets and tumor cells, as mediated by PCLP1 (Amo et al., 2014). Tumor cells are enshrouded in platelet-fibrin mesh, shielding them from NK cell contact and immune surveillance in circulation (Borsig et al., 2001).
Platelet effect on tumor cell arrest and extravasation
Platelets and platelet-derived microparticles adhered to circulating tumor cells also facilitate tethering and arrest (Honn et al., 1992; Gay and Felding-Habermann, 2011; Menter et al., 2014; Li, 2016). Platelets were found to act as chemoattractants for circulating tumor cells, potentially aiding in tumor cell homing and establishment of metastatic sites (Orellana et al., 2015). Tumor cell-activated platelets release ATP, which binds P2Y2 receptors on the endothelium, opening the transendothelial barrier and allowing tumor cells to exit the bloodstream into metastatic sites (Schumacher et al., 2013). LPA, TGFβ, MMP, PGE2, and other platelet- and leukocyte-derived factors that assisted in EMT and intravasation weaken the endothelium and also facilitate extravasation (Stegner et al., 2014). Platelet-bound tumor cells may bind directly to selectins on the endothelium, leading to tethering, rolling, and ultimately extravasation (Bendas and Borsig, 2012; Coupland et al., 2012). Myeloid cells can facilitate this process by activating the endothelium through interleukin (IL)-1α, IL-1β, and TNF-α (Labelle and Hynes, 2012). Tumor cells may also be slowed due to their large size upon reaching microvasculature, among other mechanisms (summarized in Witz, 2008). Notably, the pro-coagulant characteristics of platelet-tumor aggregates facilitate the formation of microthrombi in small vessels, further slowing tumor cell migration and enhancing arrest rate (Menter et al., 2014).
Platelet effect on tumor cell establishment and angiogenesis
Tumor cells do not necessarily remain and grow at the initial site of arrest; many cells die or become dislodged, and some cells have been observed to leave and reattach at another site (Kienast et al., 2010). Successful metastasis requires extravasation close to sufficient vasculature to allow tumor cells to obtain nutrients (Folkman, 1971) and recruit leukocytes to form premetastatic niches (Labelle and Hynes, 2012). Premetastatic niche formation depends on communication with the microenvironment (LaBarge et al., 2007; LaBarge, 2010), including platelet-derived TGF-β and P2Y12 signaling (Labelle et al., 2011; Wang et al., 2013). TGF-β reduces the effect of tumor-entrained neutrophils (TEN; a subset of CD11b+Ly-6GH+MMP-9+ cells not present in healthy individuals) (Fridlender et al., 2009), which typically kill tumor cells by producing hydrogen peroxide (Granot et al., 2011).
Platelet-activated tumor cells have enhanced expression of pro-metastatic genes including proteases, cytokines, and growth factors to facilitate invasion and metastatic seeding (Labelle et al., 2011). Among other pro-angiogenic factors (summarized in Sabrkhany et al., 2011), platelets are a primary source of vascular endothelial growth factor (VEGF), a growth factor that increases vascular permeability, promotes extravasation, and is critical for angiogenesis (Verheul et al., 1997; Sierko and Wojtukiewicz, 2004). Platelets activated by TF present on the surface of endothelial cells (Shoji et al., 1998; Verheul et al., 2000) release VEGF in malignant tissue, directly promoting angiogenesis (Verheul et al., 2000). Tumor-derived thrombin also plays an angiogenic role, inducing endothelial cell growth (Herbert et al., 1994) and increasing platelet release of VEGF. Platelets are thought to contain angiogenesis stimulators and inhibitors secreted based on stimulation of proteinase activated receptors (PARs). Some studies show angiogenesis stimulators and inhibitors are differentially released in response to selective PAR agonists to regulate angiogenesis (Ma et al., 2005; Italiano et al., 2008). However, kinetic analysis revealed no functional pattern in α-granule release, and both types of releasates were ultimately shown to stimulate angiogenesis in vitro and in vivo (Jonnalagadda et al., 2012; Huang et al., 2015).
Platelet microparticles also promote angiogenesis (Martinez and Andriantsitohaina, 2011), stimulating the formation of capillary tube and network formation (Kim et al., 2004; Prokopi et al., 2009) and stimulating tumor cell expression of pro-angiogenic factors (Janowska-Wieczorek et al., 2005). Microparticles in cancer patients also express tissue factor (Hron et al., 2007), further activating platelets and stimulating the angiogenic cascade to support metastatic tumor growth.
Cancer and coagulation
The presence of tumor cell-activated platelets in the bloodstream may predispose cancer patients to thrombotic events. The correlation between cancer and risk of venous thromboembolism (VTE), first noted in 1865 by Dr. Armand Trousseau, has been well-documented (Varki, 2007). A 2007 study found that cancer patients on chemotherapy were 47 times more likely to experience VTE (Khorana et al., 2007). In general, active cancer increases risk for VTE by four- to seven-fold, and cancer-associated VTE is on the rise (Key et al., 2016). Cancer patients with elevated pre-chemotherapy platelet counts were significantly associated with VTE, indicating that platelets likely play a role in the development of thrombotic events (Khorana et al., 2005; Kadlec et al., 2014).
Tumor cells stimulate clotting and thrombosis through multiple mechanisms (Mackman, 2008). Tissue factor produced by tumor cells and tumor-derived microparticles stimulates the coagulation cascade (Owens and Mackman, 2011; Menter et al., 2014; Phillips et al., 2015), activating platelets and promoting thrombosis via the tissue factor (extrinsic) pathway (Mackman, 2008). Indeed, plasma tissue factor was found to be predictive of VTE in pancreatic cancer (Khorana et al., 2008). Activated platelets and negatively-charged phospholipids shed by tumor cells may also stimulate coagulation via the contact activation (intrinsic) pathway (Dicke and Langer, 2015; Key et al., 2016). Tumor-derived IL-6 and hepatic thrombopoietin were also associated with thrombocytosis and thrombosis (Hisada et al., 2015). Additionally, tumor-derived microparticles have strong procoagulant activity and are associated with VTE in cancer (Manly et al., 2010; Geddings and Mackman, 2013; Mege et al., 2016). These microparticles were found to activate platelets and induce aggregation and thrombus formation, and accumulated in the thrombus by interacting with P-selectin (Thomas et al., 2009), demonstrating the integral role platelets play in the development of cancer-associated VTE.
VTE and thrombocytosis are factors associated with poor prognosis for patients with cancer (Sorensen et al., 2000; Kourelis et al., 2014; Chadha et al., 2015; Chen et al., 2015), highlighting the need for a method to quantify VTE risk in cancer patients. Markers of platelet-tumor cell interaction including P-selectin, tissue factor, and microparticles are candidates to detect early signs of VTE, as are markers of inflammation (C-reactive protein) and coagulation (D-dimer, Factor VIII; summarized in Hanna et al., 2013). Early detection of risk factors associated with VTE may influence use of thromboprophylaxis, and may substantially reduce morbidity and mortality in cancer patients. Given their critical role in tumor growth, metastasis, and cancer-associated thrombosis, markers of platelet activity should be explored as biomarkers and potential therapeutic targets for cancer progression and VTE.
Platelets play a critical role in cancer progression and metastasis, and contribute to the development of VTE in cancer. However, it is not yet clear whether platelet activation and thrombocytosis are ultimately the causative agent or the result of tumor progression. Additionally, the molecular mechanism behind platelet-induced coagulation in cancer has yet to be described. As research continues to utilize platelet biomarkers in cancer diagnosis, prognosis, and risk, much will be discovered about the platelet-cancer dynamic on a mechanistic level.
Statements
Author contributions
CM, CK, PG, LW, and RA wrote sections of the manuscript. CM and RW compiled and organized the manuscript and RW edited the manuscript.
Acknowledgments
This work is supported by NIH RO1-HL122401 (to RW).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
Al Dieri R. de Laat B. Hemker H. C. (2012). Thrombin generation: what have we learned?Blood Rev.26, 197–203. 10.1016/j.blre.2012.06.001
2
Ali R. A. Wuescher L. M. Worth R. G. (2015). Platelets: essential components of the immune system. Curr. Trends Immunol.16, 65–78.
3
Amo L. Tamayo-Orbegozo E. Maruri N. Eguizabal C. Zenarruzabeitia O. Rinon M. et al . (2014). Involvment of platelet-tumor cell interaction in immune evasion. Potential role of podocalyxin-like protein 1. Front. Oncol.4:245. 10.3389/fonc.2014.00245
4
Antczak A. J. Singh N. Gay S. R. Worth R. G. (2010). IgG-complex stimulated platelets: a source of sCD40L and RANTES in initiation of inflammatory cascade. Cell. Immunol.263, 129–133. 10.1016/j.cellimm.2010.03.009
5
Antczak A. J. Vieth J. A. Singh N. Worth R. G. (2011). Internalization of IgG-coated targets results in activation and secretion of soluble CD40 ligand and RANTES by human platelets. Clin. Vaccine Immunol.18, 210–216. 10.1128/CVI.00296-10
6
Ardekani A. M. Naeini M. M. (2010). The role of microRNAs in human diseases. Avicenna J. Med. Biotechnol.2, 161–179.
7
Aslam R. Speck E. R. Kim M. Crow A. R. Bang K. W. A. Nestel F. P. et al . (2006). Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-α production in vivo. Blood107, 637–641. 10.1182/blood-2005-06-2202
8
Assoian R. K. Sporn M. B. (1983). Transforming growth factor-beta in human platelets - identification of a major storage site, purification, and characterization. J. Biol. Chem.258, 7155–7160.
9
Assoian R. K. Sporn M. B. (1986). Type B transforming growth factor in human platelets: release during platelet degranulation and action on vascular smooth muscle cells. J. Cell Biol.102, 1217–1223. 10.1083/jcb.102.4.1217
10
Bambace N. M. Holmes C. E. (2011). The platelet contribution to cancer progression. J. Thromb. Haemost.9, 237–249. 10.1111/j.1538-7836.2010.04131.x
11
Bendas G. Borsig L. (2012). Cancer cell adhesion and metastasis: selectins, integrins, and the inhibitory potential of heparins. Int. J. Cell Biol.2012:676731. 10.1155/2012/676731
12
Bennett J. S. Berger B. W. Billings P. C. (2009). The structure and function of platelet integrins. J. Thromb. Haemost.7, 200–205. 10.1111/j.1538-7836.2009.03378.x
13
Berlacher M. D. Vieth J. A. Heflin B. C. Gay S. R. Antczak A. J. Tasma B. E. et al . (2013). FcyRIIa ligation induces platelet hypersensitivity to thrombotic stimuli. Am. J. Pathol.82, 244–254. 10.1016/j.ajpath.2012.09.005
14
Best M. G. Sol N. Kooi I. Tannous J. Westerman B. A. Rustenburg F. et al . (2015). RNA-Seq of tumor-educated platelets enables blood-based pan-cancer, multiclass, and molecular pathway cancer diagnostics. Cancer Cell28, 667–676. 10.1016/j.ccell.2015.09.018
15
Bizzozero G. (1881). Su di un nuovo elemento morfologico del sange dei mammiferi e sulla sua importanza nella trombosi e nella coagulazione. L'Osservatore. Gazz. Clin.17, 785–787.
16
Booyse F. M. Rafelson M. E. (1967). Stable messenger RNA in the synthesis of contractile protein in human platelets. Biochim. Biophys. Acta145, 188–190. 10.1016/0005-2787(67)90673-9
17
Borsig L. (2008). The role of platelet activation in tumor metastasis. Expert Rev. Anticancer Ther.8, 1247–1255. 10.1586/14737140.8.8.1247
18
Borsig L. Wong R. Feramsico J. Nadeau D. R. Varki N. M. Varki A. (2001). Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc. Natl. Acad. Sci. U.S.A.98, 3352–3357. 10.1073/pnas.061615598
19
Borsig L. Wong R. Hynes R. O. Varki N. M. Varki A. (2002). Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc. Natl. Acad. Sci. U.S.A.99, 2193–2198. 10.1073/pnas.261704098
20
Boukerche H. Berthier-Vergnes O. Penin F. Tabone E. Lizard G. McGregor J. L. (1994). Human melanoma cell lines differ in their capacity to release ADP and aggregate platelets. Br. J. Haematol.87, 763–772. 10.1111/j.1365-2141.1994.tb06736.x
21
Buergy D. Wenz F. Groden C. Brockmann M. A. (2012). Tumor-platelet interaction in solid tumors. Int. J. Cancer130, 2747–2760. 10.1002/ijc.27441
22
Callander N. S. Varki N. Rao L. V. M. (1992). Immunohistochemical identification of tissue factor in solid tumors. Cancer70, 1194–1201. 10.1002/1097-0142(19920901)70:5<1194::AID-CNCR2820700528>3.0.CO;2-E
23
Chadha S. A. Kocak-Uzel E. Das P. Minsky B. D. Delclos M. E. Mahmood U. et al . (2015). Paraneoplastic thrombocytosis independently predicts poor prognosis in patients with locally advanced pancreatic cancer. Acta Oncol.54, 971–978. 10.3109/0284186X.2014.1000466
24
Chen M. Geng J.-G. (2006). P-selectin mediates adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis. Arch. Immunol. Ther. Exp.54, 75–84. 10.1007/s00005-006-0010-6
25
Chen W. Zhang Y. Yang Y. Zhai Z. Wang C. (2015). Prognostic significance of arterial and venous thrombosis in resected specimens for non-small cell lung cancer. Thromb. Res.136, 451–455. 10.1016/j.thromres.2015.06.014
26
Cognasse F. Hamzeh H. Chavarin P. Acquart S. Genin C. Garraud O. (2005). Evidence of Toll-like receptor molecules on human platelets. Immunol. Cell Biol.83, 196–198. 10.1111/j.1440-1711.2005.01314.x
27
Coupland L. A. Chong B. H. Parish C. R. (2012). Platelets and P-selectin control tumor cell metastasis in an organ-specific manner and independently of NK cells. Cancer Res.72, 4662–4671. 10.1158/0008-5472.CAN-11-4010
28
Cox D. Kerrigan S. W. Watson S. P. (2011). Platelets and the innate immune system: mechanisms of bacterial-induced platelet activation. J. Thromb. Haemost.9, 1097–1107. 10.1111/j.1538-7836.2011.04264.x
29
Cummings M. Merone L. Keeble C. Burland L. Grzelinski M. Sutton K. et al . (2015). Preoperative neutrophil:lymphocyte and platelet:lymphocyte ratios predict endometrial cancer survival. Br. J. Cancer113, 311–320. 10.1038/bjc.2015.200
30
Dallas M. R. Chen S.-H. Streppel M. M. Sharma S. Maitra A. Konstantopoulos K. (2012). Sialofucosylated podocalyxin is a functional E- and L-selectin ligand expressed by metastatic pancreatic cancer cells. Am. J. Physiol. Cell Physiol.303, C616–C624. 10.1152/ajpcell.00149.2012
31
Dashevsky O. Varon D. Brill A. (2009). Platelet-derived microparticles promote invasiveness of prostate cancer cells via upregulation of MMP-2 production. Int. J. Cancer124, 1773–1777. 10.1002/ijc.24016
32
Date K. Hall J. Greenman J. Maraveyas A. Madden L. A. (2013). Tumour and microparticle tissue factor expression and cancer thrombosis. Thromb. Res.131, 109–115. 10.1016/j.thromres.2012.11.013
33
Denis M. M. Tolley N. D. Bunting M. Schwertz H. Jiang H. Lindemann S. et al . (2005). Escaping the nuclear confines: signal dependent pre-mRNA splicing in anucleate platelets. Cell122, 379–391. 10.1016/j.cell.2005.06.015
34
Deryugina E. I. Quigley J. P. (2006). Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev.25, 9–34. 10.1007/s10555-006-7886-9
35
Dicke C. Langer F. (2015). Pathophysiology of Trousseau's syndrome. Hamostaseologie35, 52–59. 10.5482/HAMO-14-08-0037
36
Emir S. Aydin M. Can G. Bali I. Yildirim O. Oznur M. et al . (2015). Comparison of colorectal neoplastic polyps and adenocarcnoma with regard to NLR and PLR. Eur. Rev. Med. Pharmacol. Sci.19, 3613–3618.
37
Erpenbeck L. Schon M. P. (2010). Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood115, 3427–3436. 10.1182/blood-2009-10-247296
38
Escolar G. White J. G. (1991). The platelet open canalicular system: a final common pathway. Blood Cells17, 467–485. discussion: 486–495.
39
Escolar G. Leistikow E. White J. G. (1989). The fate of the open canalicular system in surface and suspension-activated platelets. Blood74, 1983–1988.
40
Falanga A. Tartari C. J. Marchetti M. (2012). Microparticles in tumor progression. Thromb. Res.129, S132–S136. 10.1016/S0049-3848(12)70033-6
41
Felding-Habermann B. Habermann R. Saldivar E. Ruggeri Z. M. (1996). Role of beta-3 integrins in melanoma cell adhesion to activated platelets under flow. J. Biol. Chem.271, 5892–5900. 10.1074/jbc.271.10.5892
42
Feller S. Lewitzky M. (2016). Hunting for the ultimate liquid cancer biopsy - let the TEP dance begin. Cell Commun. Signal.14, 24. 10.1186/s12964-016-0147-9
43
Feng J.-F. Huang Y. Chen Q.-X. (2014a). The combination of platelet count and neutrophil lymphocyte ratio is a predictive factor in patients with esophageal squamous cell carcinoma. Transl. Oncol.7, 632–637. 10.1016/j.tranon.2014.07.009
44
Feng J.-F. Huang Y. Chen Q.-X. (2014b). Preoperative platelet lymphocyte ratio (PLR) is superior to neutrophil lymphocyte ratio (NLR) as a predictive factor in patients with esophageal squamous cell carcinoma. World J. Surg. Oncol.12:58. 10.1186/1477-7819-12-58
45
Ferroni P. Riondino S. Formica V. Cereda V. Tosetto L. La Farina F. et al . (2015). Venous thromboembolism risk prediction in ambulatory cancer patients: clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio. Int. J. Cancer136, 1234–1340. 10.1002/ijc.29076
46
Folkman J. (1971). Tumor angiogenesis: therapeutic implications. N. Engl. J. Med.285, 1182–1186. 10.1056/NEJM197111182852108
47
Fridlender Z. G. Sun J. Kim S. Kapoor V. Cheng G. Ling L. et al . (2009). Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell16, 183–194. 10.1016/j.ccr.2009.06.017
48
Furie B. Furie B. C. Flaumenhaft R. (2001). A journey with platelet P-selectin: the molecular basis of granule secretion, signalling and cell adhesion. Thromb. Haemost.86, 214–221.
49
Gardiner E. E. Andrews R. K. (2013). Platelets: envoys at the infection frontline. J. Infect. Dis.208, 871–873. 10.1093/infdis/jit305
50
Gardiner E. E. Andrews R. K. (2014). Platelet receptor expression and shedding: glycoprotein Ib-IX-V and glycoprotein VI. Transfus. Med. Rev.28, 56–60. 10.1016/j.tmrv.2014.03.001
51
Gay L. J. Felding-Habermann B. (2011). Contribution of platelets to tumour metastasis. Nat. Rev. Cancer11, 123–134. 10.1038/nrc3004
52
Geddings J. E. Mackman N. (2013). Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood122, 1873–1880. 10.1182/blood-2013-04-460139
53
Gidlöf O. van der Brug M. Öhman J. Gilje P. Olde B. Wahlestedt C. Erlinge D. (2013). Platelets activated during myocardial infarction release functional miRNA, which can be taken up by endothelial cells and regulate ICAM1 expression. Blood121, 3908. 10.1182/blood-2012-10-461798
54
Goubran H. A. Burnouf T. Radosevic M. El-Ekiaby M. (2013). The platelet-cancer loop. Eur. J. Intern. Med.24, 393–400. 10.1016/j.ejim.2013.01.017
55
Gould T. J. Vu T. T. Swystun L. L. Dwivedi D. J. Mai S. H. Weitz J. I. et al . (2014). Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler. Thromb. Vasc. Biol.34, 1977–1984. 10.1161/ATVBAHA.114.304114
56
Granot Z. Henke E. Comen E. A. King T. A. Norton L. Benezra R. (2011). Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell20, 300–314. 10.1016/j.ccr.2011.08.012
57
Grignani G. Pacchiarini L. Ricetti M. M. Dionigi P. Jemos V. Zucchella M. et al . (1989). Mechanisms of platelet activation by cultured human cancer cells and cells freshly isolated from tumor tissues. Invasion Metastasis9, 298–309.
58
Guillem-Llobat P. Dovizio M. Bruno A. Ricciotti E. Cufino V. Sacco A. et al . (2016). Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells. Oncotarget7, 32462–32477. 10.18632/oncotarget.8655
59
Hanna D. L. White R. H. Wun T. (2013). Biomolecular markers of cancer-associated thromboembolism. Crit. Rev. Oncol. Hematol.88, 19–29. 10.1016/j.critrevonc.2013.02.008
60
Herbert J. M. Dupuy E. Laplace M. C. Zini J. M. Bar Shavit R. Tobelem G. (1994). Thrombin induces endothelial cell growth via both a proteolytic and a non-proteolytic pathway. Biochem. J.303, 227–231. 10.1042/bj3030227
61
Hisada Y. Geddings J. E. Ay C. Mackman N. (2015). Venous thrombosis and cancer: from mouse models to clinical trials. J. Thromb. Haemost.13, 1372–1382. 10.1111/jth.13009
62
Honn K. V. Tang D. G. Crissman J. D. (1992). Platelets and cancer metastasis: a causal relationship?Cancer Metastasis Rev.11, 325–351. 10.1007/BF01307186
63
Houng A. K. Maggini L. Clement C. Y. Reed G. L. (1997). Identification and structure of activated-platelet protein-1, a protein with RNA-binding domain motifs that is expressed by activated platelets. Eur. J. Biochem.243, 209–218. 10.1111/j.1432-1033.1997.0209a.x
64
Hron G. Kollars M. Weber H. Sagaster V. Quehenberger P. Eichinger S. et al . (2007). Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb. Haemost.97, 119–123. 10.1160/TH06-03-0141
65
Huang Z. Miao X. Luan Y. Zhu L. Kong F. Lu Q. et al . (2015). PAR1-stimulated platelet releasate promotes angiogenic activities of endothelial progenitor cells more potently than PAR4-stimulated platelet releasate. J. Thromb. Haemost.13, 465–476. 10.1111/jth.12815
66
Hunter K. W. Crawford N. P. S. Alsarraj J. (2008). Mechanisms of metastasis. Breast Cancer Res.10(Suppl. 1):S2. 10.1186/bcr1988
67
Ishizuka M. Nagata H. Takagi K. Iwasaki Y. Kubota K. (2013). Combination of platelet count and neutrophil to lymphocyte ratio is a useful predictor of postoperative survival in patients with colorectal cancer. Br. J. Cancer109, 401–407. 10.1038/bjc.2013.350
68
Ishizuka M. Oyama Y. Abe A. Kubota K. (2014). Combination of platelet count and neutrophil to lymphocyte ratio is a useful predictor of postoperative survival in patients undergoing surgery for gastric cancer. J. Surg. Oncol.110, 935–941. 10.1002/jso.23753
69
Italiano J. E. J. Richardson J. L. Patel-Hett S. Battinelli E. Zaslavsky A. Short S. et al . (2008). Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet granules and differentially released. Blood111, 1227–1233. 10.1182/blood-2007-09-113837
70
Janowska-Wieczorek A. Wysoczynski M. Kijowski J. Marquez-Curtis L. Machalinski B. Ratajczak J. et al . (2005). Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int. J. Cancer113, 752–760. 10.1002/ijc.20657
71
Ji Y. Sheng L. Du X. Qiu G. Su D. (2015). Elevated platelet count is a strong predictor of poor prognosis in stage I non-small cell lung cancer patients. Platelets26, 138–142. 10.3109/09537104.2014.888547
72
Jia J. Zheng X. Chen Y. Wang L. Ye X. Chen Y. et al . (2015). Stage-dependent changes of preoperative neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in colorectal cancer. Tumour Biol.36, 9319–9325. 10.1007/s13277-015-3667-9
73
Jonnalagadda D. Izu L. T. Whiteheart S. W. (2012). Platelet secretion is kinetically heterogeneous in an agonist-responsive manner. Blood120, 5209–5216. 10.1182/blood-2012-07-445080
74
Jurasz P. Alonso-Escolano D. Radomski M. W. (2004). Platelet–cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. Br. J. Pharmacol.143, 819–826. 10.1038/sj.bjp.0706013
75
Jurk K. Kehrel B. E. (2005). Platelets: physiology and biochemistry. Semin. Thromb. Hemost.31, 381–392. 10.1055/s-2005-916671
76
Kadlec B. Skrickova J. Merta Z. Dusek L. Jarkovsky J. (2014). The incidence and predictors of thromboembolic events in patients with lung cancer. Sci. World J.2014:125706. 10.1155/2014/125706
77
Kasirer-Friede A. Kahn M. L. Shattil S. J. (2007). Platelet integrins and immunoreceptors. Immunol. Rev.218, 247–264. 10.1111/j.1600-065X.2007.00532.x
78
Key N. S. Khorana A. A. Mackman N. McCarty O. J. T. White G. C. Francis C. W. et al . (2016). Thrombosis in cancer: research priorities identified by a national cancer institute/national heart, lung, and blood institute strategic working group. Cancer Res.76, 1–5. 10.1158/0008-5472.CAN-15-3100
79
Khorana A. A. Francis C. W. Culakova E. Lyman G. H. (2005). Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer104, 2822–2829. 10.1002/cncr.21496
80
Khorana A. A. Francis C. W. Culakova E. Kuderer N. M. Lyman G. H. (2007). Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J. Thromb. Haemost.5, 632–634. 10.1111/j.1538-7836.2007.02374.x
81
Khorana A. A. Francis C. W. Menzies K. E. Wang J.-G. Hyriens O. Hathcock J. et al . (2008). Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J. Thromb. Haemost.6, 1983–1985. 10.1111/j.1538-7836.2008.03156.x
82
Kienast Y. von Baumgarten L. Fuhrmann M. Klinkert W. E. F. Goldbrunner R. Herms J. et al . (2010). Real-time imaging reveals the single steps of brain metastasis formation. Nat. Med.16, 116–122. 10.1038/nm.2072
83
Kim H. J. Choi G.-S. Park J. S. Park S. Y. Kawai K. Watanabe T. (2015). Clinical significance of thrombocytosis before preoperative chemoradiotherapy in rectal cancer: predicting pathologic tumor response and oncologic outcome. Ann. Surg. Oncol.22, 513–519. 10.1245/s10434-014-3988-8
84
Kim H. K. Song K. S. Chung J. H. Lee K. R. Lee S. N. (2004). Platelet microparticles induce angiogenesis in vitro. Br. J. Haematol.124, 376–384. 10.1046/j.1365-2141.2003.04773.x
85
Kim J. Bae J.-S. (2016). Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediators Inflamm.2016, 11. 10.1155/2016/6058147
86
Kim M. Chang H. Yang H. C. Kim Y. J. Lee C.-T. Lee J.-H. et al . (2014). Preoperative thrombocytosis is a significant unfavorable prognostic factor for patients with resectable non-small cell lung cancer. World J. Surg. Oncol.12:37. 10.1186/1477-7819-12-37
87
Kitagawa H. Yamamoto N. Yamamoto K. Tanoue K. Kosaki G. Yamazaki Y. (1989). Involvement of platelet membrane glycoprotein Ib and glycoprotein IIb/IIIa complex in thrombin-dependent and -independent platelet aggregations induced by tumor cells. Cancer Res.49, 537–541.
88
Kohler S. Ullrich S. Ruchter U. Schumacher U. (2010). E-/P-selectins and colon carcinoma metastasis: first in vivo evidence for their crucial role in a clinically relevant model of spontaneous metastasis formation in the lung. Br. J. Cancer102, 602–609. 10.1038/sj.bjc.6605492
89
Kolarova H. Klinke A. Kremserova S. Adam M. Pekarova M. Baldus S. et al . (2013). Myeloperoxidase induces the priming of platelets. Free Radic. Biol. Med.61, 357–369. 10.1016/j.freeradbiomed.2013.04.014
90
Kong D. Wang Z. Sarkar S. H. Li Y. Banerjee S. Saliganan A. et al . (2008). Platelet-derived growth factor-d overexpression contributes to epithelial-mesenchymal transition of PC3 prostate cancer cells. Stem Cells26, 1245–1435. 10.1634/stemcells.2007-1076
91
Kopp H. G. Placke T. Salih H. R. (2009). Platelet-derived transforming growth factor-B down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Res.69, 7775–7783. 10.1158/0008-5472.CAN-09-2123
92
Kourelis T. V. Wysonkinska E. M. Wang Y. Yang P. Mansfield A. S. Tafur A. J. (2014). Early venous thromboembolic events are associated with worse prognosis in patients with lung cancer. Lung Cancer86, 358–362. 10.1016/j.lungcan.2014.10.003
93
Kral J. B. Schrottmaier W. C. Salzmann M. Assinger A. (2016). Platelet interaction with innate immune cells. Transfus. Med. Hemother.43, 78–88. 10.1159/000444807
94
LaBarge M. A. (2010). The difficulty of targeting cancer stem cell niches. Clin. Cancer Res.16, 3121–3129. 10.1158/1078-0432.CCR-09-2933
95
LaBarge M. A. Petersen O. W. Bissell M. J. (2007). Of microenvironments and mammary stem cells. Stem Cell Rev.3, 137–146. 10.1007/s12015-007-0024-4
96
Labelle M. Hynes R. O. (2012). The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discov.2, 1091–1099. 10.1158/2159-8290.CD-12-0329
97
Labelle M. Begum S. Hynes R. O. (2011). Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell20, 576–590. 10.1016/j.ccr.2011.09.009
98
Lal I. Dittus K. Holmes C. E. (2013). Platelets, coagulation and fibrinolysis in breast cancer progression. Breast Cancer Res.15:207. 10.1186/bcr3425
99
Landry P. Plante I. Ouellet D. L. Perron M. P. Rousseau G. Provost P. (2009). Existence of a microRNA pathway in anucleate platelets. Nat. Struct. Mol. Biol.16, 961–966. 10.1038/nsmb.1651
100
Larrick J. W. Wright S. C. (1990). Cytotoxic mechanism of tumor necrosis factor-alpha. FASEB J.4, 3215–3223.
101
Laubli H. Borsig L. (2010). Selectins promote tumor metastasis. Semin. Cancer Biol.20, 169–177. 10.1016/j.semcancer.2010.04.005
102
Leblanc R. Peyruchaud O. (2015). New insights into the autotaxin/LPA axis in cancer development and metastasis. Exp. Cell Res.333, 183–189. 10.1016/j.yexcr.2014.11.010
103
Leblanc R. Peyruchaud O. (2016). Metastasis: new functional implications of platelets and megakaryocytes. Blood128, 24–31. 10.1182/blood-2016-01-636399
104
Li N. (2016). Platelets in cancer metastasis: to help the “villian” to do evil. Int. J. Cancer138, 2078–2087. 10.1002/ijc.29847
105
Li Y. Kowdley K. V. (2012). MicroRNAs in common human diseases. Genomics Proteomics Bioinformatics10, 246–253. 10.1016/j.gpb.2012.07.005
106
Lindemann S. Tolley N. D. Dixon D. A. McIntyre T. M. Prescott S. M. Zimmerman G. A. et al . (2001). Activated platelets mediate inflammatory signaling by regulated interleukin 1b synthesis. J. Cell Biol.154, 485–490. 10.1083/jcb.200105058
107
Lonsdorf A. S. Kramer B. F. Fahrleitner M. Schonberger T. Gnerlich S. Ring S. et al . (2012). Engagement of αIIbβ3 (GPIIb/IIIa) with ανβ3 integrin mediates interaction of melanoma cells with platelets. J. Biol. Chem.287, 2168–2178. 10.1074/jbc.M111.269811
108
Lou X.-L. Sun J. Gong S.-Q. Yu X.-F. Gong R. Deng H. (2015). Interaction between circulating cancer cells and platelets: clinical implication. Chin. J. Cancer Res.27, 450–460. 10.3978/j.issn.1000-9604.2015.04.10
109
Ma L. Perini R. McKnight W. Dicay M. Klein A. Hollenberg M. D. et al . (2005). Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. Proc. Natl. Acad. Sci. U.S.A.102, 216–220. 10.1073/pnas.0406682102
110
Machlus K. R. Italiano J. E. Jr. (2013). The incredible journey: from megakaryocyte development to platelet formation. J. Cell Biol.201, 785–796. 10.1083/jcb.201304054
111
Mackman N. (2008). Triggers, targets and treatments for thrombosis. Nature451, 914–918. 10.1038/nature06797
112
Manly D. A. Wang J. Glover S. L. Kasthuri R. Liebman H. A. Key N. S. et al . (2010). Increased microparticle tissue factor activity in cancer patients with venous thromboembolism. Thromb. Res.125, 511–512. 10.1016/j.thromres.2009.09.019
113
Martinez M. C. Andriantsitohaina R. (2011). Microparticles in angiogenesis: therapeutic potential. Circ. Res.109, 110–119. 10.1161/CIRCRESAHA.110.233049
114
Mazzarello P. Calligaro A. L. Calligaro A. (2001). Giulio Bizzozero: a pioneer of cell biology. Nat. Rev. Mol. Cell Biol.2, 776–784. 10.1038/35096085
115
McManus D. D. Freedman J. E. (2015). MicroRNAs in platelet function and cardiovascular disease. Nat. Rev. Cardiol.12, 711–717. 10.1038/nrcardio.2015.101
116
Mege D. Mezouar S. Dignat-George F. Panicot-Dubois L. Dubois C. (2016). Microparticles and cancer thrombosis in animal models. Thromb. Res.140S1, S21–S26. 10.1016/S0049-3848(16)30094-9
117
Menter D. G. Tucker S. C. Kopetz S. Sood A. K. Crissman J. D. Honn K. V. (2014). Platelets and cancer: a casual or causal relationship: revisited. Cancer Metastasis Rev.33, 231–269. 10.1007/s10555-014-9498-0
118
Messager M. Neofytou K. Chaudry M. A. Allum W. H. (2015). Prognostic impact of preoperative platelets to lymphocytes ratio (PLR) on survival for oesophageal and junctional carcinoma treated with neoadjuvant chemotherapy: a retrospective monocentric study on 153 patients. Eur. J. Surg. Oncol.41, 1316–1323. 10.1016/j.ejso.2015.06.007
119
Miglani R. K. Bhateja N. Bhat R. S. Kumar K. V. A. (2013). Diagnostic role of platelet lymphocyte ratio (PLR) in pancreatic head masses. Indian J. Surg.75, 4–9. 10.1007/s12262-012-0443-6
120
Mills G. B. Moolenaar W. H. (2003). The emerging role of lysophosphatidic acid in cancer. Nat. Rev. Cancer3, 583–591. 10.1038/nrc1143
121
Miyashita T. Tajima H. Makino I. Nakagawara H. Kitagawa H. Fushida S. et al . (2015). Metastasis-promoting role of extravasated platelet activation in tumor. J. Surg. Res.193, 289–294. 10.1016/j.jss.2014.07.037
122
Moschini M. Suardi N. Pellucchi F. Rocchini L. La Croce G. Capitanio U. et al . (2014). Impact of preoperative thrombocytosis on pathological outcomes and survival in patients treated with radical cystectomy for bladder carcinoma. Anticancer Res.34, 3225–3230.
123
Nakahira M. Sugasawa M. Matsumura S. Kuba K. Ohba S. Hayashi T. et al . (2016). Prognostic role of the combination of platelet count and neutrophil–lymphocyte ratio in patients with hypopharyngeal squamous cell carcinoma. Eur. Arch. Otorhinolaryngol.273, 3863–3867. 10.1007/s00405-016-3996-3
124
Nieswandt B. Hafner M. Echtenacher B. Mannel D. N. (1999). Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res.59, 1295–1300.
125
Nilsson R. J. A. Balaj L. Hulleman E. van Rijn S. Pegtel D. M. Walraven M. et al . (2011). Blood platelets contain tumor-derived RNA biomarkers. Blood118, 3680–3683. 10.1182/blood-2011-03-344408
126
Nilsson R. J. A. Karachaliou N. Berenguer J. Gimenez-Capitan A. Schellen P. Teixido C. et al . (2015). Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer. Oncotarget7, 1066–1075. 10.18632/oncotarget.6279
127
Orellana R. Kato S. Erices R. Bravo M. L. Gonzalez P. Oliva B. et al . (2015). Platelets enhance tissue factor protein and metastasis initiating cell markers, and act as chemoattractants increasing the migration of ovarian cancer cells. BMC Cancer15:290. 10.1186/s12885-015-1304-z
128
Owens A. P. III Mackman N. (2011). Microparticles in hemostasis and thrombosis. Circ. Res.108, 1284–1297. 10.1161/CIRCRESAHA.110.233056
129
Palis J. Segel G. B. (2016). Hematology of the fetus and newborn, in Williams Hematology, eds KaushanskyK.LichtmanM. A.PrchalJ. T.LeviM. M.PressO. W.BurnsL. J.CaligiuriM. A. (New York, NY: McGraw-Hill), 99–117.
130
Pang J. H. Coupland L. A. Freeman C. Chong B. H. Parish C. R. (2015). Activation of tumour cell ECM degradation by thrombin-activated platelet membranes: potentially a P-selectin and GPIIb/IIIa-dependent process. Clin. Exp. Metastasis32, 495–505. 10.1007/s10585-015-9722-5
131
Perez-Callejo D. Romero A. Provencio M. Torrente M. (2016). Liquid biopsy based biomarkers in non-small cell lung cancer for diagnosis and treatment monitoring. Transl. Lung Cancer Res.5, 455–465. 10.21037/tlcr.2016.10.07
132
Philippe C. Philippe B. Fouqueray B. Perez J. Lebret M. Baud L. (1993). Protection from tumor necrosis factor-mediated cytolysis by platelets. Am. J. Pathol.143, 1713–1723.
133
Phillips K. G. Lee A. M. Tormoen G. W. Rigg R. A. Kolatkar A. Luttgen M. et al . (2015). The thrombotic potential of circulating tumor microemboli: computational modeling of circulating tumor cell-induced coagulation. Am. J. Physiol. Cell Physiol.308, C229–C236. 10.1152/ajpcell.00315.2014
134
Placke T. Kopp H. G. Salih H. R. (2011). Modulation of natural killer cell anti-tumor reactivity by platelets. J Innate Immun.3, 371–382. 10.1159/000323936
135
Placke T. Orgel M. Schaller M. Jung G. Rammensee H. G. Kopp H. G. et al . (2012). Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res.72, 440–448. 10.1158/0008-5472.CAN-11-1872
136
Plé H. Landry P. Benham A. Coarfa C. Gunaratne P. H. Provost P. (2012). The repertoire and features of human platelet microRNAs. PLoS ONE7:e50746. 10.1371/journal.pone.0050746
137
Polgar J. Clemetson J. M. Kehrel B. E. Wiedemann M. Magnenat E. M. Wells T. N. C. et al . (1997). Platelet activation and signal transduction by convulxin, a C-type lectin from crotalus durissus terrificus (Tropical Rattlesnake) venom via the p62/GPVI collagen receptor. J. Biol. Chem.272, 13576–13583. 10.1074/jbc.272.21.13576
138
Prokopi M. Pula G. Mayr U. Devue C. Gallagher J. Xiao Q. et al . (2009). Proteomic analysis reveals presence of platelet microparticles in endothelial progenitor cell cultures. Blood114, 723–732. 10.1182/blood-2009-02-205930
139
Qi C. Wei B. Zhou W. Yang Y. Li B. Guo S. et al . (2015). P-selectin-mediated platelet adhesion promotes tumor growth. Oncotarget6, 6584–6596. 10.18632/oncotarget.3164
140
Radisky D. C. LaBarge M. A. (2008). Epithelial-mesenchymal transition and the stem cell phenotype. Cell Stem Cell2, 511–512. 10.1016/j.stem.2008.05.007
141
Rowley J. W. Chappaz S. Corduan A. Chong M. M. W. Campbell R. Khoury A. et al . (2016). Dicer1-mediated miRNA processing shapes the mRNA profile and function of murine platelets. Blood127, 1743–1751. 10.1182/blood-2015-07-661371
142
Sabrkhany S. Griffioen A. W. Oude Egbrink M. G. A. (2011). The role of blood platelets in tumor angiogenesis. Biochim. Biophys. Acta1815, 189–196. 10.1016/j.bbcan.2010.12.001
143
Sanchez-Salcedo P. de-Torres J. P. Martinez-Urbistondo D. Gonzalez-Gutierrez J. Berto J. Campo A. et al . (2016). The neutrophil to lymphocyte and platelet to lymphocyte ratios as biomarkers for lung cancer development. Lung Cancer97, 28–34. 10.1016/j.lungcan.2016.04.010
144
Schumacher D. Strilic B. Sivaraj K. K. Wettschureck N. Offermanns S. (2013). Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 Receptor. Cancer Cell24, 130–137. 10.1016/j.ccr.2013.05.008
145
Schwertz H. Tolley N. D. Foulks J. M. Denis M. M. Risenmay B. W. Buerke M. et al . (2006). Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenecity of human platelets. J. Exp. Med.203, 2433–2440. 10.1084/jem.20061302
146
Seliger B. (2008). Molecular mechanisms of MHC class I abnormalities and APM components in human tumors. Cancer Immunol. Immunother.57, 1719–1726. 10.1007/s00262-008-0515-4
147
Seliger B. (2014). The link between MHC class I abnormalities of tumors, oncogenes, tumor suppressor genes, and transcription factors. J. Immunotoxicol.11, 308–310. 10.3109/1547691X.2013.875084
148
Semple J. W. Italiano J. E. Freedman J. (2011). Platelets and the immune continuum. Nat. Rev. Immunol.11, 264–274. 10.1038/nri2956
149
Shau H. Roth M. D. Golub S. H. (1993). Regulation of natural killer function by nonlymphoid cells. Nat. Immun.12, 235–249.
150
Shoji M. Hancock W. W. Abe K. Micko C. Casper K. A. Baine R. M. et al . (1998). Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer. Am. J. Pathol.152, 399–411.
151
Sierko E. Wojtukiewicz M. Z. (2004). Platelets and angiogenesis in malignancy. Semin. Thromb. Hemost.30, 95–108. 10.1055/s-2004-822974
152
Sola-Visner M. (2012). Platelets in the neonatal period: developmental differences in platelet production, function, and hemostasis and the potential impact of therapies. Am. Soc. Hematol. Educ. Prog.2012, 506–511. 10.1182/asheducation-2012.1.506
153
Sørensen A. L. Rumjantseva V. Nayeb-Hashemi S. Clausen H. Hartwig J. H. Wandall H. H. et al . (2009). Role of sialic acid for platelet life span: exposure of β-galactose results in the rapid clearance of platelets from the circulation by asialoglycoprotein receptor–expressing liver macrophages and hepatocytes. Blood114, 1645–1654. 10.1182/blood-2009-01-199414
154
Sorensen H. T. Mellemkjaer L. Olsen J. H. Baron J. A. (2000). Prognosis of cancers associated with venous thromboembolism. N. Engl. J. Med.343, 1846–1850. 10.1056/NEJM200012213432504
155
Stegner D. Dutting S. Nieswandt B. (2014). Mechanistic explanation for platelet contribution to cancer metastasis. Thromb. Res.133, S149–S157. 10.1016/S0049-3848(14)50025-4
156
Stone J. P. Wagner D. D. (1993). P-selectin mediates adhesion of platelets to neuroblastoma and small cell lung cancer. J. Clin. Invest.92, 804–813. 10.1172/JCI116654
157
Suzuki-Inoue K. Fuller G. L. Garcia A. Eble J. A. Pohlmann S. Inoue O. et al . (2006). A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood17, 542–549. 10.1182/blood-2005-05-1994
158
Talmadge J. E. Meyers K. M. Prieur D. J. Starkey J. R. (1980). Role of NK cells in tumor growth and metastasis in beige mice. Nature284, 622–624. 10.1038/284622a0
159
Thomas G. M. Panicot-Dubois L. Lacroix R. Dignat-George F. Lombardo D. Dubois C. (2009). Cancer cell-serived microparticles bearing P-selectin glycoprotein ligand 1 accelerate thrombus formation in vivo. J. Exp. Med.206, 1913–1927. 10.1084/jem.20082297
160
van den Berg Y. W. Osanto S. Reitsma P. H. Versteeg H. H. (2012). The relationship between tissue factor and cancer progression: insights from bench and bedside. Blood119, 924–932. 10.1182/blood-2011-06-317685
161
Varki A. (2007). Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood110, 1723–1729. 10.1182/blood-2006-10-053736
162
Varon D. Hayon Y. Dashevsky O. Shai E. (2012). Involvement of platelet derived microparticles in tumor metastasis and tissue regeneration. Thromb. Res.1300, S98–S99. 10.1016/j.thromres.2012.08.289
163
Verheul H. M. Hoekman K. Broxterman H. J. van der Valk P. Kakkar A. K. Pinedo H. M. (2000). Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas. Clin. Cancer Res.6, 166–171.
164
Verheul H. M. Hoekman K. Luykx-de Bakker S. Eekman C. A. Folman C. C. Broxterman H. J. et al . (1997). Platelet: transporter of vascular endothelial growth factor. Clin. Cancer Res.3, 2187–2190.
165
Versteeg H. H. (2015). Tissue factor: old and new links with cancer biology. Semin. Thromb. Hemost.41, 747–755. 10.1055/s-0035-1556048
166
Voutsadakis I. A. (2014). Thrombocytosis as a prognostic marker in gastrointestinal cancers. World J. Gastrointest. Oncol.6, 34–40. 10.4251/wjgo.v6.i2.34
167
Wang Y. Sun Y. Li D. Zhang L. Wang K. Zuo Y. et al . (2013). Platelet P2Y12 is involved in murine pulmonary metastasis. PLoS ONE8:e80780. 10.1371/journal.pone.0080780
168
Wang Y. Xu F. Pan J. Zhu Y. Shao X. Sha J. et al . (2016). Platelet to lymphocyte ratio as an independent prognostic indicator for prostate cancer patients receiving androgen deprivation therapy. BMC Cancer16:329. 10.1186/s12885-016-2363-5
169
Watt D. G. Proctor M. J. Park J. H. Horgan P. G. McMillan D. C. (2015). The neutrophil-platelet score (NPS) predicts survival in primary operable colorectal cancer and a variety of common cancers. PLoS ONE10:e0142159. 10.1371/journal.pone.0142159
170
Weyrich A. S. Dixon D. A. Pabla R. Elstad M. R. McIntyre T. M. Prescott S. M. et al . (1998). Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets. Proc. Natl. Acad. Sci. U.S.A.95, 5556–5561. 10.1073/pnas.95.10.5556
171
Wiltrout R. H. Herberman R. B. Zhang S. R. Chirigos M. A. Ortaldo J. R. Green K. M. Jr. et al . (1985). Role of organ-associated NK cells in decreased formation of experimental metastases in lung and liver. J. Immunol.134, 4267–4275.
172
Witz I. P. (2008). The selectin-selectin ligand axis in tumor progression. Cancer Metastasis Rev.27, 19–30. 10.1007/s10555-007-9101-z
173
Worth R. G. Chien C. D. Chien P. Reilly M. P. McKenzie S. E. Schreiber A. D. (2006). Platelet FcgammaRIIA binds and internalizes IgG-containing complexes. Exp. Hematol.34, 1490–1495. 10.1016/j.exphem.2006.06.015
174
Wright J. H. (1910). The histogenesis of the blood platelets. J. Morphol.21, 263–278. 10.1002/jmor.1050210204
175
Yeaman M. R. (2014). Platelets: at the nexus of antimicrobial defence. Nat. Rev. Microbiol.12, 426–437. 10.1038/nrmicro3269
176
Yu J. L. Rak J. W. (2004). Shedding of tissue factor (TF)-containing microparticles rather than alternatively spliced TF is the main source of TF activity released from human cancer cells. J. Thromb. Haemost.2, 2065–2067. 10.1111/j.1538-7836.2004.00972.x
177
Yu M. Bardia A. Wittner B. S. Stott S. L. Smas M. E. Ting D. T. et al . (2013). Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science3369, 580–584. 10.1126/science.1228522
178
Zhang H. Zhang L. Zhu K. Shi B. Yin Y. Zhu J. et al . (2015). Prognostic significance of combination of preoperative platelet count and neutrophillymphocyte ratio (COP-NLR) in patients with non-small cell lung cancer: based on a large cohort study. PLoS ONE10:e0126496. 10.1371/journal.pone.0126496
179
Zhang S. Zhang S. Hu L. Zhai L. Xue R. Ye J. et al . (2015). NOD2 receptor is expressed in platelets and enhances platelet activation and thrombosis. Circulation131, 1160–1170. 10.1161/CIRCULATIONAHA.114.013743
180
Zhang Y. Jiang C. Li J. Sun J. Qu X. (2015). Prognostic significance of preoperative neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in patients with gallbladder carcinoma. Clin. Transl. Oncol.17, 810–818. 10.1007/s12094-015-1310-2
181
Zhou X. Du Y. Huang Z. Xu J. Qiu T. Wang J. et al . (2014). Prognostic value of PLR in various cancers: a meta-analysis. PLoS ONE9:e101119. 10.1371/journal.pone.0101119
182
Zimmerman G. A. Weyrich A. S. (2008). Signal-dependent protein synthsis by activated platelets. Arterioscler. Thromb. Vasc. Biol.28, s17–s24. 10.1161/ATVBAHA.107.160218
183
Zucchella M. Dezza L. Pacchiarini L. Meloni F. Tacconi F. Bonomi E. et al . (1989). Human tumor cells cultured “in vitro” activate platelet function by producing ADP or thrombin. Haematologica74, 541–545.
Summary
Keywords
platelet, metastasis, thrombosis, cancer, TCIPA
Citation
Meikle CKS, Kelly CA, Garg P, Wuescher LM, Ali RA and Worth RG (2017) Cancer and Thrombosis: The Platelet Perspective. Front. Cell Dev. Biol. 4:147. doi: 10.3389/fcell.2016.00147
Received
03 November 2016
Accepted
12 December 2016
Published
05 January 2017
Volume
4 - 2016
Edited by
Hasan Korkaya, Augusta University, USA
Reviewed by
Frederique Gaits-Iacovoni, Institut National de la Santé et de la Recherche Médicale (INSERM), France; Leonard C. Edelstein, Thomas Jefferson University, USA
Updates
Copyright
© 2017 Meikle, Kelly, Garg, Wuescher, Ali and Worth.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Randall G. Worth randall.worth@utoledo.edu
This article was submitted to Molecular Medicine, a section of the journal Frontiers in Cell and Developmental Biology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.