The platelets are one of the circulating particles of blood. Platelets on activation shed various particles. Platelets play a vital role in the hemostasis and certain clinical conditions. Platelets on activation shed platelet derived microparticles (PMP). These PMP are rich in GP IIb/IIIa receptors. These are member of integrin family of receptors. PMP can transfer this receptors to surface of other cells. This property of the PMP are studied in this article and their therapeutic potentiality for the therapeutic target of cancer are studied. PMP can be considered as future therapeutic targets for the cancer treatment.
"Platelets, or thrombocytes (from Greek thrombos -clot and cytes-cell), are small, irregularly-shaped anuclear cells (i.e. cells that do not have a nucleus containing DNA), 2-3Â Âµm in diameter, which are derived from fragmentation of precursor megakaryocytes.Â The average lifespan of a platelet is between 8 and 12 days".1 Though it is simple in structure it is functionally complex. Platelets are small circulating cells which upon activation releases two types of particles such as platelet derived micro-particles and exoxomes. These platelet derived microparticles contain glycoproteins receptors as that of platelets. These receptors can be transfered to other cell surfaces. Platelet derived micro-particles (PMPs) plays vital role in the hemostasis and thrombosis. we can discuss the characteristics of PMPs and its role in the disease states. The PMPs surface receptors GP IIb/IIIa and its structure , its mechanism of activation and its therapeutic potential. Also we can discuss about the possibilities of using PMPs as therapeutic target for hemostasis and cancer. To sum up with we explore the possibility of PMPs as future therapeutic target.
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There are many types of cells circulating in the blood, platelets are the smallest ones which measure about an average of 2-3Âµm in diameter, 0.5Âµm in thickness with mean cell volume of 10 femtolitres2,3. The general structure of platelets can be divided into four distinct zones to facilitate easy understanding of its complex functions. The four zones are:
The peripheral zone of platelets consists of membranes and its invaginations. Its general features includes formation of open canalicular system (OCS) which plays an important role in acceleration of clotting. This peripheral zone in turn further divided into three distinct zones includes exterior coat, unit membrane, submembrane region.
The platelet plasma membrane is fairly smooth compared with that of leukocytes in circulating blood. However, high-resolution scanning electron microscopy studies reveals that it is a fine and crumpled in appearance.4 The outer layer of the platelet membrane is thicker, along with other contents in the zone together forms a exterior coat is called glcocalyx.5 It act as barrier to separate the internal contents of the platelets from the external mileu. It is rich in glycoprotein receptors. The chief glycoprotein receptors are GP IB-IX-V complex and GP IIb-IIIa (Î±IIbÎ²3). These receptors are exceptionally important in the function of hemostasis because of its inherent ability to move.6-8
The unit membrane on which the glycocalyx rests is the typical unit membrane.9 It is rigid and cannot stretch, it serves as covering membrane. It is similar to other cell membrane in the circulating blood. It is a lipid bilayer rich in phospholipids, it afford separation between the intracellular and extracellular process. It plays a vital role in the fluid phase coagulation.10
The sub membrane is one of the vital component of the peripheral zone located just below the unit membrane. It is responsible for the maintenance of the shape and translocation of receptors and cells on the exterior surface of platelets11, including the GP IIbIIIa, GPIb-IX-V receptor complexes. The proteins which regulate the signaling process of platelet activation interact with the cytoplasmic domains of the transmembrane receptors in this region. Some of the proteins are found to be associated with filaments making the membrane contractile system5,12.
Earlier the microscopic examination of the fixed platelets shows that it contains organelles which were embedded in the irregular meshwork of fibrous materials and termed as hyaloplasm or sol-gel zone. Later the investigations revealed there are changes in the polymerization of the fibrous materials. These fibrous materials in the cytoplasm of platelets were of two types one the cytoskeleton support system the circumferential coil of microtubules, the other involved in the shape change, internal transformation, and also eventually in contraction of the hemostatic plug and retraction of clots known as actin myosin filament system13. About one half of the actin molecules were arranged as filaments in the unactivated platelets14 a portion of which constitutes the submembrane contractile system. It acts as matrix in resting cells and helps in the maintenance of shape13. Upon activation the actomyosin has unique role in physiology of platelets. It release the Î± granules and dense bodies which in turn activate the nearby platelets through the constriction of the circumferential microtubules.15,16 Thus it serve in the functions of the platelet contractile physiology.
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It is the distinct zone in the platelets contain three major types of secretory organelles includes Î± granules, densebodies (Î´ granules) and lysosomes.17 There are other membrane enclosed organelles were also present such as glycosomes,18 electron-dense clusters,19 tubular inclusions.20 The energy metabolism in platelets is served by the small number of simple mitochondria present in the cytoplasm. The platelets contain large number of Î± granule than any other organelles.21-23 which is important comparatively to other organelles. The Î± granules measures up to 200-500nm in diameter, are round and oval in shape. There are usually 60-80 granules per platelets but it varies depending on the other space occupying structures in the platelets. The inner structure of the Î± granules are further divided into zones of varying density. The submembrane zone which contain von willebrand factor organized into tubule like structures,24 the other zones such as central and peripheral are quite less dense. These zones serves as site of storage for the proteins synthesized by megakaryocytes and other varieties with binding sites.
Platelet membrane system:
The plasma membrane which forms the open canalicular system is the fourth and final zone of platelets. The OCS is the surface membrane of platelets.25-27 The OCS channels are formed by the invaginations of the surface membrane. It not only act as conduits for the discharge of the secretory products from the storage organelles also serves as major route for the uptake and transfer of products during the platelet release reaction28 especially from plasma to platelet Î± granules.29,30 The channels of the OCS plays crucial during the hemostatic reaction of platelets. The channels expand themselves to great extend so that the chemical substances and the particulate matter involved in the hemostatic reaction moves frequently to cover the site of injury. It is followed by the assembly of the actin filaments to cover the site as much as possible.31,32
Platelet functional anatomy:
Platelets one of the type of blood cells circulate freely in the blood vessels. The blood vessels are lined by monolayer of endothelial cells. Platelets responsible for the formation of platelet rich clot is being triggered by the presence of endothelial vessel wall damage. The complex serious of biochemical and cellular process can be generally grouped into four categories.33
This is the primary event in the initiation of clot formation by platelets. In this event of damage to endothelial layer of vessel wall, circulating platelets will rush to the site of injury and cover the exposed site with its adhesive proteins. Generally, platelets were tested to have only nine types of glycoproteins which are adhesive in nature. These proteins are recognized by its specific platelet membrance glycoproteins receptors. It is essential for the interaction between cells. The adhesion event is initiated by the contact of platelets at the injured surface. The circulating paltelets will stop and adhere to the site of damage which is accompanied by the interaction between two platelet glycoprotein complex. Both vessel wall and endothelial surface secretes certain proteins called von willebrand factor (vWF). vWF contains functional domains which is essential for the platelet binding to the site of damage. The adhesion of platelets to vessel wall is largely depend on the shear force.34-36 The contact will not occur if the shearing force less than threshold level. Hence the adhesion of platelets to the surface of injury is the primary hemostasis.
The stimuli obtained from the wide variety of agonist in during adhesion of platelets triggers the platelet activation. This stimuli can be further amplified by the feedback loop formed by the agonists.
Figure overview of platelet activation (adopted from kroll et al blood vol 74,no 4,1989)37
The above figure depicts the flow of events in the platelet activation. The binding of agonist to the glycoprotein receptors activate the transducer protein which transduce signals across the cellular membrane. These messenger proteins are G protein coupled inturn activate two the intracellular pathways. In the phosphoinositide pathway, the phosphoinositide (PIP2) cleaved into two intracellular second messengers. They are inositol tri phosphate (IP3) and diacylglycerol which stimulates the mobilization of calcium from the intracellular stores. The calcium is required by the other cellular enzymes for their activation.38
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In the second pathway the activation of phospholipase A2 leads to activation and liberation of arachidonate from the cell membranes. The arachidonate released from the cell membrane is converted to thromboxane A2 (TXA2). TXA2 is the potent agonist of platelets. It mediates the platelet involved thrombosis formation.
In addition to this events the other proteins such as thrombin also plays role in the platelet activation. The binding of thrombin to the surface of thrombin receptors with its lengthy N terminus which not only activates the internal signaling also it act as tethered ligand which further activate the platelets.39-41Furthemore, the protease activate receptor 1 (PAR1) is another Gprotein coupled receptor involved in the activation of platelets. The binding of thrombin to the PAR1 activates the induces the expression of other intracellular adhesion molecules which facilitate the platelet activation.
Platelet activation is followed by the secretion of platelets. Platelets contains three different types of storage granules namely Î± granules, dense bodies, lysosomes. The platelet activation results in the membrane rearrangements, cytoskeleton degradation and exteriorization of granules from the storage granules.42,43 The Î± granules contain large number of glycoproteins. They also contain platelet derived growth factors, pool of GPIIb/IIIa glycoprotein. These glycoproteins binds specifically to the GPIIb/IIIa receptors on the other platelets in the circulation. The actiation of this GPIIb/IIIa leads to two fold increase in the surface receptors.44-46
The conformational change in the GPIIb/IIIa receptors is the important response in the event of platelet activation. The structure and its mechanism of activation are discussed later. GPIIb/IIIa plays a vital role in the platelet aggregation. Its ability to form bridge between adjacent platelets is crucial for the aggregation. The ability of GPIIb/IIIa to bind with the fibrinogen in the opposite side leaves its tails portion unoccupied and can form bridge with adjacent platelets leading to platelet aggregation and clot retraction.
Platelet derived micro-particles (PMPs):
The term platelet derived micro-particles usually refers to less than 40-100 nm sized particles derived from the platelets. Platelet plays important roles in hemostasis and thrombosis depending on the circumstances. Once the vascular integrity got damaged, platelets rapidly stick to the exposed surface, activate, aggregate and secrete particles or compounds which activate other platelets for further action. This results in the formation of a platelet plug known as primary hemostasis. In addition, the formation of fibrin, an insoluble protein (secondary hemostasis) has been supported by activated platelets in platelet plug formation. It was clearer than crystal that platelets containing plasma were supporting the clot formation rather than platelet poor plasma. However, the high speed centrifugation of platelets poor plasma suggests that there is another sub cellular force which smooth the progress of clotting.48,49This sub cellular force which originated from the platelets was initially known as platelet dust demonstrated by wolf et al.50
Formation of micro-particles:
The micro-particles first reported as platelet dust and explained as the vesicles less than 40-100 nm size facilitating the clot formation50. These particles were actually the nano-fragments of the membrane with procoagulant and pro-inflammatory properties. PMPs are the circulating particles playing vital role in both normal and pathological conditions of patients with severe diseases as well as the healthy individuals51. It's also considers as the vector for the exchange of the biological information between cells.
Figure platelet derived microparticles and exosomes.(adopted from platelets 2nd edition elsevier press 2007)52
The mechanism behind the formation of the PMPs is still in fledgeling stage. The PMPs may be generated after cell activation or apoptosis. The lipids such as phosphatidylserine(PS), phosphotidylethanolamine(PE), phosphotidylcholine and sphingomyelin forms the outer lipid bilayer of the normal platelets53. These lipids carrying their respective charges were found to be distributed asymmetrically with lipids possessing negative charges covering the inner leaflet of the bilayer covering. These lipids were transported with the help of phospholipids translocases.54 once the platelets are activated the lipids transporters got deregulated and the phospholipids are scrambled resulting in the exposure of PS and PE to the external cell surface55. This event is followed by shedding of PMPs. The PMPs can be formed in following ways
Platelets can release PMPs due to activation through high shear stress,56,57complement,58 low temperatures,59contact with the surface of foreign bodies.60in vitro activated platelets can release PMPs when the first messengers such as thrombin, collagen binds to their respective receptors. This binding leads to the activation of the intracellular second messengers signal activation which in turn increase the levels of ca2+ resulting in the release of PMPs. The elevation of ca2+in the platelet cytoplasm is the essential step in the activation of platelets. It is responsible for the activation of other enzymes such as calpains and protein kinase C (PKC) which demands calcium for their activity. Calpains are protease enzyme depends on calcium which aid the release of PMPs by debasing the structural protein including the heavy chains of myosin and actin-binding protein, talin.61 Platelets also can release PMPs upon activation of PKC and its various isoforms because of the availability of intracellular ca2+ as cofactor. Simultaneously the PMPs release occurs due to exposure of aminophospholipids on the platelets surface accompanied by the widespread tyrosine dephosphorylation of various structural as well as signal transduction proteins.62 Integrin Î±IIbÎ²3 receptors on the surface of the activated platelets also plays significant role in the formation of PMPs.63Platelets can also release PMPs during the in vitro storage.64
In contrary to the concepts of PMPs formation or release from the platelets the extensive studies by various authors creates some insight in the formation of PMPs. The first contradictory starts with the role of Î±IIbÎ²3 which is not essential in the production of PMPs. It is evident from the studies conducted on the patients with platelets lacking functional Î±IIbÎ²3 (Glanzmann's thrombasthenia) produces only very low quantity of PMPs upon stimulation by the first messengers thrombin and collagen.65 Secondly, the formation PMPs during platelet ageing and platelets destruction in vitro. The prolonged storage of platelets though activates the platelets the role of apoptosis in the formation PMPs is still not clear. Regardless of the fact that platelets are anucleated cells cannot undergo apoptosis platelets are found to contain all other proteins such as caspases responsible for programmed cell death66. Though there is some evidence in illustrating the intrinsic pathway of apoptosis66so far the studies conducted to reveal the formation of PMPs during ageing and destruction of platelets produced datas which are contradictory to above directed studies.67Thirdly, the role of complement proteins in the activation of platelets, it is apparent from the studies the patient lacking specific complement receptors for the action of complement protein action generated large quantity of PMPs68 disproving the role of complement protein in the release of PMPs. This further defends the role of calcium in the formation of PMPs because calcium is essential during platelet ageing and destruction.
In short, the formation of PMPs as well the composition of PMPs though, PMPs share some of the phospholipids and glycoproteins in common need further studies to clarify the gaps in the formation of PMPs.
Detection of PMPs:69
The PMPs can be detected by various methods in the circulating blood. The flow cytometry is the usual techniques used to detect the PMPs and platelets in the blood. PMPs can be detected either directly in blood or in isolated plasma. Blood contain micro-particles originated from various cells. PMPs can be detected by using specific antigen that expressed on the surface of platelets. Flow cytometry included with the flurochrome labeled monoclonal antibodies (mAbs) specific to platelet surface antigen. Normally, we cannot differentiate platelets and PMPs in the flow cytometry using forward and side light scattering (correlating size and density). The platelets and PMPs can be differentiated using the addition of fluorescein isothiocynate (FTIC-labeled) anti GP-Ib. From the figure which is obtained by plotting the forward light scatter (size) versus side light scatter (density) shows the blood containing major events due to erythrocytes in the top right and events due to platelets in the center and in lower left events smaller than the platelets. It is not able to identify the events whereas the addition of FTIC- labeled GP-Ib provided some assistance in identification.
Figure detection of platelets adopted from 69
When the labeled FTIC-GP-Ib is added to blood which is under study clearly it is then possible to select the events based upon the fluoresecence emitted by the platelets and PMPs events. In general it is divided into three zones R1, R2, R3 in the figure. The zone R2 is positive to GP-Ib belongs to single platelets, the zone R3 is also positive for the GP-Ib which may be due to paltelet-platelets aggregates or aggregation of platelets to erythrocytes,leukocytes. From the zone R1 it is evident that the presence of small size events which positive for the GP-Ib are events of PMPs. This can be confirmed by addition of calcium inophore which release the PMPs from the platelets. The figure below clearly depicts the release of PMPs by calcium inophore before and after addition of A23187.
Figure detection of platelets derived microparticels adopted from 69
To confirm further about the origin of PMPs they can be stained with particular antibodies against the events in the PMPs surface. It is obvious that anti GP-IIIa, annexin V in the presence of calcium bind to the micro-particles which are of platelet origin. Similarly the flow cytometric analysis can be used to identify and quantify micro-particels of different origin in addition to PMPs in the clinical studies.70-73 Apart form flow cytometry and electron microscopy and ELISA can aslo be used to detect PMPs.
Characteristics of PMPs:
Micro-particles irrespective of their origin dock cytoplasmic contents of the host cells from which it originated and cell surface proteins. They also contian certain glycoproteins and phospholipids in common. The PMPs contain progoagulative and proinflammatory properties due to presence of phosphotidylserine (PS) at their surface. In addition to this PMPs also contain certain glycoprotein receptors such as GP Ib,IIb,IIIa.74,75 It was found that PMPs were rich in GP IIb/IIIa receptors on its surface. These receptors were capable of binding to four different adhesive proteins such as fibronectin, fibrinogen,von willebrandfactor and vitronectin. These proteins plays crucial role in the adhesion of platelets to subendothelium which is the first step in the formation of clot.76 Furthermore, these PMPs are found to contain chemokine receptors (CXCR4) as well as protease activated receptor 1.77,78 Among these constituents the special quality of the PMPs is they are rich in GP-IIb/IIIa receptors79 and simutaneously can transfer it to other cells. Before going deep in to that we will discuss about the qualities and properties of the GP-IIb/IIIa receptors in detail.
GP IIb/IIIa (Î±IIbÎ²3) receptors:
The role of platelets in thrombosis and hemostasis depends on its ability to bind with each other or in simple words its should aggregate itself. The role of platelet in thrombus formation is necessary for the normal body defence as well as in pathological conditions.80-82 It will create obstruction to the blood flow if it formed in excess. Glycoprotein GP IIb/IIIa a member of integrin family mediates platelets adhesion at the molecualr level.83,84 cell-cell and cell-matrix adhesion is mediated by the integrin family of proteins. It is most diverse family of adhesive made up of two subunits namely Î± and Î². There are 24 different hetrodimeric integrin proteins formed by non-covalent association of 18 different Î± subunits with 8 different Î² subunits. These proteins plays broad roles in inflammation, wound healing,cell differentiation, immunity, morphogenesis of tissue because of its structural complexity85,86. However, it also plays role in pathogenesis of many disease condition such as cancer metastasis87 when it complex structure got dysregulated.
Configuration of Î±IIbÎ²3:
The Î±IIbÎ²3 receptor is member of integrin family which essential for the platelet aggregation and thrombus formation. It is expressed predominantly on precursors of platelet and platelet surface.88,89 It is composed of type I transmembrane glycoprotein Î± and Î² subunit noncovalent complex in the ratio of 1:1.90 Each subunits were manufactured as glycosylated polypeptide chains. Exceptionally the Î±IIb remain linked by disulphide bonds though it is cleaved by the proteolytic enzymes into light and heavy chains.91 Each subunit consists of large extracellular domain, single transmembrane domain and short cytoplasmic tail.92-94 The Î± unit also known as GP IIb is compiled of 1008 amino acids95 where as Î² subunit also known as GPIIIa is compiled of 762 amino acids.92
Figure structure of Î±Î² subunits of Integrins adopted from nature reviews drug discovery vol2,sep 2003,703
The above figure clearly depicts the oraganisation of integrin and its multiple domains. During activation the orientation of the integrin domains got rearranged.
The Î² propeller domain of Î± subunit forms the N terminal portion. It is made up of amino acid residues. These amino acids residues were distributed as seven blades.94 There are four biniding sites and are formed by the oxygen molecules of backbone as well as the aminoacid residues especially by aspartic acid and asparginase. These binding sites helps to maintain the rigidity of the domains. The remaining portion in the extracellular domain of Î± subunit is arranged as Î² sheet. Apart from the above domain the Î± subunit contains a thigh domain and two calf domains 1 and 2.
The Î²3 A-domain which is made up of 6 Î²sheets encircled by 8 Î± helices forms N terminal end of the Î² subunit. There are three metal ion binding sites which are found in the Î²3 A-domain.
Figure binding sites of GP IIb/IIIa adopted from 69
The three binding site in the Î²3 A-domain of Î² subunit has been depicted clearly in the above figure , they are known as metal ion adhesion site (MIDAS), Adjacent MIDAS (ADMIDAS), ligand induced adhesion site (LIMBS).96,97 In Î² subunit also there are other domains such as PSI, four EGF domains as well as one hybrid domain.
The crystal structure studies helps to identify the point of contact between these two subunits. The main contact is between Î² propeller and Î² A domain on the other hand thigh and calf domains of Î± subunits exhibit contact with the EGF domains of Î² subunit. On the whole these subunits were arranged as globular "head" with two "stalks".98,99 The three dimensional structure of such arrangement is shown in the figure below.
Figure structure of Î±Î² subunits of Integrins adopted from nature reviews drug discovery vol2,sep 2003,703
This domain is still under discovery whereas the full structure of Î±IIbÎ²3 become apparent by using the interaction of the helices in the other domian with this domain. The amino acid sequencing and mutationla analysis further confirmed the interactions of domians bolstered by trans linking apporaches.100
The structure of the cytoplasmic tails of both Î± and Î² subunit were revealed by NMR (Nuclear Magnetic Resonance) studies. These two subunits interact with each other through the electrostatic and hydrophobic nature of the aminoacids which forms the interaction regions. This interaction is involved in the mechanism of Î±IIbÎ²3 activation.101,102
Mechanism of Î±IIbÎ²3 activation:
Î±IIbÎ²3 receptors on the surface of platelets and PMPs were activated by two ways either by inside-out signalling or by outside-in sigmalling. The inside-out mechanism of activation is portrayed by the below figure.
Figure mechanism of intergrin Inside out signaling adopted from 69
"Inside-out signaling can be induced by different agonists, which initiate different pathways that lead to the cytoplasmic tails (CTs) of Î±IIbÎ²3. Talin-H (H) is one of the potential candidates to bind directly to the Î²3-tail and unclasp the membrane-proximal complex of Î±IIb and Î²3 CT. This unclasping triggers a conformational switch in the integrin extracellular domain, resulting in its conversion from a resting to an activated state, in which it is competent to bind soluble ligand. The subsequent outside-in signaling initiated by ligand binding further propagates and enhances the inside-out signaling" cited from Edward et al.69
Functions of PMPs:
The PMPs make 90% of the human plasma micro-particles and their putative roles were discussed below.
PMPs were essential for the clot reaction which is more evident from the studies. It uses the both intrinsic and extrinsic pathways for the clot reaction. Moreover PMPs were rich in binding sites on their surface. The formation of thrombin in the surfaces of PMPs were assisted by these binding sites.103,104In role of PMPs in coagulation is more convinced by the experiments in which micro-particles depeleted plasma fails to initiate clot reaction.104 Thus PMPs are essential for the coagulation.
Inhibition of coagulation:
PMPs produce very little amounts of thrombin. It is found that the resistance to activated protein C (APC) is associated with the activation of platelets and release of PMPs. APC inhibits the activated factor Va and VIIIa which is assisted by PMPs. Hence anticoagulant property.69
Mediator of angiogenesis and tumor metastasis:
PMPs are nanofragments of the plasma membrane of the platelets. Activation of platelets results in the secretion of two types of vesicles one is PMPs, exosomes the other. PMPs is found to contain certain cell surface receptors such GP IIb/IIIa (Î±IIbÎ²3), tissue necrosis factors, p-selectin, CXCR4 chemokine receptors, protease activated receptor 1.105-107 PMPs can transfer Î±IIbÎ²3 receptors to the surface of tumor cells supported by the salanova and his coworkers study108 the progression of tumor growth and metastasis is favoured by the PMPs.
After being extravasated from the primary site of origin tumor cells are being guarded by the platelets in turn gets activated by circulating tumor cells. This tumor cell induced platelet activation (TCIPA) can induce aggregation109 this can be leads to assumption of increased concentration of PMPs at the tumor cell accumulates. This accumulated tumor cells by PMPs can affect the endothelium. It is hypothesized that the spread of tumor cells into circulation require TCIPA. This can promote survival of tumor cell accumulates in circulation. Through the TCIPA aggregate tumor cells escapes from the scrutiny of natural killer cells.110,111 Furthermore, it can permit the adhesion of tumor emboli to vessel wall and extravasation. Tumor growth can be stimulated by the release of factors such as VEGF, PDGF, bFGF etc., which helps in the formation of new vessels to tumor that can supply nutrients to tumor. It leads to progression in the growth of tumor at the secondary sites.
Therapeutic potential of PMPs:
The activation of platelets by various means leads to secretion of PMPs. Until today, PMPs were considered as markers for various diseases. It has been found to be helpful in understanding of pathological basis of various diseases. The understanding of PMPs provides new ways of management in the diseased condition. PMPs by re-establishing the hemostasis, it can reorganize the platelet function because of its procoagulant ability in conditions such as thrombocytopenia.112,113 Additionally, the recent studies on the transfection of the giloma cells with oncogeneic form of epidermal growth factor receptor (EGFR). It is found to induce formation of PMPs over expressed EGFR which can be transferred to EGFR null tumor cells. This can be used in same way to transfer protein which lost their activity due to mutation in certain forms of diseases.114
Figure therapeutic potential of PMPs adopted from Pharmacological Reports 2009, 61, 49-57
The engineered PMPs can be able to over express certain protein which can be transferred to target cells so that the action of the original protein lost due to mutation has been regained (figure A). As described above the transfer of oncogenic EGFR to target cells in one of the example of this approach. Aliotta et al115 expressed concern over PMPs ability to carry mRNA to target cell so we can also modify the phenotype by transferring mRNA; thereby mRNA is translated into new protein as shown in the (figure B). embryonic stem cell derived PMPs has ability to transfer mRNA for several transcription factors into hemotopoietic progenitors. Thereby it reprogrammes the formation of new protein by translating mRNA has been revealed by ratajczak and his co workers116 further supports this approach117. Thus, the above schematic depiction shows a new interest and creates a new opportunity to transfer and modify the desired biological message inside desired target through PMP.
Platelets derived micro-particles first considered as platelet dust involved in various physiological settings as well as in the clinical settings. It plays vital role in the maintenance of hemostasis (vascular integrity). It also established to play crucial role in the clot formation, because of its ability to form clot it came into the lime light of research. The actual probing about the quality of the PMPs has started then. PMPs play a pivotal role in the adhesion through its surface specific receptors such as Î±IIb Î²3. This receptor is member of the integrin family. The integrins are found to play a crucial role in the cell-cell, cell-matrix interactions. These integrins were found to play crucial role in the tumor progression and metastasis through its receptors such as Î±IIb Î²3. The current evidence unarguably links PMPs with tumor progression. The potential of PMPs to facilitate tumor cell survival and availability of various receptors in addition to Î±IIb Î²3 such as chemokines and cytokines which directly or indirectly aids the tumor progression. Whereas, the PMPs multifunctional presence in various physiological process makes its exploration as therapeutic target easy. From therapeutic point of view the inhibition of Î±IIb Î²3 receptors in the tumor cell accumulates can expose tumor to the natural killer cell. Focusing on PMPs ability to transfer their receptor to other cells including cancer cells can create opportunity to consider PMP as therapeutic target for cancer prevention. Till now, there is no evidence of antiplatelet drugs in the trials for the treatment of cancer progression and metastasis. Thus, the considering the prolonged usage of antiplatelet drugs and its side effects PMP can be used as potential target to prevent angiogenesis in tumor and metastasis of cancer. Apart from cancer the inhibition of Î±IIbÎ²3 receptors along with other integrin such as Î±vÎ²3 we can prevent thrombosis.
To conclude, Platelet derived micro-particles take part in wide range of physiological process and also in the pathogenesis of various diseases. Creating new interest and highlighting potential role of PMPs in the cell modulations. Formation PMP require further studies at the molecular level to understand about the role of platelet activation and other process involved in the formation of PMP.