Liquid biopsy: paving a new avenue for cancer research.

The current constraints associated with cancer diagnosis and molecular profiling, which rely on invasive tissue biopsies or clinical imaging, have spurred the emergence of the liquid biopsy field. Liquid biopsy involves the extraction of circulating tumor cells (CTCs), circulating free or circulating tumor DNA (cfDNA or ctDNA), circulating cell-free RNA (cfRNA), extracellular vesicles (EVs), and tumor-educated platelets (TEPs) from bodily fluid samples. Subsequently, these components undergo molecular characterization to identify biomarkers that are critical for early cancer detection, prognosis, therapeutic assessment, and post-treatment monitoring. These innovative biosources exhibit characteristics analogous to those of the primary tumor from which they originate or interact. This review comprehensively explores the diverse technologies and methodologies employed for processing these biosources, along with their principal clinical applications.

Tumor Educated Platelets as a Biomarker for Diagnosis of Lung cancer: A Systematic Review.

INTRODUCTION: Lung cancer is one of the commonest cause of cancer associated mortality worldwide. Platelets have emerged as key players in cancer development and progression by supporting tumor growth, and dissemination. In the present systematic review, we analyzed RNA transfer between cancer cells and platelets and explored potential role of different platelet RNA profiles as onco-signature in diagnosis, subtyping, disease progression and treatment monitoring in carcinoma lung carcinoma. MATERIALS AND METHODS: The study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Cochrane Manual of Systematic Reviews and Meta-analysis that included seven studies on patients with lung cancer, with data on tumor-educated platelets, and control group. The outcome measured was based on sensitivity, specificity, and ROC. PUBMED, SCOPUS, Central Cochrane Registry of Controlled Trials and Science Direct databases were searched using specific search terms until October 2023. QUADAS - 2 tool was used to assess quality, risk of bias and applicability concerns. RESULTS: The analysis revealed AUC > 70% for different platelet mRNAs, with sensitivity and specificity of more than 60 %. AUC and sensitivity were highest for ITGA2B (AUC 0.922; sensitivity 92.8%). lncRNA GTF2H2-1 was the most specific platelet RNA. On QUADAS-2 tool, 3/7 articles were unclear in reference standards, patient flow timing, and 1/7 had high bias in both aspects. For applicability, 1/7 studies were unclear in reference standards, and 2/7 in index tests. CONCLUSION: TEP RNA can aid in early diagnosis of lung cancer and of proven utility in its early-stage detection. TEP RNA can also monitor disease progression and treatment response.

The use of platelets as a clinical tool in oncology: opportunities and challenges.

Platelets are small circulating anucleated cells mainly involved in thrombosis and hemostasis processes. Moreover, platelets play an active role in tumorigenesis and cancer progression, stimulating angiogenesis and vascular remodelling, and protecting circulating cancer cells from shear forces and immune surveillance. Several reports indicate that platelet number in the blood circulation of cancer patients is associated with prognosis and response to treatment. However, the mechanisms of platelets "education" by cancer cells and the crosstalk between platelets and tumor are still unclear, and the role of "tumor educated platelets" (TEPs) is achieving growing interest in cancer research. TEPs are a biological source of cancer-derived biomarkers, especially RNAs that are protected by platelets membrane from circulating RNases, and could serve as a non-invasive tool for tumor detection, molecular profiling and evolution during therapy in clinical practice. Moreover, short platelet lifespan offers the possibility to get a snapshot assessment of cancer molecular profile, providing a real-time tool. We review and discuss the potential and the clinical utility, in terms of cancer diagnosis and monitoring, of platelet count together with other morphological parameters and of the more recent and innovative TEP profiling.

Tumor-Educated Platelet RNA and Circulating Free RNA: Emerging Liquid Biopsy Markers for Different Tumor Types.

The incidence and mortality from malignant tumors continue to rise each year. Consequently, early diagnosis and intervention are vital for improving patient' prognosis and survival. The traditional pathological tissue biopsy is currently considered the gold standard for cancer diagnosis. However, it suffers from several limitations including invasiveness, sometimes not repeatable or unsuitable, and the inability to capture the dynamic nature of tumors in terms of space and time. Consequently, these limit the application of tissue biopsies for the diagnosis of early-stage tumors and have redirected the research focus towards liquid biopsies. Blood-based liquid biopsies have thus emerged as a promising option for non-invasive assessment of tumor-specific biomarkers. These minimally invasive, easily accessible, and reproducible tests offer several advantages, such as being mostly complication-free and efficient at monitoring tumor progression and tracing drug resistance. Liquid biopsies show great potential for cancer prediction, diagnosis, and prognostic assessment. Circulating tumor-educated platelets (TEPs) possess the unique ability to absorb nucleic acids from the bloodstream and to modify transcripts derived from megakaryocytes in response to external signals. In addition, circulating free RNA (cfRNA) constitutes a significant portion of the biomolecules present in the bloodstream. This paper aims to provide a comprehensive overview of the current research status regarding TEP RNA and cfRNA in liquid biopsies from various tumor types. Our analysis includes cancers of the lung, liver, pancreas, breast, nasopharynx, ovary and colon, as well as multiple myeloma and sarcoma. By synthesizing this information, we intend to establish a solid theoretical foundation for exploring potential applications of circulating RNA as a reliable biomarker for tumor diagnosis and monitoring.

TEP SNORD12B, SNORA63, and SNORD14E as novel biomarkers for hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC).

PURPOSE: The alterations of RNA profile in tumor-educated platelets (TEPs) have been described as a novel biosource for cancer diagnostics. This study aimed to explore the potential snoRNAs in TEP as biomarkers for diagnostics of hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC). METHODS: Platelets were isolated using low-speed centrifugation and subjected to a quantitative polymerase chain reaction (qPCR) for snoRNAs detection. RESULTS: Down-regulated SNORD12B and SNORD14E as well as up-regulated SNORA63 were identified in TEP from HBV-related HCC, which could act as diagnostic biomarkers for HBV-related HCC as well as the early disease. Besides, TEP SNORD12B, SNORD14E, and SNORA63 facilitate the diagnostic performance of AFP and achieve favorable diagnostics efficiency for HBV-related HCC when combined with platelet parameters. CONCLUSIONS: Aberrant expression of SNORD12B, SNORA63, and SNORD14E in TEPs could serve as the novel and non-invasive biomarkers for HBV-related HCC diagnosis.

Liquid biopsy in colorectal cancer.

Liquid biopsy refers to a set of pathological samples retrieved from non-solid sources, such as blood, cerebrospinal fluid, urine, and saliva through non-invasive or minimally invasive approaches. In the recent decades, an increasing number of studies have focused on clinical applications and improving technological investigation of liquid biopsy biosources for diagnostic goals particularly in cancer. Materials extracted from these sources and used for medical evaluations include cells like circulating tumor cells (CTCs), tumor-educated platelets (TEPs), cell-free nucleic acids released by cells, such as circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), cell-free RNA (cfRNA), and exosomes. Playing significant roles in the pathogenesis of human malignancies, analysis of these sources can provide easier access to genetic and transcriptomic information of the cancer tissue even better than the conventional tissue biopsy. Notably, they can represent the inter- and intra-tumoral heterogeneity and accordingly, liquid biopsies demonstrate strengths for improving diagnosis in early detection and screening, monitoring and follow-up after therapies, and personalization of therapeutical strategies in various types of human malignancies. In this review, we aim to discuss the roles, functions, and analysis approaches of liquid biopsy sources and their clinical implications in human malignancies with a focus on colorectal cancer.

Platelet-derived circRNAs signature in patients with gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: Neuroendocrine tumors (NETs) early diagnosis is a clinical challenge that require a deep understanding of molecular and genetic features of this heterogeneous group of neoplasms. However, few biomarkers exist to aid diagnosis and to predict prognosis and treatment response. In the oncological field, tumor-educated platelets (TEPs) have been implicated as central players in the systemic and local responses to tumor growth, thereby altering tumor specific RNA profile. Although TEPs have been found to be enriched in RNAs, few studies have investigated the potential of a type of RNA, circular RNAs (circRNA), as platelet-derived biomarkers for cancer. In this proof-of-concept study, we aim to demonstrate whether the circRNAs signature of tumor educated platelets can be used as a liquid biopsy biomarker for the detection of gastroenteropancreatic (GEP)-NETs and the prediction of the early response to treatment. METHODS: We performed a 24-months, prospective proof-of-concept study in men and women with histologically proven well-differentiated G1-G2 GEP-NET, aged 18-80 years, naïve to treatment. We performed a RNAseq analysis of circRNAs obtained from TEPs samples of 10 GEP-NETs patients at baseline and after 3 months from therapy (somatostatin analogs or surgery) and from 5 patients affected by non-malignant endocrinological diseases enrolled as a control group. RESULTS: Statistical analysis based on p < 0.05 resulted in the identification of 252 circRNAs differentially expressed between GEP-NET and controls of which 109 were up-regulated and 143 were down-regulated in NET patients. Further analysis based on an FDR value ≤ 0.05 resulted in the selection of 5 circRNAs all highly significant downregulated. The same analysis on GEP-NETs at baseline and after therapy in 5 patients revealed an average of 4983 remarkably differentially expressed circRNAs between follow-up and baseline samples of which 2648 up-regulated and 2334 down-regulated, respectively. Applying p ≤ 0.05 and FDR ≤ 0.05 filters, only 3/5 comparisons gave statistically significant results. CONCLUSIONS: Our findings identified for the first time a circRNAs signature from TEPs as potential diagnostic and predictive biomarkers for GEP-NETs.

In vitro cross-talk between metastasis-competent circulating tumor cells and platelets in colon cancer: a malicious association during the harsh journey in the blood.

Background: Platelets are active players in hemostasis, coagulation and also tumorigenesis. The cross-talk between platelets and circulating tumor cells (CTCs) may have various pro-cancer effects, including promoting tumor growth, epithelial-mesenchymal transition (EMT), metastatic cell survival, adhesion, arrest and also pre-metastatic niche and metastasis formation. Interaction with CTCs might alter the platelet transcriptome. However, as CTCs are rare events, the cross-talk between CTCs and platelets is poorly understood. Here, we used our established colon CTC lines to investigate the colon CTC-platelet cross-talk in vitro and its impact on the behavior/phenotype of both cell types. Methods: We exposed platelets isolated from healthy donors to thrombin (positive control) or to conditioned medium from three CTC lines from one patient with colon cancer and then we monitored the morphological and protein expression changes by microscopy and flow cytometry. We then analyzed the transcriptome by RNA-sequencing of platelets indirectly (presence of a Transwell insert) co-cultured with the three CTC lines. We also quantified by reverse transcription-quantitative PCR the expression of genes related to EMT and cancer development in CTCs after direct co-culture (no Transwell insert) with platelets. Results: We observed morphological and transcriptomic changes in platelets upon exposure to CTC conditioned medium and indirect co-culture (secretome). Moreover, the expression levels of genes involved in EMT (p < 0.05) were decreased in CTCs co-cultured with platelets, but not of genes encoding mesenchymal markers (FN1 and SNAI2). The expression levels of genes involved in cancer invasiveness (MYC, VEGFB, IL33, PTGS2, and PTGER2) were increased. Conclusion: For the first time, we studied the CTC-platelet cross-talk using our unique colon CTC lines. Incubation with CTC conditioned medium led to platelet aggregation and activation, supporting the hypothesis that their interaction may contribute to preserve CTC integrity during their journey in the bloodstream. Moreover, co-culture with platelets influenced the expression of several genes involved in invasiveness and EMT maintenance in CTCs.

Liquid biopsy: an examination of platelet RNA obtained from head and neck squamous cell carcinoma patients for predictive molecular tumor markers.

Aim: Recently, a tumor cell-platelet interaction was identified in different tumor entities, resulting in a transfer of tumor-derived RNA into platelets, named further "tumor-educated platelets (TEP)". The present pilot study aims to investigate whether such a tumor-platelet transfer of RNA occurs also in patients suffering from head and neck squamous cell carcinoma (HNSCC). Methods: Sequencing analysis of RNA derived from platelets of tumor patients (TPs) and healthy donors (HDs) were performed. Subsequently, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used for verification of differentially expressed genes in platelets from TPs and HDs in a second cohort of patients and HDs. Data were analyzed by applying bioinformatic tools. Results: Sequencing of RNA derived from the tumor as well as from platelets of TPs and HDs revealed 426 significantly differentially existing RNA, at which 406 RNA were more and 20 RNA less abundant in platelets from TPs in comparison to that of HDs. In TPs' platelets, abundantly existing RNA coding for 49 genes were detected, characteristically expressed in epithelial cells and RNA, the products of which are involved in tumor progression. Applying bioinformatic tools and verification on a second TP/HD cohort, collagen type I alpha 1 chain (COL1A1) and zinc finger protein 750 (ZNF750) were identified as the strongest potentially platelet-RNA-sequencing (RNA-seq)-based biomarkers for HNSCC. Conclusions: These results indicate a transfer of tumor-derived messenger RNA (mRNA) into platelets of HNSCC patients. Therefore, analyses of a patient's platelet RNA could be an efficient option for liquid biopsy in order to diagnose HNSCC or to monitor tumorigenesis as well as therapeutic responses at any time and in real time.

Contents in tumor-educated platelets as the novel biosource for cancer diagnostics.

Liquid biopsy, a powerful non-invasive test, has been widely used in cancer diagnosis and treatment. Platelets, the second most abundant cells in peripheral blood, are becoming one of the richest sources of liquid biopsy with the capacity to systematically and locally respond to the presence of cancer and absorb and store circulating proteins and different types of nucleic acids, thus called "tumor-educated platelets (TEPs)". The contents of TEPs are significantly and specifically altered, empowering them with the potential as cancer biomarkers. The current review focuses on the alternation of TEP content, including coding and non-coding RNA and proteins, and their role in cancer diagnostics.

Tumor-educated platelet SNORA58, SNORA68 and SNORD93 as novel diagnostic biomarkers for esophageal cancer.

Aim: The purpose of this study was to evaluate whether tumor-educated platelet (TEP) snoRNAs could be used as a diagnostic biomarker for esophageal cancer (ESCA). Methods: Platelet precipitates were obtained from platelet-rich plasma by low-speed centrifugation, and total RNA was extracted from platelets using Trizol™ reagent. RT-qPCR was used to detect snoRNA expression, and the receiver operating characteristic was used to assess its diagnostic potential. Results: SNORA58, SNORA68 and SNORD93 were significantly upregulated in TEPs from ESCA patients and early-stage patients compared with healthy controls. Importantly, the three snoRNAs were capable of serving as circulating biomarkers of diagnostics and early diagnosis of ESCA, possessing areas under the curve of 0.846 and 0.857, respectively. Conclusion: TEP SNORA58, SNORA68 and SNORD93 could potentially serve as noninvasive biomarkers for diagnosis and early diagnosis of ESCA.

Gene Expression Behavior of a Set of Genes in Platelet and Tissue Samples from Patients with Breast Cancer.

The tumor microenvironment (TME) is constituted by a great diversity of highly dynamic cell populations, each of which contributes ligands, receptors, soluble proteins, mRNAs, and miRNAs, in order to regulate cellular activities within the TME and even promote processes such as angiogenesis or metastasis. Intravasated platelets (PLT) undergo changes in the TME that convert them into tumor-educated platelets (TEP), which supports the development of cancer, angiogenesis, and metastasis through the degranulation and release of biomolecules. Several authors have reported that the deregulation of PF4, VEGF, PDGF, ANG-1, WASF3, LAPTM4B, TPM3, and TAC1 genes participates in breast cancer progression, angiogenesis, and metastasis. The present work aimed to analyze the expression levels of this set of genes in tumor tissues and platelets derived from breast cancer patients by reverse transcription-quantitative polymerase chain reaction (RTqPCR) assays, in order to determine if there was an expression correlation between these sources and to take advantage of the new information to be used in possible diagnosis by liquid biopsy. Data from these assays showed that platelets and breast cancer tumors present similar expression levels of a subset of these genes' mRNAs, depending on the molecular subtype, comorbidities, and metastasis presence.

Identification and validation of core genes in tumor-educated platelets for human gastrointestinal tumor diagnosis using network-based transcriptomic analysis.

Gastrointestinal (GI) tumors have increasing incidence worldwide with their underlying mechanisms still not being fully understood. The use of tumor-educated platelets (TEPs) in liquid biopsy is a newly-emerged blood-based cancer diagnostic method. Herein, we aimed to investigate the genomic changes of TEPs in GI tumor development and their potential functions using network-based meta-analysis combined with bioinformatic methods. We used a total of three eligible RNA-seq datasets, which were integrated using multiple meta-analysis methods on the NetworkAnalyst website, and identified 775 DEGs (differentially expressed genes; 51 up-regulated and 724 down-regulated genes) in GI tumor relative to healthy control (HC) samples. These TEP DEGs were mostly enriched in bone marrow-derived cell types and associated with gene ontology (GO) of "carcinoma" and could affect pathways of "Integrated Cancer Pathway" and "Generic transcription pathway" respectively for highly and lowly expressed DEGs. Combined network-based meta-analysis and protein-protein interaction (PPI) analysis identified cyclin dependent kinase 1 (CDK1) and heat shock protein family A (Hsp70) member 5 (HSPA5) to be the hub genes with the highest degree centrality (DC), being up-regulated and down-regulated in TEPs, respectively. GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that the hub genes were primarily related to cell cycle and division, nucleobase-containing compound and carbohydrate transport, and endoplasmic reticulum unfolded protein response. Additionally, the nomogram model suggested that the two-gene signature owns extraordinary predictive power for GI tumor diagnosis. Further, the two-gene signature was demonstrated to have potential value for metastatic GI tumor diagnosis. The expression levels of CDK1 and HSPA5 in clinical platelet samples were verified to be consistent with the results from bioinformatic analysis. This study identified a two-gene signature encompassing CDK1 and HSPA5 that can be used as a biomarker for GI tumor diagnosis and maybe even cancer-associated thrombosis (CAT)-related prognosis.

What is the context? Gastrointestinal (GI) tumors are now responsible for the majority of cancer-related mortalities worldwide.In the majority of cases of cancer, curative treatments are not recommended at the time of diagnosis. In this case, early screening and diagnosis is very important for overall tumor prognosis. Liquid biopsy emerged as a newly introduced minimally invasive approach for cancer diagnosis by detecting blood analytes as tumor-educated platelets (TEPs). Compared to tissue-based biopsies, liquid biopsies are less invasive, easy to access, convenient for serial tracking and better in eliminating intratumoral spatial heterogeneity. In recent years, specific gene signatures have been identified for cancer diagnosis, prognosis and prediction based on gene profiling data of TEPs. However, most of these studies were performed on the independent platelet profile datasets published on the Gene Expression Omnibus (GEO) database, which may harbor enormous heterogeneity. Additionally, few study revealed TEP mRNA functions and roles in GI tumors. Therefore, there's the need of using an integrated method to re-analyze these data, so we can gain new insights for GI tumor diagnosis.What is new? Herein, through network-based RNA-seq meta-analysis, we identified the CDK1-HSPA5 signature in TEPs that has the potential as a biomarker for diagnosing GI tumors. This is the first time, to our knowledge, that a shared transcriptional signature of tumor-educated platelets has been identified in human GI tumor patients based on meta-analysis. Additionally, we found the two-gene signature has potential value for metastatic GI tumor diagnosis. We also demonstrated that HSPA5 may have different roles in blood and tumor cells, so its expression deregulation in distinct types of tissue may have opposing diagnostic and prognostic values.What is the impact? Our work provides a novel biomarker for platelet-based GI tumor prediction and diagnosis, which may also be used as novel targets for thrombosis prevention during cancer development in the future.

Platelets and their derived extracellular vesicles: The new generation of markers in non-small cell lung cancer management.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. Circulating elements have gained significant interest in the diagnosis and prognosis of NSCLC patients. Among these, platelets (PLTs) and their derived extracellular vesicles (P-EVs) are emerging eligible biosources both in terms of number and carriers of genetic materials (RNA, proteins, and lipids). PLTs are mainly produced by the shedding of megakaryocytes and together with P-EVs, participate in a variety of pathological processes including thrombosis, tumor progression, and metastasis. Here, we performed an extensive literature review focusing on PLTs and P-EVs as potential diagnostic, prognostic, and predictive markers for NSCLC patient management.

Factors influencing platelet isolation: a prospective multicenter study from Western China.

Tumor-educated platelets (TEPs) have been widely reported to have promising application potential; nonetheless, platelet isolation from peripheral blood is an important but neglected step in TEPs research for platelet-based liquid biopsy. In this article, we discussed some common influence factors for platelet isolation. To investigate the factors involved in platelet isolation, a prospective multicenter study was conducted on healthy Han Chinese adults (18 to 79 years of age). A total of 208 individuals were included in the final statistical analysis out of the 226 healthy volunteers who were prospectively enrolled from four hospitals. The primary study metric was the platelet recovery rate (PRR). The similar pattern was observed in the four hospitals, The PRR at room temperature (23°C±2°C) was slightly higher than the PRR at cold temperature (4°C±2°C). Moreover, the PRR gradually decreased as the storage time increased. The PRR for samples within 2 hours of storage is significantly higher than for samples beyond 2 hours (p < .05). Additionally, PRR was also affected by the equipment used in different centers. This study confirmed several factors that influence platelet isolation. In our study, we indicated that platelet isolation should be performed within two hours of peripheral blood draw and held at room temperature until isolation, and that centrifuge models should be fixed during the extraction process, which will further improve the research progress of platelet-based liquid biopsy in cancer.

What is the context? Globally, cancer is one of the leading cause of premature death. Early screening is important for cancer diagnosis and treatment and can even significantly lower cancer mortalityGlobally, cancer is one of the leading cause of premature death. Early screening is important for cancer diagnosis and treatment and can even significantly lower cancer mortalityFor the liquid biopsy, isolation is an important step. Early studies have explored the influencing factors of exosome, circulating tumor cells (CTCs), and other components extraction in liquid biopsy.Despite platelet also being an excellent source of liquid biopsy, few studies have explored the factors that influence platelet isolation.Considering the importance of platelet isolation in tumor-based platelet liquid biopsy, our aim is to optimize platelet isolation conditions as much as possible to obtain a high platelet recovery rate.What is new? In this study, we conducted a prospective multicenter study ofhealthy adults from four centers, combining whole blood with platelet-richplasma to investigate factors influencing platelet recovery rate (PRR) during platelet isolation.In our study, we indicated that platelet isolation should be performed within two hours at room temperature, and that centrifuge models should be fixed during the extraction process, which will further improve the research progress of platelet-based liquid biopsy in cancer.What is the impact? In future platelet-related studies, we should fix the sample storage temperature, storage time and centrifuge model in the process of platelet extraction, so as to reduce the variables affecting platelet extraction as much as possible and ensure the stable recovery rate of platelet extraction.

Platelet RNA enables accurate detection of ovarian cancer: an intercontinental, biomarker identification study.

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.

Application of tumor-educated platelets as new fluid biopsy markers in various tumors.

The incidence of malignant tumors is increasing year by year. Early detection and diagnosis of malignant tumors can improve the prognosis of patients and prolong their life. Pathological biopsy is the current gold standard for diagnosis, but the results of pathological biopsy are affected by the sampling site and cannot fully reflect the nature of the disease. Moreover, the invasive nature of pathological biopsy limits repeated detection. Liquid biopsies are non-invasive and can be used for early detection and monitoring of tumors, which considered to represent a promising tool. Platelets make themselves to be one of the richest liquid biopsy sources by the capacity to take up proteins and nucleic acids and alter their megakaryocyte-derived transcripts and proteins in response to external signals, which are called tumor-educated platelets (TEPs). In this article, we will review the application of tumor-educated platelets in various malignancies (nasopharyngeal carcinoma, prostate cancer, lung cancer, glioblastoma, colorectal cancer, pancreas cancer, ovarian cancer, sarcoma, breast cancer and hepatocellular carcinoma) and provide theoretical basis for the research of TEPs in tumor diagnosis, monitoring and treatment.

Down-regulated lncRNA ROR in tumor-educated platelets as a liquid-biopsy biomarker for nasopharyngeal carcinoma.

PURPOSES: To evaluate the diagnostic value of tumor-educated platelets (TEP) lncRNA ROR for nasopharyngeal carcinoma (NPC). METHODS: Quantitative real-time PCR was used to determine the expression level of TEP lncRNA ROR in NPC patients (n = 50) as compared to normal subjects (n = 33). The ROC curve analysis was performed to assess the diagnostic value of TEP lncRNA ROR for NPC. Correlations between TEP lncRNA ROR and clinical parameters were further analyzed. RESULTS: The median of TEP lncRNA ROR was significantly lower in NPC patients than that in normal subjects (0.0209 vs 0.0610, p = 0.0019), while no significant difference was found in plasma lncRNA ROR. ROC analysis showed that TEP lncRNA ROR had a sensitivity of 60%, specificity of 70%, and accuracy of 63.9% in diagnosing NPC, and the area under ROC curve (AUC) was 0.70. The expression level of TEP lncRNA ROR in NPC showed no significant difference among different TNM stages. However, low level of TEP lncRNA ROR correlated well with positive Epstein-Barr virus (EBV) DNA (kappa value = 0.314, p = 0.06), TEP lncRNA ROR and EBV DNA had similar diagnostic positive rate (58.3%) for NPC, and the combination of TEP lncRNA ROR and EBV DNA increased the positive rate to 74%. CONCLUSION: The expression level of TEP lncRNA ROR was down-regulated in NPC and the diagnostic value of TEP lncRNA ROR was similar to EBV DNA. Our study indicated that TEP lncRNA ROR might serve as a novel type of liquid biopsy biomarker in diagnosis of NPC patients.

The role of tumor-educated platelets in ovarian cancer: A comprehensive review and update.

Platelets have recently surfaced as critical players in cancer metastasis and the local and systemic responses to tumor growth. The emerging concept of "Tumor-educated platelets (TEPs)" comprises the exchange of biomolecules between tumor cells and platelets, thereby leading to the "education" of platelets. Increased platelet numbers have long been associated with cancer patients' tumor metastasis and poor clinical prognosis. However, it is very recently that researchers have delved deeper into the tumor-microenvironment and probed the mechanism of interactions between tumor cells and platelets. Designing strategies to target the TEPs and the communications between platelets and tumor cells can prove to be a promising breakthrough in cancer therapy. Through this review, we aim to analyze the recent developments in this field and discuss the characteristics of TEPs, focusing on ovarian cancer-associated TEPs and their characteristics, the interplay between ovarian cancer-associated TEPs and cancer cells, and the purview of TEP-targeted cancer diagnosis and therapy, including platelet biomarkers and inhibitors.

Emerging Role of Tumor-Educated Platelets as a New Liquid Biopsy Tool for Colorectal Cancer.

Colorectal cancer (CRC) is a major cause of cancer-associated death universally. Currently, the diagnosis, prognosis, and treatment monitoring of CRC mostly depends on endoscopy integrated with tissue biopsy. Recently, liquid biopsy has gained more and more attention in the area of molecular detection and monitoring of tumors due to ease of sampling, and its safe, non-invasive, and dynamic nature. Platelets, despite their role in hemostasis and thrombosis, are known to have an active, bifacial relationship with cancers. Platelets are the second most common type of cell in the blood and are one of the wealthy liquid biopsy biosources. These cells have the potential to absorb nucleic acids and proteins and modify their transcriptome with regard to external signals, which are termed tumor-educated platelets (TEPs). Liquid biopsies depend on TEPs' biomarkers which can be used to screen and also detect cancer in terms of prognosis, personalized treatment, monitoring, and prediction of recurrence. The value of TEPs as an origin of tumor biomarkers is relatively new, but platelets are commonly isolated using formidable and rapid techniques in clinical practice. Numerous preclinical researches have emphasized the potential of platelets as a new liquid biopsy biosource for detecting several types of tumors. This review discusses the potential use of platelets as a liquid biopsy for CRC.