The Role of Platelet microRNAs in Cancer

Abstract

There is strong evidence that platelets significantly contribute to cancer progression. Numerous studies have shown that microRNAs in platelet microvesicles play an important role in different stages of cancer and can serve as new diagnostic and prognostic biomarkers. Since platelet microRNAs have opposing purposes, it is challenging to make clear-cut judgements regarding their involvement in carcinogenesis. However, it is well known that the processes regulated by microRNAs in cancer include cell proliferation, cell death, epithelial–mesenchymal transition, cancer metastasis, and angiogenesis. This review focusses on and summarizes current research in the field of platelet–cancer interactions and discusses the role of platelet microRNAs in cancer development, which is a promising area for future research and therapeutic development.

 

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Keywords

microRNA - platelet microvesicles - cancer - platelet–tumour interaction

Introduction

Platelets are anucleate discoid cells derived from bone marrow megakaryocytes, circulating in the bloodstream with a normal count of 150,000 to 450,000 platelets per μL of blood and a lifespan of 8 to 10 days.[1] It is now widely recognized that platelet functions extend beyond haemostasis and thrombosis to encompass roles in inflammatory and immunological responses. Platelets participate in various pathophysiological processes, including inflammation, atherogenesis, and cancer progression.[2] [3] [4] The association between cancer and thrombosis is a common finding. Cancer patients exhibit an elevated risk of arterial and venous thrombotic events, which are associated with poorer prognosis and survival outcomes.[5] [6]

There is strong evidence that platelets can modulate tumour proliferation and growth, facilitate intravasation into the bloodstream and enhance survival in the circulation, promote arrest and adhesion to the vascular endothelium, and enable extravasation into secondary sites during the haematogenous dissemination of tumour cells.[7] [8] The formation of new blood vessels from a pre-existing vasculature is a prerequisite of primary tumour growth, cancer cell intravasation, extravasation, and growth of cancer foci at distant sites. Platelets are implicated in angiogenesis, positioning them as significant contributors to tumour formation and dissemination within the body.[3] [5] Interactions between platelets and tumour cells may occur at both cellular and molecular levels within the circulation and tumour microenvironment.[5] Platelets were demonstrated to be involved in the tumour microenvironment through extensive tumour neovascularization.[9] Recently, it was shown that platelet-derived microvesicles (PMVs) may transfer RNAs to tumour cells and it is now evident that microRNAs (miRNAs) contained in platelets are pivotal in cancer progression.[10]

MicroRNA are genome-encoded small non-coding RNAs that influence various aspects of cellular function through the regulation of gene expression.[11] Platelets possess a store of RNAs, including microRNAs originating from megakaryocytes.[12] MicroRNAs are crucial in regulating platelet function and the pathways of platelet reactivity. Certain microRNAs can target mRNAs that encode proteins implicated in activation and aggregation, hence modulating their expression.[2] Although the majority of microRNAs are located intracellularly, a substantial quantity is present in the extracellular environment, including blood and other body fluids.[13] Circulating microRNAs can be detected in plasma, serum, or whole blood and may serve as novel diagnostic and prognostic biomarkers, in addition to potential therapeutic targets.[11] Circulating microRNAs are cofractionated with protein complexes such as those stabilized by the Ago2 protein, or are encapsulated in cellular microvesicles (MVs).[14] Since the major pool of the microvesicles in blood originates from platelets,[15] circulating platelet microRNAs may be pivotal in cancer.

Аn increasing amount of data has emerged on the role of microRNAs, stored in PMV, in tumour suppression.[16] Several PMV microRNAs, including miR-27a, miR-24, miR-155, miR-195, let-7a/b, and miR-223, target both tumour suppressor genes and oncogenes in various types of cancer and are currently considered as diagnostic and prognostic markers of malignant neoplasms.[17] [18] [19] [20] [21] For example, miR-24 and miR-223 are each associated with multiple types of cancer, and their targets include both tumour suppressors and oncogenes, with ongoing discoveries of additional targets and mechanisms of action.[19] [20] MicroRNAs are classified as either suppressor or oncogenic based on their role in tumour development. Suppressor microRNAs inhibit the expression of oncogenes or apoptosis-inducing genes, while oncogenic microRNAs activate tumourigenesis or inhibit the expression of suppressor genes.[22]

The processes regulated by microRNAs in cancer include:

• Cell proliferation, both by targeting cell cycle components and by regulating multiple signalling pathways[23] [24];

• Cell death by regulating components of the extrinsic apoptosis pathway[25] [26];

• Epithelial–mesenchymal transition (EMT) and cancer metastasis[5] [27];

• Angiogenesis—the process of developing new blood vessels from existing ones to satisfy the demands for nutrients and oxygen during tumour growth and metastasis.[5]

Thus, it is obvious that microRNAs play an important role in cancer, but the mechanisms of their involvement in this pathological process are far from being fully understood. In this narrative review, we summarize recent research evidence and discuss the role of platelet microRNAs in cancer, which represents a promising area for research and development of therapeutic strategies.

 

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Discovery of Platelet MicroRNAs

MicroRNAs are small non-coding sequences, approximately 22 nucleotides in length, that regulate messenger RNA (mRNA) translation and subsequent protein production. In humans, 60% of the protein-coding transcriptome is regulated by microRNAs.[28] MicroRNAs are responsible for modulating a wide range of metabolic pathways and are involved in many biological processes, including inflammation, regulation of the immune system, platelet biogenesis, and function.[29] [30] The first to provide evidence for the presence of microRNAs in platelets were Kannan and his colleagues.[31] In 2009, Landry and colleagues confirmed that human platelets contain abundant and diverse microRNAs. They identified 219 microRNAs in human platelets, with the most abundant being microRNA-142-5p.[32] In 2010, 281 transcripts were identified by qPCR, including 228 related mature microRNAs and 53 associated minor microRNAs.[33] In 2012, the complete sequence and characterization of microRNA in human platelets were determined using high-throughput sequencing. Plé and colleagues described approximately 500 microRNAs present in platelets, with the let-7 family accounting for almost half of the total.[34] A team of authors, headed by Bray, cataloged microRNAs in washed platelets from four healthy volunteers, raising the total number of known platelet microRNAs to approximately 750.[35] Although platelets contain significantly fewer microRNAs than nucleated cells, they possess a broad array of microRNAs, accounting for approximately 30% of previously identified mature human microRNAs (miRBase v22.1).[35] [36] Summarizing the data from the above studies, the common microRNAs in platelets are let-7, miR-199, miR-223, miR-103, miR-142, miR-23, miR-21, miR-126, miR-451, and miR-15b, and less common are miR-17, miR-27, miR-221, miR-130a, miR-425, miR-24, miR-183, miR-18, miR-939, and others.[32] [34] [35]

 

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Formation of Platelet MicroRNAs and their Biological Role

Platelet microRNAs arise in the nucleus of megakaryocytes in the form of unprocessed pri-microRNA transcripts, which undergo initial processing and are exported to the cytosol of megakaryocytes in the form of short hairpin pre-miRNAs.[37] Platelets inherit mature microRNAs and pre-miRNAs from megakaryocytes and possess all proteins required for RNA maintenance.[32] Notably, microRNAs in platelets are more prevalent than pre-miRNAs, and platelets possess the ability to self-process pre-miRNAs ([Fig. 1]).[12]

Fig. 1 Origin and transmission of platelet microRNAs[10]: MicroRNAs and their pre-miRNAs that originate in megakaryocytes are present in platelets, which are eventually derived from megakaryocytes. The proteins Dicer, TRBP2, and Ago2 present in platelets further process platelet pre-miRNA, resulting in the formation of new mature microRNAs. Activated platelets release microparticles (PMPs) and exosomes, which serve as transfer vectors for platelet microRNAs.

Human platelets have been found to contain enzymes necessary for microRNA maturation, such as Dicer, TRBP2, and Argonaute 2 (Ago2).[32] Deletion of Dicer1, a ribonuclease responsible for processing microRNA precursors into mature microRNAs, in mouse megakaryocytes has been shown to alter platelet microRNA and mRNA profiles, and the ability of Dicer1-deficient platelets to process let-7a-3 pre-miRNA is significantly diminished.[38]

The main function of microRNAs is to regulate the expression of protein-coding genes by targeting mRNAs: it is assumed that most microRNAs can target numerous mRNAs, and most mRNAs possess targets for various microRNAs. The binding of microRNAs to mRNA occurs through complementary Watson-Crick base pairing ([Fig. 2]), with the sequences typically located in the 3′ untranslated region (UTR) of the mRNA; however, this is not the case universally.[39]

Fig. 2 The primary role of microRNA[39]: The microRNA seed region (2–8 bp) binds to complementary sites on the 3′-UTR of the target mRNA, mainly resulting in reduced mRNA levels, although it may also impede translation. RISC, RNA-induced silencing complex.[101]

The seed region of nucleotides 2 to 8 at the 5′ end of the microRNA exhibits perfect complementarity, and this sequence is essential for the microRNA family. The microRNA sequence in the 3′ region of the seed sequence exhibits poor complementarity to the mRNA. Upon binding to their target mRNAs, microRNAs cause translational repression in cases of incomplete complementarity, or facilitate target mRNA destruction in cases of perfect complementarity.[26]

MicroRNAs are crucial in the cellular processes of differentiation, proliferation, maturation, and apoptosis. Studies show that microRNAs are stably expressed in human serum/plasma and that their expression can serve as a biomarker for numerous diseases, including cancer.[40] Studies also show that cells can selectively secrete microRNAs through MVs in response to various stimuli and that MV-encapsulated microRNAs are associated with Ago2 complexes.[41] [42] Cell-secreted microRNAs in MV can be efficiently delivered to target cells, in which they silence their target genes and thus influence the function of recipient cells. Therefore, cell-secreted microRNAs in MVs may serve as a new class of signalling molecules that mediate remote intercellular communication.[43]

However, the pool of extracellular microRNAs also includes protein-associated microRNAs. A recent study showed that microRNAs were more abundant in non-vesicular than vesicular fractions[44] and that these non-vesicular microRNAs were associated with the Ago2 protein.[21] It is believed that Ago2, as a microRNA carrier, may be responsible for all non-vesicular microRNAs; however, other microRNA complexes may also exist in plasma, such as those associated with nucleoplasmin or high-density lipoproteins.[21]

Several potential pathways for microRNA transfer by platelets are discussed in the literature ([Fig. 3]).[14]

Fig. 3 Platelet-mediated microRNA delivery[12]: Activated platelets release microvesicles, generally expressing on their surface phosphatidylserine (PS), that are taken up by recipient cells (which was demonstrated both in vitro and in vivo). Recipient cells can also directly internalize platelets through phagocytosis, as demonstrated in vitro. Other ways microRNA can be delivered include connexin-based gap junctions and tunnel nanotubes, which are long extensions of the cell membrane that help cells share nucleic acids. However, the feasibility of these delivery routes remains to be determined.

Upon activation, platelets release MVs that are subsequently absorbed by recipient cells both in vitro and in vivo. Furthermore, platelets can be directly internalized via phagocytosis by recipient cells.[14] Another potential mechanism for platelet-mediated microRNA transfer involves the formation of connexin-based gap junctions for interplatelet communication; however, the role of these hemichannels in the transfer of platelet microRNAs is not fully understood.[14]

 

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MicroRNA of Platelet Microvesicles

MVs circulating in blood predominantly originate from megakaryocytes; however, they are also produced by activated platelets and their amount significantly increases under pathophysiological conditions such as atherosclerosis, diabetes, coronary heart disease, cancer, viral and bacterial infections, and others.[23] [45] [46] [47] PMVs are microscopic extracellular structures ranging from 100 to 1,000 nm in diameter. They represent a substantial fraction of MVs in the circulation and are linked to numerous pathophysiological diseases.[48] PMVs were first described in 1967 as “platelet dust.”[49] The exact percentage that platelet-derived EVs account for is controversial and varies from 30 to 85%, with most studies reporting a higher percentage.[50] [51] PMV release is increased in patients with solid tumours, but its role in cancer progression is not fully understood.[5]

The production of PMV is a complex process that can be triggered by the following mechanisms: activation of platelets by soluble agonists (such as adrenaline, thrombin, adenosine diphosphate, collagen, A23187, fibrinolysin, complement C, antiplatelet antibodies) and under high shear stress, and by glycoprotein (GP) IIb/IIIa activation (outside-in signalling).[52]

Agonists or shear stress activates platelets, resulting in intracellular signal transduction following sustained elevation in intracellular calcium.[53] This is the main step of MV formation, leading to the activation of several calcium-dependent enzymes and alterations in the lipid bilayer, including the loss of phospholipid asymmetry and the externalization of negatively charged phospholipid, mainly phosphatidylserine.[54] It has been shown that unstimulated platelets can produce PMV through direct GPIIb/IIIa signalling, which destabilizes the actin cytoskeleton and leads to PMV formation in the absence of stimulation by soluble agonists.[55]

Circulating PMVs are enriched in microRNA, which are conserved and potent regulators of gene expression.[21] [56] Importantly, microRNA abundance in PMVs appears to represent subsets of microRNA cohorts in platelets, suggesting that microRNAs аre selectively chosen and encapsulated in PMVs for secretion.[21] Purified PMVs can transfer their microRNAs into recipient cells with distinct physiological effects associated with the transport of specific microRNAs to different cell types.[56] A prerequisite for efficient microRNA transfer is the close proximity between donor and recipient cells, facilitated by a wide range of platelet surface molecules such as P-selectin, glycoprotein (GP)Ib, GPIIb/IIIa, intercellular adhesion molecule (ICAM) 2, and Ligand CD40 (CD40L), the levels of which typically rise following platelet activation. This combination of microRNA transfer with platelet activation ensures a coordinated and precisely regulated release of cellular material at specific sites in the human body.[14]

 

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Platelet MicroRNA and Cancer

Numerous studies have shown that human malignancies exhibit abnormal microRNA expression patterns. Alterations in microRNA expression profiles may directly indicate chromosomal or genomic changes in cancer-related genes.[57] Over the past decade, hundreds of cases of aberrant microRNAs detected in the plasma and serum of cancer patients compared to healthy participants have been reported, while other researchers have recognized circulating microRNAs as potential biomarkers for cancer diagnosis and prognosis, cancer development, and treatment effectiveness.[18] [23] [58] [59] [60] Shi et al examined microRNAs as potential biomarkers for the early detection of pancreatic cancer in individuals with chronic pancreatitis.[60] They found that serum-derived miR-205-5p was a promising predictor candidate that could discriminate between patients with pancreatitis and pancreatic cancer with a reported accuracy of 91.5%. Circulating miR-1247-5p, miR-301b-3p, miR-105-5p, and miR-141 have also been shown to be promising candidates for clinical biomarkers of non-small cell lung cancer.[58] [59] Tumours such as lymphoma, glioma, breast cancer, colorectal cancer, and prostate cancer exhibit abnormal microRNA expression levels that are either decreased or increased.[57] [61] It was found that the expression levels of miR-17-5p, miR-125a, miR-125b, miR-200a, Let-7a, miR-34a, miR-21, miR-99a, and miR-497 in serum have predictive and prognostic value in breast cancer.[62] [63]

Numerous clinical trials of diagnostic microRNAs have been completed, although results have not been presented. For instance, miR-155 has been used to diagnose non-muscle-invasive bladder cancer (ClinicalTrials.gov identifier: NCT03591367), while microRNA profiling has been used to predict breast cancer development (ClinicalTrials.gov identifier: NCT04516330). A number of diagnostic clinical trials using patient blood or tissue samples are currently ongoing. The diagnostic and predictive capacity of serum microRNA-451 and microRNA-23a for glioma is under evaluation (ClinicalTrials.gov identifier: NCT06178692).

The interactions between tumour cells and platelets significantly contribute to cancer progression. Cancer cells can induce platelet activation via both direct and indirect pathways, hence facilitating PMV generation.[5] Substantial evidence suggests that activated platelets and PMV are involved in cancer progression, but recent studies propose they may potentially inhibit tumour growth.[21] [48] Some PMV microRNAs have dual functions targeting both tumour suppressor genes and oncogenes (in several types of cancer). These microRNAs include miR-27a, miR-24, miR-155, miR-195, miR-126, let-7a/b, and miR-223.[17] [21] [48] [64] Besides facilitating tumour progression, several PMV microRNAs are implicated in the development of tumour resistance to therapy.[65] In addition, microRNAs may actively participate in cancer-associated thrombosis by suppressing the expression of tissue factor pathway inhibitor (TFPI) or tissue factor (TF).[66]

[Table 1] presents a summary of microRNAs, previously identified in platelets or PMVs, involved in cancer formation and cancer-associated thrombosis and their known targets. Studies that investigated and described the functions of different platelet microRNAs in different types of cancer were selected for presentation.

Table 1 Platelet-derived microRNAs and their role in cancer

microRNA	Role	Cell type	Reference
miR-223	Suppression of FBXW7 and EFNA1, possibly resulting in apoptosis	Human umbilical vein endothelial cells (HUVEC)	[38] [40]
	Suppression of EPB41L3, leading to increased invasiveness	Lung cancer cells	[62]
	Promotes Mef2c/β-catenin mediated invasion	Breast cancer	[63]
	Suppression of TF expression	Monocytes, endothelial cells	[64]
miR-183	Suppression of natural killer cell activation, possibly via silencing of DAP12	Natural killer cells	[65]
miR-195	Downregulation of tissue factor pathway inhibitor-2	Glioblastoma	[66]
miR-24	Mitochondrial dysfunction and tumour cell apoptosis, leading to suppression of tumour growth	Lung and colon cancer cells	[45]
miR-939	Triggering the epithelial–mesenchymal transition by diminishing E-cadherin expression while augmenting the expression of N-cadherin, vimentin, fibronectin, and other genes associated with the acquisition of mesenchymal features; stimulation of proliferation and migration in ovarian cancer cells	Epithelial ovarian cancer cells	[67]
miR-27a, miR-451	Induction of P-glycoprotein expression, a product of the MDR1 gene, which is classified among multiple drug resistance proteins	Human ovarian cancer cell line A2780 and its multidrug-resistant counterpart A2780DX5; human cervical carcinoma cell line KB-3-1 and its MDR variant KB-V1	[60]
miR-27a/b	Downregulation of tissue factor pathway inhibitor α	Breast cancer (MCF7 cell line)	[68]
miR-126-3p	Exhibits suppressor activity by specifically targeting components of the PIK3/AKT signalling cascade	Breast cancer (triple negative and luminal subtype A)	[69]
	Abnormal accumulation of VEGF-A and subsequent uncontrolled cell invasion and proliferation	Epithelial ovarian cancer	[70]
	n/d	VTE predictor	[71]
	Acts as a tumour suppressor by inhibiting proliferation, migration, and invasion by downregulating MMP2, MMP9 expression, and inactivating the JAK2/STAT3 signalling pathway through targeting ZEB1	Cervical cancer	[72]
miR-34c-3p, miR-18a-5p	Regulation of TEP tumour-educated platelets	Nasopharyngeal carcinoma (NPC)	[73]
miR-34c-3p	Inhibition of proliferation and invasion by blocking eIF4E expression and the PAC1-MAPK pathway	Non-small cell lung cancer	[74]
miR-15а-5р	Acts as a tumour suppressor gene, inhibiting the proliferation and division of liver cancer cells by influencing BDNF	Human hepatocellular carcinoma (HCC)	[75]
miR-142	Targets and inhibits TGF-β, resulting in decreased cell viability, proliferation, EPT, and proangiogenesis capacity	Hepatocellular carcinoma (HCC)	[76]
miR-21	Induces angiogenesis and vascular permeability by acting on KRIT1	Colorectal cancer (CRC)	[77]
	Induction of tumour angiogenesis by targeting PTEN, resulting in activation of AKT and ERK1/2 signalling pathways and thereby enhancing HIF-1α and VEGF expression	Prostate cancer cells	[78]

Abbreviations: BDNF, brain-derived neurotrophic factor; DAP12, DNAX activating protein 12 kDa; EFNA1, the gene encoding Ephrin A1; EPB41L3, erythrocyte membrane protein band 4.1 like 3; FBXW7, F-box and WD40 domain containing protein gene 7, acts as a tumour suppressor gene in numerous cancers; HIF1α, hypoxia inducible factor 1 subunit alpha; KRIT1, Krev interaction trapped protein 1; MDR, multidrug resistance; PTEN, phosphatase and tensin homolog; TGF-β, transforming growth factor beta; VEGF-A, vascular endothelial growth factor A; ZEB1, zinc-finger E-box-binding homeobox 1.

Involvement of Platelet MicroRNAs in Cancer Progression

Tumour growth is a significant pathophysiological condition potentially influenced by PMVs and their associated microRNAs.[67] It was shown that microRNA released by platelets aggravates the invasion of lung cancer cells. Notably, miR-223 levels were significantly elevated in PMVs of patients with non-small cell lung cancer.[68] Following co-culture with A549 cells, PMVs transferred miR-223 to recipient cells. Thereafter, the introduced miR-223 aggravated A549 cell invasion by targeting EPB41L3.[68]

During cancer metastasis, some cancer cells from the primary tumour exhibit invasiveness, detach from the primary tumour tissue, migrate to the nearby stroma, and eventually enter the blood or lymphatic system.[29] PMVs can induce EMT in tumour cells.[69] It has been shown that miR-939 present in PMVs, upon transfection into epithelial ovarian cancer cells, triggers EMT by downregulating E-cadherin expression, and upregulating N-cadherin, vimentin, fibronectin, and other genes associated with the acquisition of mesenchymal characteristics.[70]

Platelet-derived miR-34c-3p and miR-18a-5p are prospective biomarkers for diagnosing nasopharyngeal carcinoma (NPS). According to recent research, the expression levels of miR-34c-3p and miR-18a-5p were significantly higher in patients with NPC compared to healthy donors. The diagnostic positive rates of platelet miR-34c-3p and miR-18a-5p for NPC were 93.8 and 87.5%, respectively.[71]

These data indicate the involvement of platelet microRNAs in the regulation of angiogenesis and may contribute to developing cancer by promoting tumour growth and modifying the activity of target proteins in cells. However, the existing research is inconsistent, which may be due to the use of different models in studying the role of microRNAs, as well as the choice of model object (types of microRNAs and target cells).

 

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Tumour Suppressive Effects of Platelets MicroRNAs

Despite the generally accepted concept that platelets facilitate tumour formation and dissemination, and despite substantial evidence supporting this view, certain studies suggest that platelets may, in some cases, exert an inhibitory effect on tumour growth and metastasis.[72]

Thus, it was shown in mice that mitochondrial mt-Nd2 and Snora75, small non-coding nucleolar RNAs, are direct targets of PMV miR-24. These target RNAs were downregulated in cancer cells, leading to mitochondrial dysfunction and inhibition of tumour growth.[48] Another study showed that miR-126-3p of PMV reduced the expression of AKT2 kinase, hence inhibiting proliferation and invasion in both triple-negative and less aggressive luminal breast cancer subtype A.[73]

The mechanism by which PMV microRNAs mediate tumour growth suppression is poorly understood and requires further investigation. The mechanisms of PMV tumour infiltration, attachment to tumour cells, and microRNA transfer, as well as the array of transmitted microRNAs and their overall impact on tumour cell gene expression, remain to be fully understood. However, it is clear that platelets themselves may primarily promote cancer growth, while tumour-infiltrating PMVs may serve to suppress cancer development, at least in primary solid tumours.[56]

 

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Platelet MicroRNA in Cancer-Associated Thrombosis

Cancer-associated thrombosis is one of the leading causes of mortality in oncological diseases.[6] [74] The risk for cancer-associated venous thromboembolism is influenced by various patient-, cancer-, and treatment-related factors. Specific molecular mechanisms that are involved in development of venous thromboembolism (VTE) in cancer include expression of tissue factor and podoplanin on cancer cells and subsequent activation of the coagulation system and platelets.[18] [66] [75] All of the listed pathways are regulated by microRNA, including platelet-derived microRNA ([Table 1]).

Although the expression of podoplanin could be suppressed by several microRNAs,[76] [77] including miR-29b, miR-125a, and miR-363, their relevance to cancer-associated thrombosis was not determined. MicroRNA could regulate TF pathway of blood coagulation by either downregulation of TFPI (miR-27a/b,[78] miR-195[79]), or suppression of TF expression by other cells (miR-223-3p).[80] However, among all TF-targeting microRNAs only miR-223 is contained in PMVs.[81] There are several platelet-derived microRNAs which are deregulated in VTE, or associated with recurrent events in VTE[82]: miR-15b-5p, miR-21–5p, miR-27b-3p, miR-221,[83] and miR-126.[84] While for miR-27, its association with thrombosis is evident, for miR-126[85] and miR-221,[86] which are associated with regulation of endothelial cells and angiogenesis, their role in cancer-associated thrombosis could be rather complex. Recently, it was demonstrated that intraplatelet miR-126 promotes thrombosis through upregulation of PI3K-dependent platelet activation.[87] However, relevance of these data to cancer-associated thrombosis are yet to be determined.

Nevertheless, a few studies looked at the listed microRNAs in cancer-associated thrombosis. In the study of Oto et al,[88] the authors successfully used pre-surgery levels of several microRNAs, including miR-222-3p (a paralog of miR-221) and miR-126-5p, to predict VTE after surgery for 100 patients with intracranial tumours.

 

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Key Mechanisms Behind Changes in Platelet MicroRNA Profiles in Cancer

Alterations in the platelet microRNA profile in cancer may result from various processes ([Fig. 4]):

Fig. 4 Mechanisms underlying alterations in platelet microRNA profiles in cancer.

1. Direct platelet–tumour interaction. The relationship between tumour cells and platelets is bidirectional and complex. Platelets may alter their microRNA expression in response to external or internal stimuli or by direct uptake from the microenvironment. Cancer cells release extracellular vesicles (EVs) containing microRNAs into the bloodstream. Platelets can directly uptake EVs, incorporating tumour-derived microRNA into their RNA content.[89] Conversely, PMVs infiltrate solid tumours and transfer platelet-derived microRNAs into tumour cells, resulting in changes in tumour cell gene expression.[2] [48]

2. Indirect effects of tumours on platelets. Tumours can secrete factors such as tissue factor (TF), podoplanin, and ADP, which affect platelet activation and aggregation. In addition, cancer-associated oxidative stress has also been shown to promote chronic platelet activation.[15] Platelet activation, along with the uptake and storage of tumour-derived microRNAs, can result in alterations in platelet RNA processing—a phenomenon described as tumour-educated platelets.[71] [74] [90] This “learning” process can occur through several mechanisms: incorporation of tumour-derived proteins, nucleic acids, and vesicles, regulation of specific mRNA splicing events, and changes in megakaryocytes.[5] Increased platelet activity results in the production of circulating PMVs containing various microRNAs, suggesting an important role for these microRNAs beyond platelets in oncogenesis.[2] [41] The increase in circulating PMVs depends on the type of cancer but generally increases with cancer stage progression.[10] [56]

3. Reprogramming of megakaryocytes. Megakaryocytes, the bone marrow cells that generate platelets, can be reprogrammed by cancer cells, resulting in the production of platelets with altered RNA profiles. Certain microRNAs, including miR-34a, may regulate gene expression in megakaryocytes. These microRNAs can either suppress or stimulate the expression of certain genes involved in cell differentiation and function.[91] Cancer cells can also release soluble factors that alter the bone marrow microenvironment. These factors may then influence megakaryocytes, causing increased platelet production or modifications in their function.[21] [92] Studies have shown that some tumours are capable of producing thrombopoietin (TPO) and IL-6.[93] [94] TPO is a major regulator of megakaryocyte precursor differentiation and platelet production, whereas IL-6-induced thrombopoiesis is TPO-dependent.[95]

Thus, the mechanisms listed highlight the complex interaction between tumours and platelets. On the one hand, as a part of the tumour microenvironment, platelets are educated by cancer cells and change their microRNA profile to promote cancer cell survival and dissemination. On the other hand, cancer cells may influence platelet production from megakaryocytes and induce platelet activation leading to alternations of platelet microRNAs that may influence tumour cell function.

 

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Challenges in MicroRNA Analysis

Circulating microRNAs are attractive, non-invasive, readily available biomarkers for different types of cancer because of their stability, and cost and time-effectiveness of the analysis.

However, there are certain challenges in analyzing microRNAs including platelet microRNAs as biomarkers, consisting of blood sampling, platelet and their MV isolation, platelet activation, method of microRNA extraction, detection and quantification, data analysis and normalization.[96] [97]

First of all, the microRNA spectrum may vary significantly depending on the source: serum, plasma, MVs, exosomes.[98] [99] Moreover, a high individual variability of microRNA levels (depending on age, body mass index, sex, diet) requires conducting a larger number оf experiments to reach statistical signifficance.[97] [98] [99] Sample collection is another challenging issue that can influence the results of experiments. Samples for microRNA analysis may be contaminated by blood cell microRNA due to cell lysis during blood collection and storage and unsuitable algorithm of centrifugation.[96] [100] For instance, various variations in methods for platelets release microparticle (PMP) isolation as a source of platelet microRNAs may influence the results of analysis.

Protocols for isolating MVs differ significantly, including: (a) variations in methods of platelet isolation from whole blood,[14] [41] [43] [70] which can lead to contamination with other blood cells and their MVs; (b) variations in type and concentration of platelet agonists,[14] [41] [43] which may influence microRNA content[73]; (c) different protocols for PMP isolation from platelet suspension by centrifugation (variations in centrifugation speed and time),[14] [41] [43] [70] which can lead to the heterogeneous isolation of particles by size (both MVs and exosomes) and affect the results of the experiment. In studies involving the delivery of MVs to tumour cells, the methods for assessing the quantity of isolated PMPs vary,[41] [43] which can also affect the outcome and interpretation of the results.

Additional factors affecting the variability of research results include differences in methods for detecting and counting the amount of microRNA in samples (RT-qPCR or microarrays), proper selection of primers, quality control of the samples, and strategies for normalization to compare the samples measured by RT-qPCR.[29] [96] [100]

Thus, quality control and uniform sampling methodologies are essential to ensure compatibility of samples between patients and studies.

 

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Conclusion

The interaction between platelet microRNAs and tumour cells is complex and multifaceted. On the one hand, platelet microRNAs promote cancer progression, and on the other hand, they can directly inhibit tumour growth. In addition, transfer of microRNAs via PMVs to other cell types, such as immune cells, may indirectly contribute to cancer development.

Although microRNAs exhibit potential as important diagnostic and prognostic markers for cancer, extensive clinical investigations are required to confirm their efficacy. For most tumour cell types, specific microRNAs and their mRNA targets have not yet been identified, and the phenotypic results of mRNA silencing may vary depending on the tumour type. Complexity also lies in the transfer of PMV microRNAs into vascular cells. Elucidating these mechanisms is of great interest and will uncover possible targets for cancer therapy.

 

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Conflict of Interest

The authors declare that they have no conflict of interest.

Author Contributions

Dremuk I.A.: conceptualization, draft preparation, writing, review, and editing.

Shamova E.V.: conceptualization, writing, review, editing, and supervision.

Sveshnikova A.N.: writing, review, editing, and supervision.

Ethics Statement

Ethical approval was not required.

Declaration of Competing Interests

There are no competing interests to disclose.

Data Availability Statement

Not applicable as no new unpublished data were generated for this review.

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Publication History

Received: 16 May 2025

Accepted: 21 May 2025

Article published online:
14 July 2025