Abstract
Platelets serve as “first responders” during normal wounding and homeostasis. Arising from bone marrow stem cell lineage megakaryocytes, anucleate platelets can influence inflammation and immune regulation. Biophysically, platelets are optimized due to size and discoid morphology to distribute near vessel walls, monitor vascular integrity, and initiate quick responses to vascular lesions. Adhesion receptors linked to a highly reactive filopodia-generating cytoskeleton maximizes their vascular surface contact allowing rapid response capabilities. Functionally, platelets normally initiate rapid clotting, vasoconstriction, inflammation, and wound biology that leads to sterilization, tissue repair, and resolution. Platelets also are among the first to sense, phagocytize, decorate, or react to pathogens in the circulation. These platelet first responder properties are commandeered during chronic inflammation, cancer progression, and metastasis. Leaky or inflammatory reaction blood vessel genesis during carcinogenesis provides opportunities for platelet invasion into tumors. Cancer is thought of as a non-healing or chronic wound that can be actively aided by platelet mitogenic properties to stimulate tumor growth. This growth ultimately outstrips circulatory support leads to angiogenesis and intravasation of tumor cells into the blood stream. Circulating tumor cells reengage additional platelets, which facilitates tumor cell adhesion, arrest and extravasation, and metastasis. This process, along with the hypercoagulable states associated with malignancy, is amplified by IL6 production in tumors that stimulate liver thrombopoietin production and elevates circulating platelet numbers by thrombopoiesis in the bone marrow. These complex interactions and the “first responder” role of platelets during diverse physiologic stresses provide a useful therapeutic target that deserves further exploration.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
1 Platelet “first responder” properties
“First responders” describe platelets as active participants in the hemostasis, wounding, immune, and metastatic processes (Fig. 1) [1, 2]. Platelets often remain unheeded during in vivo experimental studies or pathologic observations. The primary reason is due to small size/volume (mean platelet volumes range is 9.7–12.8 femtoliter or spheres 2 to 3 μm in diameter) and the lack of a nucleus makes identification more difficult compared to the typical nucleated cell. Although platelets are visible by high magnification light microscopy, ultrastructural analysis is typically done to effectively observe subcellular morphologic or activational structural changes and newer methods may prove even more observationally effective [3,4,5,6]. Individual and aggregates of activated platelets can be detected by immunohistochemistry at the microscopic level but this is not a routine approach for pathologists.
Platelet “first responders” facilitate wound response, threat recognition, immune function, cancer progression, and metastasis. Platelets elicit the initial response to any wound or breach in blood vessels. Platelets respond first by adhering to the perivascular extracellular matrix basement membrane and collagen. This causes resting platelets to change shape, aggregate, and release both alpha and dense granule components that attract and activate more platelets as well as immune cells. Anucleate platelets are key bone marrow stem cell-megakaryocyte derived subcellular product that are attracted to leaky angiogeneic vessels and can invade into perivascular spaces. The platelet aggregation process is held in check by prostacyclin (PGI2). Platelets can also slow down in the presence of shear stress of rapidly flowing blood by forming slip-catch bonds with von Willebrand factor (VWF) that causes rolling behavior at the endothelial cell surface. A local inflammatory response that follows involves complement (enzymatically processed to C3a and C5a), prostaglandin E2 (PGE2), interleukin-6 (IL-6), IL-1alpha (IL1α), and other inflammatory cytokines. Platelets can also interact with ultralarge VWF to form tethers. Another first responder behavior is the recognition of damage by toll-like receptors (TLRs), sialic acid-binding immunoglobulin-type lectins (Siglecs), damage-associated molecular patterns (DAMPs), infectious pathogens harboring pathogen-associated molecular patterns (PAMPs). Other platelet threat receptors include C-type lectin-like type II transmembrane receptor (CLEC-2), complement receptor type 2 (CR-2), C–C chemokine receptors (CCR 1,3 and 4), dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), and coxsackie adenovirus receptor (CAR) and integrins. Primary tumors secrete IL6, which induces thrombospondin release in the liver and initiates thrombocytosis in the bone marrow. Platelets also induce physical and molecular wounding damage signals. This can lead to further platelet activation and cyclic inflammatory release of tumor and platelet microparticles and exosomes that molecularly and biologically cross-educate one another along with additional pro-inflammatory and angiogenic factors. After full intravasation into the blood stream, direct contact with circulating tumor cells (CTCs) initiate tumor cell induced platelet aggregation (TCIPA) that causes further platelet activation and alpha (α) and dense granule release. Alpha granules contain numerous proteins, growth factors such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VGEF) that stimulate tumor growth and angiogenesis. Dense granule release includes platelet G-protein coupled receptor stimulants such as adenosine diphosphate (ADP) and serotonin (5-HT, 5-hydroxytryptamine). Platelet activation also leads to thromboxane A2 (TxA2) synthesis and release. Direct platelet-tumor cell contact glycoproteins such as P-selectin and tissue factor (TF) or via microparticles bearing procoagulants stimulate thrombin production and fibrin clot formation. The heterotypic platelet-tumor cell aggregates help protect them from vascular shear forces and may mask them from other immune cells along with providing a reservoir for growth factors. Following hematogenous spread additional platelets are engaged at secondary sites facilitating and stabilizing the adhesion and arrest of heterotypic emboli prior to extravasation. Released molecules also recruit granulocytes by bone marrow derived cell induction and immune cell differentiation. Transforming growth factor beta (TGF-β) from platelets and PGE2 release stimulate marrow derived stem cells (MDSC) and T-cell differentiation or inhibition, which includes cell cluster of differentiation 8 positive (CD8+) cytotoxic T-cells, T-helper1 (TH1), and T-helper17 (TH17) T-regulatory cells (Treg). Concurrently, bone marrow derived dendritic cells (BMDC) induction can occur in response to cytokines, C-X-C motif chemokine 5 (CXCL-5), and CXCL-7. Secreted TGF-β induces epithelial-mesenchymal-transition (EMT) genes and also facilitates myeloid polarization of macrophages and neutrophils toward immunosuppressive phenotypes. This may occur within the tumor or in the circulation at platelet facilitated arrest sites during the establishment of metastasis. Thus, these platelet-tumor cell microenvironmental niches may direct tumor-associated macrophages (TAMs) toward a protumor (M2) from an antitumor (M1) phenotype. Similarly, tumor-associated neutrophils (TANs) TANs may acquire a protumor phenotype (similar to M2), largely driven by TGF-β to become “N2” neutrophils
Biophysically, resting platelets exhibit a plate-like discoid shape that maximizes planar surface interactions [7,8,9]. These physical characteristics facilitate their segregation toward the outer fluid shear fields of flowing blood [10,11,12,13,14,15,16,17]. Normal human platelets range between 150,000–400,000 per microliter (μl) in numbers with those that concentrate near vessel walls being 2–3 times greater than at the central fluid stream. Platelet flow patterns, near wall excess, and proximity enhance encounters and recognition of any vascular wall lesions or wounds. These platelet recognition properties include the exposure of the subendothelial basement membrane or underlying matrix induced by wounding or endothelial retraction [18,19,20,21,22,23]. The rapid formation of filopodia facilitated by a variety of adhesion receptors linked to a highly reactive cytoskeleton helps maximize dynamic surface contacts and the rapid response rate of platelets [24,25,26,27,28,29,30,31].
2 Platelet “first response” facilitated clot/wound biology
Normally, platelets serve as “first responders” during the wounding process and hemostasis. A lacerated blood vessel exposes platelets to subendothelial elements that initiate their first response through receptor-based recognition of extracellular matrix. This recognition triggers platelet activation and aggregation. Once activated, within a matter of seconds, platelets begin to change shape, degranulate, and release proteins, growth factors, bioactive lipids, and other factors that recruit additional platelets and immune cells along with initiating thrombogenesis and clotting to fill any exposed gaps.
This process occurs in response to an injury that exposes collagen and extracellular matrix proteins, which results in interactions with the exposed subendothelium. These first responder interactions are driven by a variety of platelet glycoprotein receptors that can fail in many congenital platelet disorders [2, 32]. These receptors can bind extracellular matrix factors that include proteoglycans, laminin, fibronectin, and vitronectin along with various isoforms of collagen. von Willebrand factor (VWF) binds to exposed collagen I, III, and VI fibers. VWF is also recruited into matrix networks by forming tethering fiber strands [33,34,35,36,37].
Platelet surface GPIb forms multimeric complexes that initiate catch bond interactions with exposed tethering fiber strands [33,34,35,36,37]. Catch-slip-tethering bonds cause platelets to begin rolling within blood fluid shear stress fields [33,34,35,36,37]. Four transmembrane proteins contribute to functional GPIb complexes including two 20-kDa GPIX subunits, two 26-kDa GPIbβ subunits, two 135-kDa GPIbα subunits, and one central 82-kDa GPV subunit [38, 39]. GPIb receptors belong to the LRR receptor family of proteins that are uniquely expressed by platelets [38, 39]. Genetic loss of GPIb expression leads to Bernard-Soulier syndrome bleeding disorders [40]. GPIb-IX-V glycosphingolipid domain multimeric complexes interact with VWF multimers [41]. Tethering can also occur with ultralarge von Willebrand factor (ULVWF) and endothelial cells to attract platelets to these protein strands along with other cells such as leukocytes and potentially tumor cells [42,43,44]
Platelets contextually encounter numerous circulating ligands, cells, pathogens, and extracellular matrix ligands in the bloodstream. Immediate responses are mediated by a variety of integrin receptors through transmembrane glycoprotein α and β heterodimers once ligands are engaged. Resting platelets express low-affinity conformation integrins that are bent over protecting binding sites. Once activated, α and β subunits protrude forming high affinity or open binding state that efficiently interact with ligands. Rolling platelet behavior is initiated by multimeric GPIb-complex interactions with VWF, which activates a key stabilization integrin αIIbβ3 [45,46,47,48] shifting them from a closed to an open state. In the open state, transmembrane αIIbβ3 heterodimers that are very promiscuous and bind multiple RGD-ligand containing proteins [45,46,47,48]. These RGD-ligand containing proteins include: fibrin, fibrinogen, fibronectin, vitronectin, thrombospondin or VWF complexes. Abnormal αIIbβ3 integrin receptor expression is involved in Glanzmann’s thrombasthenia [49,50,51].
More selective ligand binding integrins also stabilize interactions with the vascular microenvironment. For example, the collagen receptor α2β1 is a key matrix-stabilizing integrin [52, 53]. Once activated, α2β1 stabilizes adhesive contacts and initiates lamellipodia formation and platelet spreading. In contrast, circulating or extracellular matrix fibronectin is engaged by platelet α5β1 integrin heterodimers [54]. The α5β1 integrin binding is activation state dependent, binding more selectively to fibronectin RGD peptide sites under static conditions. Tyrosine phosphorylation and changes in calcium levels can also facilitate filopodia formation [55]. Platelets also express α6β1 integrin receptors that selectively bind to laminin in the basement membrane and induce filopodia formation [56, 57]. The activation of α6β1 integrin receptors typically involves crosstalk with platelet collagen receptor glycoprotein VI (GPVI) to achieve stable adhesion.
Additional receptors are involved in biologic responses of platelets such as GPVI, which belongs to the Ig receptor superfamily and is found exclusively in platelets [58, 59]. GPVI is a major collagen receptor that recognizes the quaternary structure of collagen, and activates platelets [60, 61]. Platelet GPVI monomers shift from low affinity and signal transduction potential to multimers that gain high affinity collagen periodic structure [41, 62,63,64,65].
Platelet C-type LECtin-like receptor (CLEC-2/aggrus) is another platelet receptor that initiates platelet activation through molecular multimerization [41, 62, 66,67,68]. CLEC-2 binds to mucin glycoprotein podoplanin [69,70,71]. Podoplanin is expressed on cells of the lymphatic endothelia, type I lung epithelia, choroid plexus epithelia, kidney podocytes, lymph node stroma along with cancer cells and potentiates migration and invasion [69,70,71,72]. Podoplanin is a transmembrane sialomucin glycoprotein [41, 69, 73, 74], which interacts with platelet CLEC-2 receptors triggering signal transduction [41, 67, 68, 75].
Platelet P-selectin is also known as membrane glycoprotein GMP-140 [76, 77]. P-selectin binds to P-selectin glycoprotein ligand (PSGL)-1 [78], neutrophil leukocyte-endothelial cell adhesion molecule 1 (LECAM-1) [79], endothelial cell-leukocyte adhesion molecule 1 (ELAM-1) [80], and sialyl Lewis(x) oligosaccharide [81]. P-selectin interaction with a variety of immune cells and endothelial cells is important in mediating inflammation, autoimmunity, and wound healing [82,83,84]. P-selectins along with L- and E-selectins help tethering and rolling of cells flowing past the vascular luminal surfaces during the initial phases of intravascular adhesive interactions that are stabilized by other receptors [85,86,87,88,89,90,91].
Thrombus formation relies on platelet “first responder” mediated rolling, adherence, spreading, migration, aggregation, and stabilization. Nitric oxide, prostacyclin (PGI2), and CD39-mediated reduction of local purine nucleotides help maintain the resting state of circulating platelets [92,93,94,95,96]. Injury-induced exposure of subendothelial matrix occurs transient tethering bonds are made between matrix-bound VWF and platelet GPIb-IX-V receptor complexes [33,34,35,36,37, 39]. Transient tethers support rolling and slow platelet movement. Slower movement permits more intimate interactions between collagen fibers and platelet GPVI surface receptors shift integrins from a closed to an open state [58, 59]. Activated α2β1 binding with collagen and αIIbβ3 binding to fibrinogen stimulate platelet shape change and degranulation [45,46,47,48]. Release of α-granules and dense granules amplifies secondary platelet responses and initiates tissue repair. Activation forms platelets prothrombotic nucleation centers for tissue factor initiated coagulation [97]. Platelets interact with nearby platelets through αIIbβ3 receptors and bind fibrinogen and fibrin fibers [45,46,47,48]. Progressive cycles of platelet activation, adherence, spreading, migration, aggregation, and stabilization form a thrombus that builds a fibrin network and entraps other blood cells. Thrombotic plug formation is stabilized and counterbalanced by the disaggregation of platelets and fibrinolysis. Platelets migrate and initiate tissue repair [98,99,100,101,102].
First responder reactions are rapidly enhanced by activating molecules such as thrombin or ADP that are triggered at the cell surface or as a result of the release reaction. Activation results in release of granular contents or molecular export, which include proteins and molecules such as thromboxane A2 (TXA2) that amplify the local platelet response to recruit additional platelets to the forming clot and accelerate the thrombogenesis/clotting process [103, 104]. The production of TXA2 along with other lipids initiates vasoconstriction [105, 106]. As a primary stimulant of platelet recruitment and aggregation, TXA2 is among the shorter-lived prostaglandins due to molecular epoxide bond strain in the active part of the molecule that is prone to hydrolysis in <30 s [107, 108]. These rapid changes accelerate over a matter of minutes and generate a fibrin network that traps and activates more platelets within the forming clot in a cyclic fashion and limits blood loss. This first responder amplification process occurs over approximately a 20-minute time frame or less and clot maturation and solidification continues for an hour or so and initiates immune cell recruitment and inflammation over the next few days to weeks. Recruitment of fibroblasts and immune cells through platelet-initiated angiogenic repair mechanisms stimulates wound healing and resolution [99]. Proliferation, tissue remodeling, and wound repair that resolves normally over a month to a year timeline.
The release of platelet dense granule components influences the vascular microenvironment. The release of calcium and magnesium ions promotes platelet activation and aggregation. The release of nucleotides such as ADP activates platelets through P2Y1 and P2Y12 receptors [109, 110] and stimulates vasoconstriction [111]. The dense granule release or engagement of membrane tetraspanins, CD9, CD63, CD151, Tspan9, and Tspan32, regulates cell surface interactions [112, 113]. CD9 is the most abundant platelet tetraspanin and engages Fc RIIA, a low-affinity receptor for IgG or GPVI collagen receptors during platelet interactions [112,113,114]. Platelet dense granule membranes also contain lysosomal associated membrane proteins (LAMPs), which aid in the breakdown cellular debris [115, 116]. The release of neurotransmitters serotonin (5-hydroxytryptamine; 5-HT), epinephrine, and histamine can potentiate ADP-induced platelet activation and aggregation [109, 110, 117].
3 “Threat response and damage control”
Also, as part of their first responder characteristics, platelets actively transmigrate across any leaky or inflamed vessel wall in response to a variety of stimuli to aid in wound sterilization and tissue regeneration [118,119,120,121,122,123,124]. Stromal cell-derived factor-1 (SDF1 or C-X-C chemokine ligand 12:CXCL12) acts as a very potent stimulus that triggers platelet migration into extravascular spaces [125,126,127,128,129,130]. In addition to CXCL12, platelets release many transmigration stimulating chemokines and cytokines, CXCL1 (GRO-α), CXCL4 (platelet factor 4, PF4), CXCL5 (epithelial-derived neutrophil-activating peptide-78; ENA-78), CXCL7 (pro-platelet basic protein, PPBP; β-thromboglobulin, βTG), and CXCL8 (interleukin-8; IL8) among numerous others from storage granules. Once released from platelets, these factors can initiate the migration and invasion of additional platelets, immune cells (neutrophils macrophages and leukocytes), as well as bone marrow progenitor and endothelial progenitor cells or tumor cells [131,132,133,134]. The notion of “first responders” is further strengthened by the discovery of C-X-C chemokine receptor 4 and 7 (CXCR-4, CXCR7) the cognate receptors for SDF1: CXCL12 on platelets.
As part of their immune surveillance properties, platelets can recognize foreign bodies or invading pathogens [1, 135,136,137]. Additional inflammation and pathogen defense mediating receptors on platelets and pathogen signals, include toll-like receptors (TLRs), sialic acid-binding immunoglobulin-type lectins (Siglecs), damage-associated molecular patterns (DAMPs, e.g., alarmins), infectious pathogens harboring pathogen-associated molecular patterns (PAMPs), platelet C-type lectin-like type II transmembrane receptor (CLEC-2), complement receptor type 2 (CR-2), C–C chemokine receptors (CCR 1,3 and 4), dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), and coxsackie adenovirus receptor (CAR) [121, 138,139,140,141,142,143,144,145,146,147,148,149]. Self-associated molecular patterns (SAMPs) that can be mimicked by pathogens have also been proposed but their disposition and influence on platelets remains to be fully determined [150].
Platelets exhibit optimal tissue migration properties. Utilizing these immediate-threat sensing receptors to rapidly initiate migration during potential first responses, platelets are ideally suited for movement because of the highly active cytoskeletal responses linked to activation, adhesion, and aggregation [1, 18, 36, 151,152,153]. Platelets are more streamlined and suited for vascular transmigration, not only because they are small in size and minimal displacement volume coupled with their highly active cytoskeleton [154,155,156]. An even greater vascular transmigration advantage may arise from being unencumbered by the presence of nuclei, which limits the migration of other immune cells [127, 154,155,156,157]. The absence of nuclei may also limit the distance that platelets can move into tissue. Due to limited protein synthesis capabilities, they cannot indefinitely maintain the replacement of proteins [158, 159]. All of these immune surveillance and rapid response properties facilitate speedy sterilization along with the ability to quickly initiate the repair process during the wound response.
4 Platelet mediated thrombogenesis, inflammatory, and resolution responses
Platelets release membrane fragments with bioactive molecules in the form of platelet microparticles (PMPs) on activation, permitting distant effects [160,161,162,163,164]. Platelet cytoskeletal rearrangement results in budding of PMPs, which exposes phosphatidylserine (PS), membrane antigens (Ag), and cytoplasm components. The exposure PS-Ag-Cyto complexes on the outer leaflet of PMP creates surface for assembly of a factor V and factor Xa catalytic complexes that generate thrombin. Thrombin-mediated cleavage of fibrinogen leads to fibrin clot formation and entrapment of additional platelets at wound sites [165,166,167,168]. Fibrinolysis then ensues to control clot growth [165, 166]. PMPs also interact with immune cells via adhesion molecules such as selectins that selectively bind carbohydrate molecules associated with immune function [121, 142, 144, 169]. Aggregates can have additional immune functions such as neutrophil-ensnared traps (NETs), which are collections of DNA and anti-microbial biomolecules [145, 170].
Platelets help initiate or coordinate the immune responses as key subcomponents of systemic biology [121, 144,145,146,147, 169]. They initiate inflammation by releasing a heterogeneous mix of protein molecules that include, transforming growth factor beta (TGF-β), P-selectin, CD40L, and RANTES [121, 171,172,173]. These molecules include an assortment of cytokines and adhesion molecules that directly bind or activate or elicit homing responses for monocytes, neutrophils, and even T-lymphocytes as chemoattractants to the endothelium; inhibit apoptotic signals; and promotes extravasation into affected sites [121, 142, 144, 169]. Platelets can also activate the complement system of which C3a and C5a are potent anaphylatoxins that amplify inflammatory responses.
The first responder role to threats is thought to be the reason why platelets evolved to have both hemostatic and immune properties [2, 163, 174,175,176]. This is best highlighted in the wound response model whereby platelets have a unique role in recognizing tissue damage and stimulating more specialized immune cells to infiltrate and initiate the sterilization of the area, particularly where a pathogen may have been introduced past physical barriers. In studies of skin injury, these phases have been described crudely into hemostasis, inflammation, proliferation, and resolution. Platelets with a primary role in hemostasis are uniquely poised to initiate inflammation synergistically with resident cells within damaged tissues such as macrophages. Other non-immune resident cells that platelets stimulate include fibroblasts. These evolve into myofibroblasts as they enter the granulomatous tissue that leads to resolution and retraction [177,178,179]. Platelet release of TGF-β coordinates with extracellular matrix (ECM) tension help drive fibroblasts to transition into a myofibroblast phenotype that help with repair [180, 181]. TGF-β systemic release also enhances mesenchymal stem cells (MSCs) differentiation and functions as a mechano-stimulatory factor to improve wound closure [182]. Platelet TGF-β also helps neutrophils infiltrate into wounds that are replaced by macrophages. These immune cells initially to acquire a pro-inflammatory phenotype during wound inflammation and proliferation phases and then facilitate myeloid polarization of macrophages and neutrophils toward immunosuppressive phenotypes during tissue repair and resolution phases [183,184,185,186]. Platelets are thereby intrinsically linked to the immune and wound repair system.
5 Platelet “first response” facilitated cancer progression
Cancer is generally considered as a chronic or non-healing wound [187,188,189] that can continuously engage platelets any time exposure to tumor components occurs. As a part of the metastatic process, platelet receptors recognize complexes of tumor cell receptors surface bound matrix proteins or cellular products as they invade blood vessels due to platelet-tumor cell first response interactions [2, 130, 190]. Extensive membrane changes occur at bilayer interfaces between platelets and tumor cells [1, 2, 191, 192]. Tumor cells form extensive membrane/cytoskeletal processes that heavily interdigitate with a central platelet aggregate and involves the uptake of platelet fragments and mitochondria [1, 2, 191, 192]. These interactions are thought to result in the suppression of immune recognition/cytotoxicity or the promotion of cell arrest at the endothelium, or entrapment in the microvasculature. These responses all support survival and spread of cancer cells and the establishment of secondary lesions. Additional mechanisms of the platelet-metastasis relationship may include the production of platelet exosomes or extravascular migratory behavior of platelets helping to drive cancer progression or preconditioning of secondary metastatic sites [1, 2, 191, 192]. In contrast to the many mechanisms involved in platelet-metastasis relationships, little is known about the role of platelets in precancerous lesion development. This paucity of knowledge exists despite numerous large randomized clinical trials illustrating the cancer preventive effects of non-steroidal anti-inflammatory drugs (NSAIDs), particularly aspirin in reducing the cancer incidence, mortality, and metastasis [193,194,195]. Additional aspirin studies also reduced cancer incidence and all-cause mortality [196,197,198,199]. In the case of prior colorectal cancer [200] or colorectal adenomas [201], those taking aspirin showed fewer new adenomas compared to controls. In The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP) trial, aspirin reduced adenomas in Lynch syndrome patients [202]. In the ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED) trial, the effects of aspirin will also be examined using various biomarker endpoints [203]. The ASPIRED study will determine how aspirin influences adenoma biology.
Aspirin covalently acetylates and inactivates platelet cyclooxygenase 1 and thereby eliminates all downstream prostaglandin production from arachidonic acid (AA) by platelets [193]. This includes the key bioactive lipid involved in platelet activation, TxA2, which can be counterbalanced by PGI2 and its analogs that inhibit platelet activation [192, 204, 205]. Metabolically, the genesis of TxA2 and other bioactive lipids are also impacted by ω-3 polyunsaturated fatty acid substrate substitution for AA [193]. Although not well studied, this places platelets not only at the center of the metastasis discussion but also the progression of pre-malignancies. Since neoangiogenesis produces leaky blood vessels during early cancer progression, it stands to reason that platelets are the “first responders” to extravasate, activate, and release their stroma stimulating, proangiogenic, chemoattractive, and immunomodulatory contents [1, 2]. These normal platelet functions and products undoubtedly promote precancerous lesion progression as a series of cyclic amplification events. Platelets are suspected to have a key role within the full spectrum of the cancer progression continuum, which makes limiting their first response an important target for both prevention and therapy.
6 Platelets as “first responders” in cancer metastasis
“First responders” describes platelets as active participants in metastatic processes [1]. Platelets are thought to facilitate cancer and metastasis by various mechanisms [1, 192, 206, 207]. Due to these combined properties, during metastasis, circulating platelets can also elicit a first response to the exposure, sloughing or active invasion of tumor cells into the blood stream at primary tumor sites. Obstruction of blood flow and angiogenesis associated with primary tumor growth is likely to further enhance the probability of platelet/tumor cell encounters through membrane interactions [208,209,210]. The net result is likely to be platelet activation either to subdue cells at the primary site or generate tumor cell-platelet emboli in circulation [1, 19, 191]. Based on such significant numbers in circulation, small size, biophysical shear properties, adhesion, aggregation, and streamline migration properties, platelets are well suited to serve as “first responders” to a variety of pathologic stimuli, including metastasis.
7 Tumor cell migration, invasion, and intravasation
The proliferation and migration of cancer cells within primary tumors drives a number of events that can impact metastasis [211,212,213,214,215]. Direct impact can occur by shedding, sloughing, or active entry of tumor cells into the blood vessels. Based on single cell profiling of circulating tumor cells (CTCs), there is a large diversity of cells found in the circulation that reflect tumor heterogeneity [216, 217]. Within the diversity spectrum, CTCs also frequently exhibit stem cell properties [218]. A variety of triggers can initiate entry of CTCs into the circulation. For example, decreased availability of blood vessels can increase the induction of hypoxia as tumors outgrow their blood supply and release of angiogenesis or wounding related factors [219,220,221]. These factors stimulate the formation of new blood vessels that are typically abnormal and leaky, enabling entry of tumor cells into the blood stream [222,223,224]. Although not extensively studied, there is also potential for leakage or migration of platelets into the tumor that may further enhance the angiogenesis/leaky blood vessel genesis cycle [125, 225,226,227]. More aggressive tumor cells that enter the circulation often undergo epithelial-mesenchymal transition EMT [228]. In fact, direct signaling between platelets and cancer cells induces an EMT and promotes metastasis in vitro and in vivo [229,230,231]. Cells with EMT characteristics are more fibroblastic in morphology and are typically much more motile and invasive as a result [229, 230]. These EMT cells are prone to actively invade blood vessels by using matrix metalloproteinase (MMP) to digest the extracellular matrix and basement membrane of blood vessels [232, 233]. As a part of the invasion process interactions between platelets and tumor cells increase the production of MMP-9 [230]. This tumor cell invasive process is termed intravasation and is considered an early dissemination step of the hematogenous metastatic cascade [234].
8 Hematogenous spread, extravasation, and secondary site metastasis
Billroth in 1878 was the first to identify cancer-cell-containing thrombi with the spread of tumors [235]. Wood first observed real-time arrest and formation of platelet thrombi along with tumor cell migration into the perivascular spaces [207, 236]. Baserga and Safi-Otti observed the intravascular arrest and proliferation of anaplastic carcinoma (T1SO) cells prior to extravasation. Both studies identified thrombus formation and tumor cell arrest in small arterioles [207, 236, 237]. When tumor growth occurred intravasculary, it resulted in the destruction of the vessel then tumor cell extravasation. Jones et al. observed the formation of tumor cell-platelet emboli and fibrin using electron microscopy and immunofluorescence after tail vein injection in rats [238]. Early stage emboli formation revealed neutrophils and lymphocytes followed by fibrin formation even after the disappearance of platelets [239] confirmed by others [240]. The release of platelet vesicles and adhesion to vessel walls was observed in vitro [241] along with tumor cell migration through the endothelial layer from the adherent embolus [242]. Rat AH-130 ascites hepatoma cells also revealed tumor cell-platelet emboli in microvessels of the lung [243]. Gastpar also performed intravital capillary microscopy in the mesentery of rats to test sulfinpyrazone inhibition of lethal pulmonary tumor cell emboli [244].
Advancements in time-lapse, deep-tissue imaging using intravital microscopy have demonstrated the importance of tumor cell migration in vivo [245]. Invasion through the genesis of invadopodia illustrate a dependence on prostaglandin signaling [246]. Intravital fluorescence microscopy has also revealed dynamic platelet-melanoma cell interactions in mice [247]. Platelet depletion significantly reduced melanoma cell adhesion to the injured vascular wall in vivo [247]. Platelet interactions and metastasis of B16 melanoma cells to the lungs were decreased after treatment with mAb blocking the αIIbβ3 or αvβ3 integrin [247]. Platelets from the perivascular space can also migrate into extravascular tissues in support of tumor cell invasion and formation of metastases [1, 125,126,127,128,129, 230]. Nonetheless platelet migration may exhibit certain constraints, the lack of nuclei and protein synthesis may limit the distance that platelets migrate because they cannot indefinitely sustain the replacement of proteins [158, 159]. Thus, platelets may potentially prepare or enable extravasation at secondary metastatic sites [2, 67, 130, 248,249,250,251]. The use of intravital microscopy coupled with fluorescent platelets is expected to reveal even more details of this rapidly occurring process.
Enzymatic digestion of minced tumor fragments using collagenase, and trypsin inhibitors followed by counterflow centrifugal retained the representative receptor expression profile and other intrinsic properties that are closer to the native tumor state. Tail vein injections of these pure tumor cell preparations into syngeneic mice enabled accurate characterization of the resulting intravascular biology in vivo [191, 252]. In these experiments, platelet-aggregating activities of Lewis lung carcinoma, B16 amelanotic melanoma and 16C mammary adenocarcinoma resulted in tumor cell-platelet emboli formation in the lungs [191]. Platelets aggregated with tumor cells as early as 2 min followed by biphasic association with arrested tumor cells that peaked at 10–30 min and 4–24 h [191]. Ultrastructurally, tumor cells formed processes that extended into the platelet aggregate. At early time intervals (2–10 min), intravascular platelet degranulation in association with tumor cell processes. Tumor cells also engulfed platelet fragments in vivo [191]. Follow-up studies using the same models focused on tumor cell interactions with endothelial cells and the subendothelial matrix [19]. Mitoses were observed after 24 h with cell division and the development of intravascular tumor nodules. The final step in the extravasation sequence was dissolution of the basement membrane by the attached tumor cells [19]. In other mouse studies, platelet adhesive glycoprotein receptors and their counterparts expressed by tumor cells participated in tumor cell induced platelet aggregation (TCIPA) as an early step in the development of metastatic lesions [253].
9 Thrombocytosis
Cancer induces thrombocytosis resulting in elevated circulating platelets linked to Trousseau’s syndrome [254,255,256]. A multicenter study of epithelial ovarian cancer revealed mechanistic associations between platelet counts and disease outcome [130]. Thrombocytosis associated with tumor interleukin-6 (IL-6) and liver generated thrombopoietin has been associated with shortened survival in ovarian cancer patients [130]. Orthotopic ovarian mouse models revealed tumor-derived IL-6 stimulated hepatic thrombopoietin synthesis and paraneoplastic induction of thrombocytosis [130]. These studies showed a paracrine link between cancer and thrombocytosis. More CD63-positive platelet microparticles were also found in the circulation of ovarian cancer patients compared to those with benign tumors [257]. Procoagulant microparticles were found along with venous thromboemboli in cancer patients [258, 259]. The impact of IL6 on thrombocytosis has been observed elsewhere and in other cancers [260, 261].
10 Next response?
This overview illustrates the importance of platelet “first responder” characteristics to hemostasis wound repair, cancer immune function, and cancer biology. Thrombocytosis and thrombogenesis remain key areas of interest for biologic and prognostic characteristics of cancer. The critical nature of platelets to carcinogenesis as well as platelet-tumor cell heterotypic emboli to metastasis will continue to advance. Advancements in intravital microscopy coupled with fluorescent platelets are expected to facilitate elucidation of the rapid process of platelet-tumor cell invasion. The impact of platelets on tumor immunity is an exciting new field of interest with a bright rapidly responding future.
References
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 Reviews, 33(1), 231–269.
Menter, D., Davis, J., Tucker, S., Hawk, E., Crissman, J., Sood, A., et al. (2017). Platelets “First Responders” in cancer progression and metastasis. In P. Gresele, N. Kleiman, J. Lopez, & C. Page (Eds.), Platelets in thrombotic and non-thrombotic disorders (Vol. 2, pp. 1111–1132). Switzerland: Springer International Publishing.
Leunissen, T. C., Wisman, P. P., van Holten, T. C., de Groot, P. G., Korporaal, S. J., Koekman, A. C., et al. (2016). The effect of P2Y12 inhibition on platelet activation assessed with aggregation- and flow cytometry-based assays. Platelets, 1–9.
Liu, X., Li, Y., Zhu, H., Zhao, Z., Zhou, Y., Zaske, A. M., et al. (2015). Use of non-contact hopping probe ion conductance microscopy to investigate dynamic morphology of live platelets. Platelets, 26(5), 480–485.
Lof, A., Muller, J. P., Benoit, M., & Brehm, M. A. (2017). Biophysical approaches promote advances in the understanding of von Willebrand factor processing and function. Advances in Biological Regulation, 63, 81–91.
Heijnen, H., & Korporaal, S. (2017). Platelet morphology and ultrastructure. In P. Gresele, N. Kleiman, J. Lopez, & C. Page (Eds.), Platelets in thrombotic and non-thrombotic disorders (Vol. 2, pp. 21–37). Switzerland: Springer International Publishing.
O'Brien, S., Kent, N. J., Lucitt, M., Ricco, A. J., McAtamney, C., Kenny, D., et al. (2012). Effective hydrodynamic shaping of sample streams in a microfluidic parallel-plate flow-assay device: matching whole blood dynamic viscosity. IEEE Transactions on Biomedical Engineering, 59(2), 374–382.
Jen, C. J., & Tai, Y. W. (1992). Morphological study of platelet adhesion dynamics under whole blood flow conditions. Platelets, 3(3), 145–153.
Folie, B. J., & McIntire, L. V. (1989). Mathematical analysis of mural thrombogenesis. Concentration profiles of platelet-activating agents and effects of viscous shear flow. Biophysical Journal, 56(6), 1121–1141.
Fedosov, D. A., Noguchi, H., & Gompper, G. (2014). Multiscale modeling of blood flow: from single cells to blood rheology. Biomechanics and Modeling in Mechanobiology, 13(2), 239–258.
Kumar, A., & Graham, M. D. (2012). Mechanism of margination in confined flows of blood and other multicomponent suspensions. Physical Review Letters, 109(10), 108102.
Tokarev, A. A., Butylin, A. A., & Ataullakhanov, F. I. (2011). Platelet adhesion from shear blood flow is controlled by near-wall rebounding collisions with erythrocytes. Biophysical Journal, 100(4), 799–808.
Tokarev, A. A., Butylin, A. A., Ermakova, E. A., Shnol, E. E., Panasenko, G. P., & Ataullakhanov, F. I. (2011). Finite platelet size could be responsible for platelet margination effect. Biophysical Journal, 101(8), 1835–1843.
Lee, S. Y., Ferrari, M., & Decuzzi, P. (2009). Design of bio-mimetic particles with enhanced vascular interaction. Journal of Biomechanics, 42(12), 1885–1890.
Stukelj, R., Schara, K., Bedina-Zavec, A., Sustar, V., Pajnic, M., Paden, L., et al. (2017). Effect of shear stress in the flow through the sampling needle on concentration of nanovesicles isolated from blood. European Journal of Pharmaceutical Sciences, 98, 17–29.
De Gruttola, S., Boomsma, K., & Poulikakos, D. (2005). Computational simulation of a non-newtonian model of the blood separation process. Artificial Organs, 29(12), 949–959.
Nesbitt, W. S., Westein, E., Tovar-Lopez, F. J., Tolouei, E., Mitchell, A., Fu, J., et al. (2009). A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nature Medicine, 15(6), 665–673.
Menter, D. G., Steinert, B. W., Sloane, B. F., Gundlach, N., O'Gara, C. Y., Marnett, L. J., et al. (1987). Role of platelet membrane in enhancement of tumor cell adhesion to endothelial cell extracellular matrix. Cancer Research, 47(24 Pt 1), 6751–6762.
Crissman, J. D., Hatfield, J. S., Menter, D. G., Sloane, B., & Honn, K. V. (1988). Morphological study of the interaction of intravascular tumor cells with endothelial cells and subendothelial matrix. Cancer Research, 48(14), 4065–4072.
Walsh, T. G., Metharom, P., & Berndt, M. C. (2015). The functional role of platelets in the regulation of angiogenesis. Platelets, 26(3), 199–211.
Kim, K. H., Barazia, A., & Cho, J. (2013). Real-time imaging of heterotypic platelet-neutrophil interactions on the activated endothelium during vascular inflammation and thrombus formation in live mice. Journal of Visualized Experiments, 74.
Spectre, G., Zhu, L., Ersoy, M., Hjemdahl, P., Savion, N., Varon, D., et al. (2012). Platelets selectively enhance lymphocyte adhesion on subendothelial matrix under arterial flow conditions. Thrombosis and Haemostasis, 108(2), 328–337.
Gardiner, E., & Andrews, R. (2017). Platelet adhesion. In P. Gresele, N. Kleiman, J. Lopez, & C. Page (Eds.), Platelets in thrombotic and non-thrombotic disorders (Vol. 2, pp. 309–319). Switzerland: Springer International Publishing.
Pothapragada, S., Zhang, P., Sheriff, J., Livelli, M., Slepian, M. J., Deng, Y., et al. (2015). A phenomenological particle-based platelet model for simulating filopodia formation during early activation. International Journal of Numerical Methods in Biomedical Engineering, 31(3), e02702.
Kunert, S., Meyer, I., Fleischhauer, S., Wannack, M., Fiedler, J., Shivdasani, R. A., et al. (2009). The microtubule modulator RanBP10 plays a critical role in regulation of platelet discoid shape and degranulation. Blood, 114(27), 5532–5540.
Jackson, S. P., Nesbitt, W. S., & Westein, E. (2009). Dynamics of platelet thrombus formation. Journal of Thrombosis and Haemostasis, 7(Suppl 1), 17–20.
Italiano Jr., J. E., Bergmeier, W., Tiwari, S., Falet, H., Hartwig, J. H., Hoffmeister, K. M., et al. (2003). Mechanisms and implications of platelet discoid shape. Blood, 101(12), 4789–4796.
Hartwig, J. H., Barkalow, K., Azim, A., & Italiano, J. (1999). The elegant platelet: signals controlling actin assembly. Thrombosis and Haemostasis, 82(2), 392–398.
White, J. G., & Rao, G. H. (1998). Microtubule coils versus the surface membrane cytoskeleton in maintenance and restoration of platelet discoid shape. The American Journal of Pathology, 152(2), 597–609.
Polanowska-Grabowska, R., Geanacopoulos, M., & Gear, A. R. (1993). Platelet adhesion to collagen via the alpha 2 beta 1 integrin under arterial flow conditions causes rapid tyrosine phosphorylation of pp125FAK. Biochemical Journal, 296(Pt 3), 543–547.
Falet, H. (2017). Anatomy of the platelet cytoskeleton. In P. Gresele, N. Kleiman, J. Lopez, & C. Page (Eds.), Platelets in thrombotic and non-thrombotic disorders (Vol. 2, pp. 139–156). Switzerland: Springer International Publishing.
Nurden, A. T., & Nurden, P. (2014). Congenital platelet disorders and understanding of platelet function. British Journal of Haematology, 165(2), 165–178.
Coburn, L. A., Damaraju, V. S., Dozic, S., Eskin, S. G., Cruz, M. A., & McIntire, L. V. (2011). GPIbalpha-vWF rolling under shear stress shows differences between type 2B and 2M von Willebrand disease. Biophysical Journal, 100(2), 304–312.
Colace, T. V., & Diamond, S. L. (2013). Direct observation of von Willebrand factor elongation and fiber formation on collagen during acute whole blood exposure to pathological flow. Arteriosclerosis, Thrombosis, and Vascular Biology, 33(1), 105–113.
Fredrickson, B. J., Dong, J. F., McIntire, L. V., & Lopez, J. A. (1998). Shear-dependent rolling on von Willebrand factor of mammalian cells expressing the platelet glycoprotein Ib-IX-V complex. Blood, 92(10), 3684–3693.
Jackson, S. P., Mistry, N., & Yuan, Y. (2000). Platelets and the injured vessel wall—“rolling into action”: focus on glycoprotein Ib/V/IX and the platelet cytoskeleton. Trends in Cardiovascular Medicine, 10(5), 192–197.
Yago, T., Lou, J., Wu, T., Yang, J., Miner, J. J., Coburn, L., et al. (2008). Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF. The Journal of Clinical Investigation, 118(9), 3195–3207.
Clemetson, K. J. (2007). A short history of platelet glycoprotein Ib complex. Thrombosis and Haemostasis, 98(1), 63–68.
Li, R., & Emsley, J. (2013). The organizing principle of the platelet glycoprotein Ib-IX-V complex. Journal of Thrombosis and Haemostasis, 11(4), 605–614.
Bernard, J., & Soulier, J. (1948). Sur une nouvelle variété de dystrophie thrombocytaire-hémorragipare congénitale. Semin Hôp Paris, 24, 3217–3223.
Ozaki, Y., Suzuki-Inoue, K., & Inoue, O. (2013). Platelet receptors activated via mulitmerization: glycoprotein VI, GPIb-IX-V, and CLEC-2. Journal of Thrombosis and Haemostasis, 11(Suppl 1), 330–339.
Bernardo, A., Ball, C., Nolasco, L., Choi, H., Moake, J. L., & Dong, J. F. (2005). Platelets adhered to endothelial cell-bound ultra-large von Willebrand factor strings support leukocyte tethering and rolling under high shear stress. Journal of Thrombosis and Haemostasis, 3(3), 562–570.
De Ceunynck, K., De Meyer, S. F., & Vanhoorelbeke, K. (2013). Unwinding the von Willebrand factor strings puzzle. Blood, 121(2), 270–277.
Desch, A., Strozyk, E. A., Bauer, A. T., Huck, V., Niemeyer, V., Wieland, T., et al. (2012). Highly invasive melanoma cells activate the vascular endothelium via an MMP-2/integrin alphavbeta5-induced secretion of VEGF-A. The American Journal of Pathology, 181(2), 693–705.
Coller, B. S., & Shattil, S. J. (2008). The GPIIb/IIIa (integrin alphaIIbbeta3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend. Blood, 112(8), 3011–3025.
Kim, C., & Kim, M. C. (2013). Differences in alpha-beta transmembrane domain interactions among integrins enable diverging integrin signaling. Biochemical and Biophysical Research Communications, 436(3), 406–412.
Kim, C., Lau, T. L., Ulmer, T. S., & Ginsberg, M. H. (2009). Interactions of platelet integrin alphaIIb and beta3 transmembrane domains in mammalian cell membranes and their role in integrin activation. Blood, 113(19), 4747–4753.
Shattil, S. J. (2009). The beta3 integrin cytoplasmic tail: protein scaffold and control freak. Journal of Thrombosis and Haemostasis, 7(Suppl 1), 210–213.
Nurden, A. T., & Caen, J. P. (1974). An abnormal platelet glycoprotein pattern in three cases of Glanzmann's thrombasthenia. British Journal of Haematology, 28(2), 253–260.
Phillips, D. R., Jenkins, C. S., Luscher, E. F., & Larrieu, M. (1975). Molecular differences of exposed surface proteins on thrombasthenic platelet plasma membranes. Nature, 257(5527), 599–600.
Glanzmann, E. (1918). Hereditare hammorhagische thrombastehnie. Beitr Pathologie Bluplatchen J Kinderkt, 88, 113–141.
Zhang, C., Zhang, L., Zhang, Y., Sun, N., Jiang, S., Fujihara, T. J., et al. (2016). Development of antithrombotic nanoconjugate blocking integrin alpha2beta1-collagen interactions. Scientific Reports, 6, 26292.
Szanto, T., Joutsi-Korhonen, L., Deckmyn, H., & Lassila, R. (2012). New insights into von Willebrand disease and platelet function. Seminars in Thrombosis and Hemostasis, 38(1), 55–63.
Maurer, E., Schaff, M., Receveur, N., Bourdon, C., Mercier, L., Nieswandt, B., et al. (2015). Fibrillar cellular fibronectin supports efficient platelet aggregation and procoagulant activity. Thrombosis and Haemostasis, 114(6), 1175–1188.
McCarty, O. J., Zhao, Y., Andrew, N., Machesky, L. M., Staunton, D., Frampton, J., et al. (2004). Evaluation of the role of platelet integrins in fibronectin-dependent spreading and adhesion. Journal of Thrombosis and Haemostasis, 2(10), 1823–1833.
Schaff, M., Tang, C., Maurer, E., Bourdon, C., Receveur, N., Eckly, A., et al. (2013). Integrin alpha6beta1 is the main receptor for vascular laminins and plays a role in platelet adhesion, activation, and arterial thrombosis. Circulation, 128(5), 541–552.
Inoue, O., Suzuki-Inoue, K., McCarty, O. J., Moroi, M., Ruggeri, Z. M., Kunicki, T. J., et al. (2006). Laminin stimulates spreading of platelets through integrin alpha6beta1-dependent activation of GPVI. Blood, 107(4), 1405–1412.
Clemetson, K. J. (1995). Platelet activation: signal transduction via membrane receptors. Thrombosis and Haemostasis, 74(1), 111–116.
Moroi, M., Jung, S. M., Okuma, M., & Shinmyozu, K. (1989). A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion. The Journal of Clinical Investigation, 84(5), 1440–1445.
Asselin, J., Knight, C. G., Farndale, R. W., Barnes, M. J., & Watson, S. P. (1999). Monomeric (glycine-proline-hydroxyproline)10 repeat sequence is a partial agonist of the platelet collagen receptor glycoprotein VI. Biochemical Journal, 339(Pt 2), 413–418.
Kehrel, B., Wierwille, S., Clemetson, K. J., Anders, O., Steiner, M., Knight, C. G., et al. (1998). Glycoprotein VI is a major collagen receptor for platelet activation: it recognizes the platelet-activating quaternary structure of collagen, whereas CD36, glycoprotein IIb/IIIa, and von Willebrand factor do not. Blood, 91(2), 491–499.
Zahid, M., Mangin, P., Loyau, S., Hechler, B., Billiald, P., Gachet, C., et al. (2012). The future of glycoprotein VI as an antithrombotic target. Journal of Thrombosis and Haemostasis, 10(12), 2418–2427.
Li, P., Qiao, J. L., & Xu, K. L. (2017). Advances of studies on platelet GPVI as antithrombotic target—review. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 25(1), 264–269.
Poulter, N. S., Pollitt, A. Y., Owen, D. M., Gardiner, E. E., Andrews, R. K., Shimizu, H., et al. (2017). Clustering of glycoprotein VI (GPVI) dimers upon adhesion to collagen as a mechanism to regulate GPVI signaling in platelets. Journal of Thrombosis and Haemostasis, 15(3), 549–564.
Pierre, S., Linke, B., Suo, J., Tarighi, N., Del Turco, D., Thomas, D., et al. (2017). GPVI and thromboxane receptor on platelets promote proinflammatory macrophage phenotypes during cutaneous inflammation. The Journal of Investigative Dermatology, 137(3), 686–695.
Bergmeier, W., & Stefanini, L. (2013). Platelet ITAM signaling. Current Opinion in Hematology, 20(5), 445–450.
Takemoto, A., Okitaka, M., Takagi, S., Takami, M., Sato, S., Nishio, M., et al. (2017). A critical role of platelet TGF-beta release in podoplanin-mediated tumour invasion and metastasis. Scientific Reports, 7, 42186.
Nakazawa, Y., Sato, S., Naito, M., Kato, Y., Mishima, K., Arai, H., et al. (2008). Tetraspanin family member CD9 inhibits aggrus/podoplanin-induced platelet aggregation and suppresses pulmonary metastasis. Blood, 112(5), 1730–1739.
Navarro-Nunez, L., Langan, S. A., Nash, G. B., & Watson, S. P. (2013). The physiological and pathophysiological roles of platelet CLEC-2. Thrombosis and Haemostasis, 109(6), 991–998.
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. Blood, 107(2), 542–549.
Suzuki-Inoue, K., Kato, Y., Inoue, O., Kaneko, M. K., Mishima, K., Yatomi, Y., et al. (2007). Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. The Journal of Biological Chemistry, 282(36), 25993–26001.
Pula, B., Witkiewicz, W., Dziegiel, P., & Podhorska-Okolow, M. (2013). Significance of podoplanin expression in cancer-associated fibroblasts: a comprehensive review. International Journal of Oncology, 42(6), 1849–1857.
Watson, A. A., Brown, J., Harlos, K., Eble, J. A., Walter, T. S., & O'Callaghan, C. A. (2007). The crystal structure and mutational binding analysis of the extracellular domain of the platelet-activating receptor CLEC-2. The Journal of Biological Chemistry, 282(5), 3165–3172.
Watson, A. A., & O'Callaghan, C. A. (2005). Crystallization and X-ray diffraction analysis of human CLEC-2. Acta Crystallographica. Section F, Structural Biology and Crystallization Communications, 61(Pt 12), 1094–1096.
Suzuki-Inoue, K., Inoue, O., & Ozaki, Y. (2011). Novel platelet activation receptor CLEC-2: from discovery to prospects. Journal of Thrombosis and Haemostasis, 9(Suppl 1), 44–55.
Johnston, G. I., Cook, R. G., & McEver, R. P. (1989). Cloning of GMP-140, a granule membrane protein of platelets and endothelium: sequence similarity to proteins involved in cell adhesion and inflammation. Cell, 56(6), 1033–1044.
Stenberg, P. E., McEver, R. P., Shuman, M. A., Jacques, Y. V., & Bainton, D. F. (1985). A platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation. The Journal of Cell Biology, 101(3), 880–886.
Zarbock, A., Muller, H., Kuwano, Y., & Ley, K. (2009). PSGL-1-dependent myeloid leukocyte activation. Journal of Leukocyte Biology, 86(5), 1119–1124.
Picker, L. J., Warnock, R. A., Burns, A. R., Doerschuk, C. M., Berg, E. L., & Butcher, E. C. (1991). The neutrophil selectin LECAM-1 presents carbohydrate ligands to the vascular selectins ELAM-1 and GMP-140. Cell, 66(5), 921–933.
Polley, M. J., Phillips, M. L., Wayner, E., Nudelman, E., Singhal, A. K., Hakomori, S., et al. (1991). CD62 and endothelial cell-leukocyte adhesion molecule 1 (ELAM-1) recognize the same carbohydrate ligand, sialyl-Lewis x. Proceedings of the National Academy of Sciences of the United States of America, 88(14), 6224–6228.
Foxall, C., Watson, S. R., Dowbenko, D., Fennie, C., Lasky, L. A., Kiso, M., et al. (1992). The three members of the selectin receptor family recognize a common carbohydrate epitope, the sialyl Lewis(x) oligosaccharide. The Journal of Cell Biology, 117(4), 895–902.
Habets, K. L., Huizinga, T. W., & Toes, R. E. (2013). Platelets and autoimmunity. European Journal of Clinical Investigation, 43(7), 746–757.
Kazmi, R. S., Cooper, A. J., & Lwaleed, B. A. (2011). Platelet function in pre-eclampsia. Seminars in Thrombosis and Hemostasis, 37(2), 131–136.
Nurden, A. T. (2011). Platelets, inflammation and tissue regeneration. Thrombosis and Haemostasis, 105(Suppl 1), S13–S33.
Borsig, L. (2008). The role of platelet activation in tumor metastasis. Expert Review of Anticancer Therapy, 8(8), 1247–1255.
Dammacco, F., Vacca, A., Procaccio, P., Ria, R., Marech, I., & Racanelli, V. (2013). Cancer-related coagulopathy (Trousseau's syndrome): review of the literature and experience of a single center of internal medicine. Clinical and Experimental Medicine, 13(2), 85–97.
Erpenbeck, L., & Schon, M. P. (2010). Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood, 115(17), 3427–3436.
Gay, L. J., & Felding-Habermann, B. (2011). Contribution of platelets to tumour metastasis. Nature Reviews. Cancer, 11(2), 123–134.
Gay, L. J., & Felding-Habermann, B. (2011). Platelets alter tumor cell attributes to propel metastasis: programming in transit. Cancer Cell, 20(5), 553–554.
Kyriazi, V., & Theodoulou, E. (2013). Assessing the risk and prognosis of thrombotic complications in cancer patients. Archives of Pathology & Laboratory Medicine, 137(9), 1286–1295.
McEver, R. P. (1997). Selectin-carbohydrate interactions during inflammation and metastasis. Glycoconjugate Journal, 14(5), 585–591.
Dangel, O., Mergia, E., Karlisch, K., Groneberg, D., Koesling, D., & Friebe, A. (2010). Nitric oxide-sensitive guanylyl cyclase is the only nitric oxide receptor mediating platelet inhibition. Journal of Thrombosis and Haemostasis, 8(6), 1343–1352.
Koziak, K., Sevigny, J., Robson, S. C., Siegel, J. B., & Kaczmarek, E. (1999). Analysis of CD39/ATP diphosphohydrolase (ATPDase) expression in endothelial cells, platelets and leukocytes. Thrombosis and Haemostasis, 82(5), 1538–1544.
Moncada, S., Gryglewski, R., Bunting, S., & Vane, J. R. (1976). An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature, 263(5579), 663–665.
Sabetkar, M., Naseem, K. M., Tullett, J. M., Friebe, A., Koesling, D., & Bruckdorfer, K. R. (2001). Synergism between nitric oxide and hydrogen peroxide in the inhibition of platelet function: the roles of soluble guanylyl cyclase and vasodilator-stimulated phosphoprotein. Nitric Oxide, 5(3), 233–242.
Zimmermann, H. (1999). Nucleotides and cd39: principal modulatory players in hemostasis and thrombosis. Nature Medicine, 5(9), 987–988.
Aleman, M. M., Gardiner, C., Harrison, P., & Wolberg, A. S. (2011). Differential contributions of monocyte- and platelet-derived microparticles towards thrombin generation and fibrin formation and stability. Journal of Thrombosis and Haemostasis, 9(11), 2251–2261.
Feng, D., Nagy, J. A., Pyne, K., Dvorak, H. F., & Dvorak, A. M. (1998). Platelets exit venules by a transcellular pathway at sites of F-met peptide-induced acute inflammation in guinea pigs. International Archives of Allergy and Immunology, 116(3), 188–195.
Gawaz, M., & Vogel, S. (2013). Platelets in tissue repair: control of apoptosis and interactions with regenerative cells. Blood, 122(15), 2550–2554.
Lowenhaupt, R. W., Glueck, H. I., Miller, M. A., & Kline, D. L. (1977). Factors which influence blood platelet migration. The Journal of Laboratory and Clinical Medicine, 90(1), 37–45.
Nathan, P. (1973). The migration of human platelets in vitro. Thrombosis et Diathesis Haemorrhagica, 30(1), 173–177.
Schmidt, E. M., Munzer, P., Borst, O., Kraemer, B. F., Schmid, E., Urban, B., et al. (2011). Ion channels in the regulation of platelet migration. Biochemical and Biophysical Research Communications, 415(1), 54–60.
Banerjee, D., Mazumder, S., & Kumar Sinha, A. (2016). Involvement of nitric oxide on calcium mobilization and arachidonic acid pathway activation during platelet aggregation with different aggregating agonists. International Journal of Biomedical Sciences, 12(1), 25–35.
Philipose, S., Konya, V., Lazarevic, M., Pasterk, L. M., Marsche, G., Frank, S., et al. (2012). Laropiprant attenuates EP3 and TP prostanoid receptor-mediated thrombus formation. PloS One, 7(8), e40222.
Feletou, M., Huang, Y., & Vanhoutte, P. M. (2010). Vasoconstrictor prostanoids. Pflügers Archiv, 459(6), 941–950.
Kandhi, S., Zhang, B., Froogh, G., Qin, J., Alruwali, N., Le, Y., et al. (2017). EETs promote hypoxic pulmonary vasoconstriction via constrictor prostanoids. American Journal of Physiology. Lung Cellular and Molecular Physiology ajplung 00038 02017.
Bhagwat, S. S., Hamann, P. R., Still, W. C., Bunting, S., & Fitzpatrick, F. A. (1985). Synthesis and structure of the platelet aggregation factor thromboxane A2. Nature, 315(6019), 511–513.
Hamberg, M., Svensson, J., & Samuelsson, B. (1975). Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proceedings of the National Academy of Sciences of the United States of America, 72(8), 2994–2998.
Fukami, M. H., & Salganicoff, L. (1977). Human platelet storage organelles. A review. Thrombosis and Haemostasis, 38(4), 963–970.
Koseoglu, S., & Flaumenhaft, R. (2013). Advances in platelet granule biology. Current Opinion in Hematology, 20(5), 464–471.
Wihlborg, A. K., Wang, L., Braun, O. O., Eyjolfsson, A., Gustafsson, R., Gudbjartsson, T., et al. (2004). ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(10), 1810–1815.
Goschnick, M. W., & Jackson, D. E. (2007). Tetraspanins-structural and signalling scaffolds that regulate platelet function. Mini Reviews in Medicinal Chemistry, 7(12), 1248–1254.
Haining, E. J., Yang, J., & Tomlinson, M. G. (2011). Tetraspanin microdomains: fine-tuning platelet function. Biochemical Society Transactions, 39(2), 518–523.
Protty, M. B., Watkins, N. A., Colombo, D., Thomas, S. G., Heath, V. L., Herbert, J. M., et al. (2009). Identification of Tspan9 as a novel platelet tetraspanin and the collagen receptor GPVI as a component of tetraspanin microdomains. Biochemical Journal, 417(1), 391–400.
Israels, S. J., McMillan, E. M., Robertson, C., Singhory, S., & McNicol, A. (1996). The lysosomal granule membrane protein, LAMP-2, is also present in platelet dense granule membranes. Thrombosis and Haemostasis, 75(4), 623–629.
Xu, L., Harada, H., & Taniguchi, A. (2008). The effects of LAMP1 and LAMP3 on M180 amelogenin uptake, localization and amelogenin mRNA induction by amelogenin protein. Journal of Biochemistry, 144(4), 531–537.
Vanags, D. M., Rodgers, S. E., Duncan, E. M., Lloyd, J. V., & Bochner, F. (1992). Potentiation of ADP-induced aggregation in human platelet-rich plasma by 5-hydroxytryptamine and adrenaline. British Journal of Pharmacology, 106(4), 917–923.
Petito, E., Momi, S., & Gresele, P. (2017). The migration of platelets and their interaction with other migrating cells. In P. Gresele, N. Kleiman, J. Lopez, & C. Page (Eds.), Platelets in thrombotic and non-thrombotic disorders (Vol. 2, pp. 337–351). Switzerland: Springer International Publishing.
Sandri, G., Bonferoni, M. C., Rossi, S., Ferrari, F., Mori, M., Cervio, M., et al. (2015). Platelet lysate embedded scaffolds for skin regeneration. Expert Opinion on Drug Delivery, 12(4), 525–545.
Kurokawa, T., & Ohkohchi, N. (2017). Platelets in liver disease, cancer and regeneration. World Journal of Gastroenterology, 23(18), 3228–3239.
Mancuso, M. E., & Santagostino, E. (2017). Platelets: much more than bricks in a breached wall. British Journal of Haematology, 4, 1–10.
Anitua, E., Troya, M., Zalduendo, M., & Orive, G. (2017). Personalized plasma-based medicine to treat age-related diseases. Materials Science & Engineering. C, Materials for Biological Applications, 74, 459–464.
Meschi, N., Castro, A. B., Vandamme, K., Quirynen, M., & Lambrechts, P. (2016). The impact of autologous platelet concentrates on endodontic healing: a systematic review. Platelets, 27(7), 613–633.
Mlynarek, R. A., Kuhn, A. W., & Bedi, A. (2016). Platelet-rich plasma (PRP) in orthopedic sports medicine. American Journal of Orthopedics (Belle Mead, N.J.), 45(5), 290–326.
Goubran, H. A., Stakiw, J., Radosevic, M., & Burnouf, T. (2014). Platelets effects on tumor growth. Seminars in Oncology, 41(3), 359–369.
Unwith, S., Zhao, H., Hennah, L., & Ma, D. (2015). The potential role of HIF on tumour progression and dissemination. International Journal of Cancer, 136(11), 2491–2503.
Schmidt, E. M., Kraemer, B. F., Borst, O., Munzer, P., Schonberger, T., Schmidt, C., et al. (2012). SGK1 sensitivity of platelet migration. Cellular Physiology and Biochemistry, 30(1), 259–268.
Kraemer, B. F., Borst, O., Gehring, E. M., Schoenberger, T., Urban, B., Ninci, E., et al. (2010). PI3 kinase-dependent stimulation of platelet migration by stromal cell-derived factor 1 (SDF-1). Journal of Molecular Medicine (Berlin), 88(12), 1277–1288.
Brandt, E., Ludwig, A., Petersen, F., & Flad, H. D. (2000). Platelet-derived CXC chemokines: old players in new games. Immunological Reviews, 177, 204–216.
Stone, R. L., Nick, A. M., McNeish, I. A., Balkwill, F., Han, H. D., Bottsford-Miller, J., et al. (2012). Paraneoplastic thrombocytosis in ovarian cancer. The New England Journal of Medicine, 366(7), 610–618.
Kraemer, B. F., Schmidt, C., Urban, B., Bigalke, B., Schwanitz, L., Koch, M., et al. (2011). High shear flow induces migration of adherent human platelets. Platelets, 22(6), 415–421.
Chatterjee, M., Huang, Z., Zhang, W., Jiang, L., Hultenby, K., Zhu, L., et al. (2011). Distinct platelet packaging, release, and surface expression of proangiogenic and antiangiogenic factors on different platelet stimuli. Blood, 117(14), 3907–3911.
Shenkman, B., Brill, A., Brill, G., Lider, O., Savion, N., & Varon, D. (2004). Differential response of platelets to chemokines: RANTES non-competitively inhibits stimulatory effect of SDF-1 alpha. Journal of Thrombosis and Haemostasis, 2(1), 154–160.
Gleissner, C. A., von Hundelshausen, P., & Ley, K. (2008). Platelet chemokines in vascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(11), 1920–1927.
Rossaint, J., & Zarbock, A. (2015). Platelets in leucocyte recruitment and function. Cardiovascular Research, 107(3):386–95.
Garraud, O., Berthet, J., Hamzeh-Cognasse, H., & Cognasse, F. (2011). Pathogen sensing, subsequent signalling, and signalosome in human platelets. Thrombosis Research, 127(4), 283–286.
von Hundelshausen, P., & Weber, C. (2007). Platelets as immune cells: bridging inflammation and cardiovascular disease. Circulation Research, 100(1), 27–40.
Rath, D., Chatterjee, M., Borst, O., Muller, K., Langer, H., Mack, A. F., et al. (2015). Platelet surface expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 is associated with clinical outcomes in patients with coronary artery disease. Journal of Thrombosis and Haemostasis, 13(5), 719–728.
Rafii, S., Cao, Z., Lis, R., Siempos, I. I., Chavez, D., Shido, K., et al. (2015). Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration. Nature Cell Biology, 17(2), 123–136.
Chatterjee, M., Seizer, P., Borst, O., Schonberger, T., Mack, A., Geisler, T., et al. (2014). SDF-1alpha induces differential trafficking of CXCR4-CXCR7 involving cyclophilin A, CXCR7 ubiquitination and promotes platelet survival. The FASEB Journal, 28(7), 2864–2878.
Rath, D., Chatterjee, M., Borst, O., Muller, K., Stellos, K., Mack, A. F., et al. (2014). Expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 on circulating platelets of patients with acute coronary syndrome and association with left ventricular functional recovery. European Heart Journal, 35(6), 386–394.
Iannacone, M. (2016). Platelet-mediated modulation of adaptive immunity. Seminars in Immunology, 28(6), 555–560.
Danese, S., & Fiocchi, C. (2016). Endothelial cell-immune cell interaction in IBD. Digestive Diseases, 34(1–2), 43–50.
Chatterjee, M., & Geisler, T. (2016). Inflammatory contribution of platelets revisited: new players in the arena of inflammation. Seminars in Thrombosis and Hemostasis, 42(3), 205–214.
Carestia, A., Kaufman, T., & Schattner, M. (2016). Platelets: new bricks in the building of neutrophil extracellular traps. Frontiers in Immunology, 7, 271.
Lam, F. W., Vijayan, K. V., & Rumbaut, R. E. (2015). Platelets and their interactions with other immune cells. Comprehensive Physiology, 5(3), 1265–1280.
Kapur, R., Zufferey, A., Boilard, E., & Semple, J. W. (2015). Nouvelle cuisine: platelets served with inflammation. Journal of Immunology, 194(12), 5579–5587.
Cognasse, F., Nguyen, K. A., Damien, P., McNicol, A., Pozzetto, B., Hamzeh-Cognasse, H., et al. (2015). The inflammatory role of platelets via their TLRs and Siglec receptors. Frontiers in Immunology, 6, 83.
Chatterjee, M., Rath, D., & Gawaz, M. (2015). Role of chemokine receptors CXCR4 and CXCR7 for platelet function. Biochemical Society Transactions, 43(4), 720–726.
Varki, A. (2011). Since there are PAMPs and DAMPs, there must be SAMPs? Glycan “self-associated molecular patterns” dampen innate immunity, but pathogens can mimic them. Glycobiology, 21(9), 1121–1124.
Menter, D. G., Steinert, B. W., Sloane, B. F., Taylor, J. D., & Honn, K. V. (1987). A new in vitro model for investigation of tumor cell-platelet-endothelial cell interactions and concomitant eicosanoid biosynthesis. Cancer Research, 47(9), 2425–2432.
Chopra, H., Timar, J., Rong, X., Grossi, I. M., Hatfield, J. S., Fligiel, S. E., et al. (1992). Is there a role for the tumor cell integrin alpha IIb beta 3 and cytoskeleton in tumor cell-platelet interaction? Clinical & Experimental Metastasis, 10(2), 125–137.
Bennett, J. S., Zigmond, S., Vilaire, G., Cunningham, M. E., & Bednar, B. (1999). The platelet cytoskeleton regulates the affinity of the integrin alpha(IIb)beta(3) for fibrinogen. The Journal of Biological Chemistry, 274(36), 25301–25307.
Breckenridge, M. T., Egelhoff, T. T., & Baskaran, H. (2010). A microfluidic imaging chamber for the direct observation of chemotactic transmigration. Biomedical Microdevices, 12(3), 543–553.
Ellingsen, T., Storgaard, M., Moller, B. K., Buus, A., Andersen, P. L., Obel, N., et al. (2000). Migration of mononuclear cells in the modified Boyden chamber as evaluated by DNA quantification and flow cytometry. Scandinavian Journal of Immunology, 52(3), 257–263.
Friedl, P., Wolf, K., & Lammerding, J. (2011). Nuclear mechanics during cell migration. Current Opinion in Cell Biology, 23(1), 55–64.
Bdeir, K., Gollomp, K., Stasiak, M., Mei, J., Papiewska-Pajak, I., Zhao, G., et al. (2017). Platelet-specific chemokines contribute to the pathogenesis of acute lung injury. American Journal of Respiratory Cell and Molecular Biology, 56(2), 261–270.
Bruce, I. J., & Kerry, R. (1987). The effect of chloramphenicol and cycloheximide on platelet aggregation and protein synthesis. Biochemical Pharmacology, 36(11), 1769–1773.
Borisova, T. A., & Markosian, R. A. (1977). Age and biosynthesis and breakdown of thrombocyte proteins. Biulleten' Eksperimental'noĭ Biologii i Meditsiny, 83(1), 20–21.
Pagel, O., Walter, E., Jurk, K., & Zahedi, R. P. (2017). Taking the stock of granule cargo: platelet releasate proteomics. Platelets, 28(2), 119–128.
Melki, I., Tessandier, N., Zufferey, A., & Boilard, E. (2017). Platelet microvesicles in health and disease. Platelets, 28(3), 214–221.
Wang, Z. T., Wang, Z., & Hu, Y. W. (2016). Possible roles of platelet-derived microparticles in atherosclerosis. Atherosclerosis, 248, 10–16.
Franco, A. T., Corken, A., & Ware, J. (2015). Platelets at the interface of thrombosis, inflammation, and cancer. Blood, 126(5), 582–588.
Cointe, S., Lacroix, R., & Dignat-George, F. (2017). Platelet-derived microparticles. In P. Gresele, N. Kleiman, J. Lopez, & C. Page (Eds.), Platelets in thrombotic and non-thrombotic disorders (Vol. 2, pp. 379–392). Switzerland: Springer International Publishing.
Zilberman-Rudenko, J., Sylman, J. L., Lakshmanan, H. H. S., McCarty, O. J. T., & Maddala, J. (2017). Dynamics of blood flow and thrombus formation in a multi-bypass microfluidic ladder network. Cellular and Molecular Bioengineering, 10(1), 16–29.
Whyte, C. S., Mitchell, J. L., & Mutch, N. J. (2017). Platelet-mediated modulation of fibrinolysis. Seminars in Thrombosis and Hemostasis, 43(2), 115–128.
Biolik, G., Kokot, M., Sznapka, M., Swieszek, A., Ziaja, D., Pawlicki, K., et al. (2017). Platelet reactivity in thromboelastometry. Revision of the FIBTEM test: a basic study. Scandinavian Journal of Clinical and Laboratory Investigation, 77(3), 216–222.
Mammadova-Bach, E., Ollivier, V., Loyau, S., Schaff, M., Dumont, B., Favier, R., et al. (2015). Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation. Blood, 126(5), 683–691.
Kral, J. B., Schrottmaier, W. C., Salzmann, M., & Assinger, A. (2016). Platelet interaction with innate immune cells. Transfusion Medicine and Hemotherapy, 43(2), 78–88.
Clark, S. R., Ma, A. C., Tavener, S. A., McDonald, B., Goodarzi, Z., Kelly, M. M., et al. (2007). Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nature Medicine, 13(4), 463–469.
Joshi, S., & Whiteheart, S. W. (2017). The nuts and bolts of the platelet release reaction. Platelets, 28(2), 129–137.
Suades, R., Padro, T., & Badimon, L. (2015). The role of blood-borne microparticles in inflammation and hemostasis. Seminars in Thrombosis and Hemostasis, 41(6), 590–606.
Gill, P., Jindal, N. L., Jagdis, A., & Vadas, P. (2015). Platelets in the immune response: revisiting platelet-activating factor in anaphylaxis. The Journal of Allergy and Clinical Immunology, 135(6), 1424–1432.
Momi, S., & Wiwanitkit, V. (2017). Phylogeny of blood platelets. In P. Gresele, N. Kleiman, J. Lopez, & C. Page (Eds.), Platelets in thrombotic and non-thrombotic disorders (Vol. 2, pp. 11–19). Switzerland: Springer International Publishing.
Roch, G. J., & Sherwood, N. M. (2014). Glycoprotein hormones and their receptors emerged at the origin of metazoans. Genome Biology and Evolution, 6(6), 1466–1479.
He, W., Tang, Y., Qi, B., Lu, C., Qin, C., Wei, Y., et al. (2014). Phylogenetic analysis and positive-selection site detecting of vascular endothelial growth factor family in vertebrates. Gene, 535(2), 345–352.
Mercer, P. F., & Chambers, R. C. (2013). Coagulation and coagulation signalling in fibrosis. Biochimica et Biophysica Acta, 1832(7), 1018–1027.
Yamaguchi, Y., & Yoshikawa, K. (2001). Cutaneous wound healing: an update. The Journal of Dermatology, 28(10), 521–534.
Gerarduzzi, C., & Di Battista, J. A. (2017). Myofibroblast repair mechanisms post-inflammatory response: a fibrotic perspective. Inflammation Research, 66(6), 451–465.
Greaves, N. S., Ashcroft, K. J., Baguneid, M., & Bayat, A. (2013). Current understanding of molecular and cellular mechanisms in fibroplasia and angiogenesis during acute wound healing. Journal of Dermatological Science, 72(3), 206–217.
Carthy, J. M. (2017). TGFbeta signaling and the control of myofibroblast differentiation: implications for chronic inflammatory disorders. Journal of Cellular Physiology. doi:10.1002/jcp.25879.
Ghosh, D., McGrail, D. J., & Dawson, M. R. (2017). TGF-beta1 pretreatment improves the function of mesenchymal stem cells in the wound bed. Frontiers in Cell and Development Biology, 5, 28.
Valcourt, U., Carthy, J., Okita, Y., Alcaraz, L., Kato, M., Thuault, S., et al. (2016). Analysis of epithelial-mesenchymal transition induced by transforming growth factor beta. Methods in Molecular Biology, 1344, 147–181.
Das, U. N. (2016). Inflammatory bowel disease as a disorder of an imbalance between pro- and anti-inflammatory molecules and deficiency of resolution bioactive lipids. Lipids in Health and Disease, 15, 11.
Gensel, J. C., & Zhang, B. (2015). Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Research, 1619, 1–11.
Shinde, A. V., & Frangogiannis, N. G. (2014). Fibroblasts in myocardial infarction: a role in inflammation and repair. Journal of Molecular and Cellular Cardiology, 70, 74–82.
Arwert, E. N., Hoste, E., & Watt, F. M. (2012). Epithelial stem cells, wound healing and cancer. Nature Reviews. Cancer, 12(3), 170–180.
Dovizio, M., Sacco, A., & Patrignani, P. (2017). Curbing tumorigenesis and malignant progression through the pharmacological control of the wound healing process. Vascular Pharmacology, 89, 1–11.
Dvorak, H. F. (2015). Tumors: wounds that do not heal-redux. Cancer Immunology Research, 3(1), 1–11.
Lichtenberger, L., Fang, D., Bick, R., Poindexter, B., Phan, T., Bergeron, A., et al. (2017). Unlocking aspirin's chemopreventive activity: role of irreversibly inhibiting platelet cyclooxygenase-1. Cancer Prevention Reseach, 10, 142–152.
Menter, D. G., Hatfield, J. S., Harkins, C., Sloane, B. F., Taylor, J. D., Crissman, J. D., et al. (1987). Tumor cell-platelet interactions in vitro and their relationship to in vivo arrest of hematogenously circulating tumor cells. Clinical & Experimental Metastasis, 5(1), 65–78.
Menter, D. G., Harkins, C., Onoda, J., Riorden, W., Sloane, B. F., Taylor, J. D., et al. (1987). Inhibition of tumor cell induced platelet aggregation by prostacyclin and carbacyclin: an ultrastructural study. Invasion & Metastasis, 7(2), 109–128.
Umar, A., Steele, V. E., Menter, D. G., & Hawk, E. T. (2016). Mechanisms of nonsteroidal anti-inflammatory drugs in cancer prevention. Seminars in Oncology, 43(1), 65–77.
Drew, D. A., Cao, Y., & Chan, A. T. (2016). Aspirin and colorectal cancer: the promise of precision chemoprevention. Nature Reviews. Cancer, 16(3), 173–186.
Holmes, C. E., Jasielec, J., Levis, J. E., Skelly, J., & Muss, H. B. (2013). Initiation of aspirin therapy modulates angiogenic protein levels in women with breast cancer receiving tamoxifen therapy. Clinical and Translational Science, 6(5), 386–390.
Bardia, A., Ebbert, J. O., Vierkant, R. A., Limburg, P. J., Anderson, K., Wang, A. H., et al. (2007). Association of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs with cancer incidence and mortality. Journal of the National Cancer Institute, 99(11), 881–889.
Bosetti, C., Rosato, V., Gallus, S., Cuzick, J., & La Vecchia, C. (2012). Aspirin and cancer risk: a quantitative review to 2011. Annals of Oncology, 23(6), 1403–1415.
Chan, A. T., Manson, J. E., Feskanich, D., Stampfer, M. J., Colditz, G. A., & Fuchs, C. S. (2007). Long-term aspirin use and mortality in women. Archives of Internal Medicine, 167(6), 562–572.
Ratnasinghe, L. D., Graubard, B. I., Kahle, L., Tangrea, J. A., Taylor, P. R., & Hawk, E. (2004). Aspirin use and mortality from cancer in a prospective cohort study. Anticancer Research, 24(5B), 3177–3184.
Sandler, R. S., Halabi, S., Baron, J. A., Budinger, S., Paskett, E., Keresztes, R., et al. (2003). A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. The New England Journal of Medicine, 348(10), 883–890.
Baron, J. A., Cole, B. F., Sandler, R. S., Haile, R. W., Ahnen, D., Bresalier, R., et al. (2003). A randomized trial of aspirin to prevent colorectal adenomas. The New England Journal of Medicine, 348(10), 891–899.
Burn, J., Gerdes, A. M., Macrae, F., Mecklin, J. P., Moeslein, G., Olschwang, S., et al. (2011). Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet, 378(9809), 2081–2087.
Drew, D. A., Chin, S. M., Gilpin, K. K., Parziale, M., Pond, E., Schuck, M. M., et al. (2017). ASPirin intervention for the REDuction of colorectal cancer risk (ASPIRED): a study protocol for a randomized controlled trial. Trials, 18(1), 50.
Honn, K. V., Cicone, B., & Skoff, A. (1981). Prostacyclin: a potent antimetastatic agent. Science, 212(4500), 1270–1272.
Honn, K. V., Menter, D., Cavanaugh, P. G., Neagos, G., Moilanen, D., Taylor, J. D., et al. (1983). A review of prostaglandins and the treatment of tumor metastasis. Acta Clinica Belgica, 38(1), 53–67.
Gasic, G. J., Gasic, T. B., & Stewart, C. C. (1968). Antimetastatic effects associated with platelet reduction. Proceedings of the National Academy of Sciences of the United States of America, 61(1), 46–52.
Woods, J. R. (1964). Experimental studies of the intravascular dissemination of Ascitic V2 carcinoma cells in the rabbit, with special reference to fibrinogen and fibrinolytic agents. Bulletin der Schweizerischen Akademie der Medizinischen Wissenschaften, 20, 92–121.
Horejsova, M., Pavlickova, V., Koukolik, F., & Strritesky, J. (1995). Morphologic verification of neoplastic portal vein obstruction. Casopís Lékar̆ů C̆eských, 134(20), 655–657.
Benazzi, C., Al-Dissi, A., Chau, C. H., Figg, W. D., Sarli, G., de Oliveira, J. T., et al. (2014). Angiogenesis in spontaneous tumors and implications for comparative tumor biology. ScientificWorldJournal, 2014, 919570.
Fein, M. R., & Egeblad, M. (2013). Caught in the act: revealing the metastatic process by live imaging. Disease Models & Mechanisms, 6(3), 580–593.
Starke, J., Wehrle-Haller, B., & Friedl, P. (2014). Plasticity of the actin cytoskeleton in response to extracellular matrix nanostructure and dimensionality. Biochemical Society Transactions, 42(5), 1356–1366.
Gritsenko, P. G., Ilina, O., & Friedl, P. (2012). Interstitial guidance of cancer invasion. The Journal of Pathology, 226(2), 185–199.
Friedl, P., Sahai, E., Weiss, S., & Yamada, K. M. (2012). New dimensions in cell migration. Nature Reviews. Molecular Cell Biology, 13(11), 743–747.
Friedl, P., Wolf, K., & Zegers, M. M. (2014). Rho-directed forces in collective migration. Nature Cell Biology, 16(3), 208–210.
Haeger, A., Krause, M., Wolf, K., & Friedl, P. (2014). Cell jamming: collective invasion of mesenchymal tumor cells imposed by tissue confinement. Biochimica et Biophysica Acta, 1840(8), 2386–2395.
Deng, G., Krishnakumar, S., Powell, A. A., Zhang, H., Mindrinos, M. N., Telli, M. L., et al. (2014). Single cell mutational analysis of PIK3CA in circulating tumor cells and metastases in breast cancer reveals heterogeneity, discordance, and mutation persistence in cultured disseminated tumor cells from bone marrow. BMC Cancer, 14, 456.
Powell, A. A., Talasaz, A. H., Zhang, H., Coram, M. A., Reddy, A., Deng, G., et al. (2012). Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PloS One, 7(5), e33788.
Tang, J., Gao, X., Zhi, M., Zhou, H. M., Zhang, M., Chen, H. W., et al. (2015). Plateletcrit: a sensitive biomarker for evaluating disease activity in Crohn's disease with low hs-CRP. Journal of Digestive Diseases, 16(3), 118–124.
Pasula, S., Cai, X., Dong, Y., Messa, M., McManus, J., Chang, B., et al. (2012). Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling. The Journal of Clinical Investigation, 122(12), 4424–4438.
Hellberg, C., Ostman, A., & Heldin, C. H. (2010). PDGF and vessel maturation. Recent Results in Cancer Research, 180, 103–114.
Carmeliet, P. (2005). VEGF as a key mediator of angiogenesis in cancer. Oncology, 69(Suppl 3), 4–10.
Keskin, D., Kim, J., Cooke, V. G., Wu, C. C., Sugimoto, H., Gu, C., et al. (2015). Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Reports, 10(7), 1066–1081.
Nagy, J. A., Dvorak, A. M., & Dvorak, H. F. (2012). Vascular hyperpermeability, angiogenesis, and stroma generation. Cold Spring Harbor Perspectives in Medicine, 2(2), a006544.
Fukumura, D., & Jain, R. K. (2008). Imaging angiogenesis and the microenvironment. APMIS, 116(7–8), 695–715.
Kisucka, J., Butterfield, C. E., Duda, D. G., Eichenberger, S. C., Saffaripour, S., Ware, J., et al. (2006). Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage. Proceedings of the National Academy of Sciences of the United States of America, 103(4), 855–860.
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 Cell, 24(1), 130–137.
O'Byrne, K. J., & Steward, W. P. (2001). Tumour angiogenesis: a novel therapeutic target in patients with malignant disease. Expert Opinion on Emerging Drugs, 6(1), 155–174.
Satelli, A., Mitra, A., Brownlee, Z., Xia, X., Bellister, S., Overman, M. J., et al. (2015). Epithelial-mesenchymal transitioned circulating tumor cells capture for detecting tumor progression. Clinical Cancer Research, 21(4), 899–906.
Labelle, M., & Hynes, R. O. (2012). The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discovery, 2(12), 1091–1099.
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 Cell, 20(5), 576–590.
van Es, N., Sturk, A., Middeldorp, S., & Nieuwland, R. (2014). Effects of cancer on platelets. Seminars in Oncology, 41(3), 311–318.
Nistico, P., Bissell, M. J., & Radisky, D. C. (2012). Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. Cold Spring Harbor Perspectives in Biology, 4(2), 1–10.
Gresele, P., Falcinelli, E., Sebastiano, M., & Momi, S. (2017). Matrix metalloproteinases and platelet function. Progress in Molecular Biology and Translational Science, 147, 133–165.
Fidler, I. J. (1978). Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Research, 38(9), 2651–2660.
Billroth, T. (1878). Lectures on surgical pathology and therapeutics, a handbook for students and practitioners (Vol. II). London: The New Sydenham Society.
Johnson, J. H., & Woods, J. R. (1963). An in vitro study of fibrinolytic agents on V2 carcinoma cells and intravascular thrombi in rabbits. Bulletin of the Johns Hopkins Hospital, 113, 335–346.
Baserga, R., & Saffiotti, U. (1955). Experimental studies on histogenesis of blood-borne metastases. A.M.A. Archives of Pathology, 59(1), 26–34.
Jones, D. S., Wallace, A. C., & Fraser, E. E. (1971). Sequence of events in experimental metastases of Walker 256 tumor: light, immunofluorescent, and electron microscopic observations. Journal of the National Cancer Institute, 46(3), 493–504.
Chew, E. C., & Wallace, A. C. (1976). Demonstration of fibrin in early stages of experimental metastases. Cancer Research, 36(6), 1904–1909.
Warren, B. A., & Vales, O. (1972). The adhesion of thromboplastic tumour emboli to vessel walls in vivo. British Journal of Experimental Pathology, 53(3), 301–313.
Warren, B. A., & Vales, O. (1972). The release of vesicles from platelets following adhesion to vessel walls in vitro. British Journal of Experimental Pathology, 53(2), 206–215.
Warren, B. A. (1976). Some aspects of blood borne tumour emboli associated with thrombosis. Zeitschrift für Krebsforschung und Klinische Onkologie. Cancer Research and Clinical Oncology, 87(1), 1–15.
Kinjo, M. (1978). Lodgement and extravasation of tumour cells in blood-borne metastasis: an electron microscope study. British Journal of Cancer, 38(2), 293–301.
Gastpar, H. (1978). Inhibition of cancer cell stickiness, a model for the testing of in vivo thrombocyte aggregation inhibitors. IV. Effect of sulfinpyrazone. Fortschritte der Medizin, 96(36), 1823–1827.
Paul, C. D., Mistriotis, P., & Konstantopoulos, K. (2017). Cancer cell motility: lessons from migration in confined spaces. Nature Reviews. Cancer, 17(2), 131–140.
Tonisen, F., Perrin, L., Bayarmagnai, B., van den Dries, K., Cambi, A., & Gligorijevic, B. (2017). EP4 receptor promotes invadopodia and invasion in human breast cancer. European Journal of Cell Biology, 96(2), 218–226.
Lonsdorf, A. S., Kramer, B. F., Fahrleitner, M., Schonberger, T., Gnerlich, S., Ring, S., et al. (2012). Engagement of alphaIIbbeta3 (GPIIb/IIIa) with alphanubeta3 integrin mediates interaction of melanoma cells with platelets: a connection to hematogenous metastasis. The Journal of Biological Chemistry, 287(3), 2168–2178.
Lichtenberger, L. M., Fang, D., Bick, R. J., Poindexter, B. J., Phan, T., Bergeron, A. L., et al. (2017). Unlocking aspirin’s chemopreventive activity: role of irreversibly inhibiting platelet cyclooxygenase-1. Cancer Prevention Research (Philadelphia, Pa.), 10(2), 142–152.
Hu, Q., Wang, M., Cho, M. S., Wang, C., Nick, A. M., Thiagarajan, P., et al. (2016). Lipid profile of platelets and platelet-derived microparticles in ovarian cancer. BBA Clin, 6, 76–81.
Haemmerle, M., Bottsford-Miller, J., Pradeep, S., Taylor, M. L., Choi, H. J., Hansen, J. M., et al. (2016). FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal. The Journal of Clinical Investigation, 126(5), 1885–1896.
Qi, C., Li, B., Guo, S., Wei, B., Shao, C., Li, J., et al. (2015). P-selectin-mediated adhesion between platelets and tumor cells promotes intestinal tumorigenesis in Apc(min/+) mice. International Journal of Biological Sciences, 11(6), 679–687.
Crissman, J. D., Hatfield, J., Schaldenbrand, M., Sloane, B. F., & Honn, K. V. (1985). Arrest and extravasation of B16 amelanotic melanoma in murine lungs. A light and electron microscopic study. Laboratory Investigation, 53(4), 470–478.
Oleksowicz, L., Mrowiec, Z., Schwartz, E., Khorshidi, M., Dutcher, J. P., & Puszkin, E. (1995). Characterization of tumor-induced platelet aggregation: the role of immunorelated GPIb and GPIIb/IIIa expression by MCF-7 breast cancer cells. Thrombosis Research, 79(3), 261–274.
Bouvenot, G., Escande, M., Xeridat, B., Simonin, G., Boucoiran, J., & Delboy, C. (1977). Thrombocytosis and cancer. Apropos of a chronological series of 100 patients. La Semaine des Hôpitaux, 53(36), 1921–1925.
Honn, K. V., Tang, D. G., & Crissman, J. D. (1992). Platelets and cancer metastasis: a causal relationship? Cancer Metastasis Reviews, 11(3–4), 325–351.
Levin, J., & Conley, C. L. (1964). Thrombocytosis associated with malignant disease. Archives of Internal Medicine, 114, 497–500.
Rank, A., Liebhardt, S., Zwirner, J., Burges, A., Nieuwland, R., & Toth, B. (2012). Circulating microparticles in patients with benign and malignant ovarian tumors. Anticancer Research, 32(5), 2009–2014.
Nieuwland, R., Berckmans, R. J., Rotteveel-Eijkman, R. C., Maquelin, K. N., Roozendaal, K. J., Jansen, P. G., et al. (1997). Cell-derived microparticles generated in patients during cardiopulmonary bypass are highly procoagulant. Circulation, 96(10), 3534–3541.
van Doormaal, F., Kleinjan, A., Berckmans, R. J., Mackman, N., Manly, D., Kamphuisen, P. W., et al. (2012). Coagulation activation and microparticle-associated coagulant activity in cancer patients. An exploratory prospective study. Thrombosis and Haemostasis, 108(1), 160–165.
Cokic, V. P., Mitrovic-Ajtic, O., Beleslin-Cokic, B. B., Markovic, D., Buac, M., Diklic, M., et al. (2015). Proinflammatory cytokine IL-6 and JAK-STAT signaling pathway in myeloproliferative neoplasms. Mediators of Inflammation, 2015, 453020.
Matsuo, K., Hasegawa, K., Yoshino, K., Murakami, R., Hisamatsu, T., Stone, R. L., et al. (2015). Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma. European Journal of Cancer, 51(14), 1978–1988.
Acknowledgements
Grant and other support
Boone Pickens Distinguished Chair for Early Prevention of Cancer, Duncan Family Institute, Colorectal Cancer Moon Shot, P30CA016672-41, 1R01CA187238-01, 5R01CA172670-03, and 1R01CA184843-01A1, CA177909, and the American Cancer Society Research Professor Award.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interests
The authors declare that they have no conflicts of interest.
Rights and permissions
About this article
Cite this article
Menter, D.G., Kopetz, S., Hawk, E. et al. Platelet “first responders” in wound response, cancer, and metastasis. Cancer Metastasis Rev 36, 199–213 (2017). https://doi.org/10.1007/s10555-017-9682-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10555-017-9682-0