Platelet activation and eicosanoid signaling in ovarian cancer: implications for biomarker development

This narrative review was conducted to summarize current knowledge on biomarkers related to oxidative stress, inflammation, and PLT activity in OC, with a particular focus on eicosanoids and thromboxane B 2 (TxB 2 ). A literature search was performed using electronic databases, including PubMed, Scopus and Google Scholar. The search covered studies published in English up to 2024 and was subsequently updated to include relevant publications published through August 2026, using combinations of the following keywords: “cancer”, “ovarian cancer”, “eicosanoids”, ”thromboxane B2”, “platelets”, “metastasis”, “CA125”, “HE4”, “ROMA algorithm”. Original research articles, clinical studies and relevant reviews were considered. Studies were selected based on their relevance to the role of inflammatory processes, oxidative stress, platelet activation and eicosanoid pathways in cancer biology and diagnostics, especially ovarian cancer. Studies were included if they addressed ovarian cancer and investigated oxidative stress, inflammation, platelet activation, eicosanoid signaling, or biomarkers relevant to diagnosis or prognosis. Studies unrelated to ovarian cancer or without relevance to the biological or diagnostic focus of the review were excluded. Given the narrative nature of this review, no formal systematic review protocol or meta-analysis was applied. Included studies were qualitatively assessed and synthesized to provide an overview of current evidence and to identify potential directions for future original research.

OC is a broad term encompassing a heterogeneous group of malignancies that differ in cellular origin, molecular background, clinical behavior, and prognosis. Based on histopathological classification, OC are divided into three main groups: epithelial ovarian cancers (EOC), germ cell tumors, and sex cord–stromal tumors [ 9 ]. Among these, EOC represent the vast majority of ovarian malignancies and the most clinically significant subtype due to their aggressive nature and high mortality rate [ 10 , 11 ]. EOC is further classified into five principal histological subtypes: high-grade serous ovarian carcinoma (HGSC), low-grade serous carcinoma (LGSC), endometrioid carcinoma (EC), clear cell carcinoma (CCC), and mucinous carcinoma (MC) (Table  1 ). These subtypes differ not only in morphology but also in molecular alterations, patterns of progression, and response to therapy. EOC have also been broadly conceptualized as type I and type II tumors based on differences in molecular alterations, genomic stability, and clinical behavior [ 12 ]. Type I tumors are generally characterized by indolent growth, relative genomic stability, and well-defined precursor lesions, whereas type II tumors are aggressive, genetically unstable, and associated with rapid disease progression. Table 1 Types of EOC according to histopathology of cancer cells and their frequency, adapted from [ 10 ] with authors’ modification Histological Subtype High-Grade Serous Carcinoma Endometrioid Carcinoma Clear Cell Carcinoma Mucinous Carcinoma Low-Grade Serous Carcinoma Abbreviation HGSC EC CCC MC LGSC Frequency 70% 10% 10% 3% < 5% Types of EOC according to histopathology of cancer cells and their frequency, adapted from [ 10 ] with authors’ modification The majority of EOC belong to the type II category, with HGSC being the most common and clinically aggressive subtype. Approximately 70–75% of patients with HGSC are diagnosed at an advanced stage of disease, corresponding to FIGO stages III and IV, often involving bilateral ovarian lesions, fallopian tubes, peritoneal dissemination, and distant metastases [ 9 ]. Increasing evidence suggests that many HGSCs originate from the epithelium of the fallopian tubes, particularly from serous tubal intraepithelial carcinoma lesions, before spreading to the ovaries and peritoneal cavity. Distinct molecular alterations underlie the various histological subtypes of EOC. LGSCs frequently harbor activating mutations in genes involved in the mitogen-activated protein kinase (MAPK) signaling pathway, including alterations in KRAS , BRAF , and ERBB2 [ 7 ]. These mutations, while characteristic of specific subtypes, lack sufficient specificity to serve as standalone diagnostic biomarkers. HGSC is molecularly distinguished by a high prevalence of tumor protein p53 ( TP53) mutations, detected in the vast majority of cases. These mutations are considered a defining feature of HGSC and contribute to genomic instability and aggressive tumor behavior. Frequent CCNE1 amplification in HGSC is associated with cell cycle dysregulation and poor prognosis but is not specific to early disease and may occur independently of TP53 status [ 9 ]. Consequently, while these molecular changes are critical for understanding disease biology, their clinical utility as early diagnostic markers remains limited. EC and CC carcinomas are frequently associated with endometriosis and arise through distinct molecular pathways. Common genetic alterations in endometrioid carcinomas include mutations in the CTNNB1 gene, leading to aberrant activation of the Wnt/β-catenin signaling pathway. However, such mutations are not exclusive to malignant cells and can also be detected in benign or premalignant lesions, limiting their diagnostic specificity [ 13 ]. OC heterogeneity, reflected in its histological and molecular classification, poses significant challenges for early diagnosis and patient stratification. Although current classification systems are essential for clinical management, they also highlight the limitations of existing diagnostic approaches and the need for novel biomarkers to improve early detection and prognostic assessment. Therefore, although genomic alterations provide valuable insights into tumor biology and subtype classification, they may not fully reflect dynamic biological processes associated with tumor development, such as oxidative stress, inflammation, and PLT activation. In particular, OC progression is associated with oxidative stress, chronic inflammation, activation of coagulation pathways, and PLT activation [ 14 ]. These processes are closely linked to arachidonic acid (AA) metabolism, while phospholipase A 2 (PLA₂) contributes to the release of AA for subsequent eicosanoid biosynthesis [ 15 ]. This suggests that lipid mediators may complement genomic markers in OC diagnosis and prognosis.

Although OC diagnosis relies on clinical evaluation, imaging, and biomarker assessment, the molecular characteristics of circulating biomarkers remain central to improving early detection and risk stratification. Initial evaluation includes pelvic examination followed by transvaginal ultrasonography (TVS) in patients with suspicious findings. Imaging is complemented by biomarker assessment, most commonly Cancer Antigen 125 (CA125) and Human Epididymis Protein 4 (HE4). Although additional biomarkers may be measured, the guidelines do not specify the optimal combination of markers for routine diagnostics. This lack of standardization remains an important unmet medical need [ 59 ]. CA125, also known as mucin 16 (MUC16), remains a standard tool in OC diagnosis. A concentration of CA125 above 35 U/mL is generally considered indicative of EOC. However, CA125 is not fully specific. Its levels may rise in healthy individuals during menstruation or pregnancy, in patients with benign ovarian tumors, or in those with other malignancies such as lung or colorectal cancer [ 60 , 61 ]. Increased CA125 levels have been observed in patients with endometriosis, inflammatory bowel disease, or cardiovascular disease. In these cases, elevated levels are thought to result from inflammation and the release of cytokines, including IL-6 [ 62 ]. HE4 is protein biomarker encoded by the WFDC2 gene and commonly used in OC diagnosis. HE4 is overexpressed in endometrioid and serous subtypes of EOC and may contribute to tumor growth through modulation of immune responses by natural killer (NK) cells and lymphocyte activation [ 63 , 64 ]. HE4 is considered more specific for OC than CA125; however, its specificity alone is insufficient for use as a diagnostic marker [ 64 ]. Moreover, HE4, unlike CA125, reaches elevated levels across all stages of the disease, whereas CA125 typically shows markedly increased concentrations in advanced stages (III and IV) of cancer [ 65 ]. Although CA125 remains the most widely used biomarker, its sensitivity in early-stage disease is poor, whereas HE4 demonstrates higher specificity but is variable across histological subtypes. To improve the accuracy of OC diagnostics, the Risk of Ovarian Malignancy Algorithm (ROMA) was developed. ROMA combines CA125 and HE4 levels with patient menopausal status to provide a calculated risk of ovarian malignancy. This approach improves specificity compared to using either marker alone, and it is widely applied in clinical practice for both premenopausal and postmenopausal women. Despite these advantages, ROMA cannot reliably determine tumor aggressiveness or the presence of metastases, which remain major challenges in OC management [ 66 ]. The ROMA algorithm improves overall diagnostic performance; however, studies report inconsistent accuracy depending on menopausal status and disease stage. Early detection of OC is critical because stage I disease is associated with cure rates of up to 90%, yet only about 20% of cases are diagnosed at this stage. This highlights the need for more specific biomarkers and improved diagnostic strategies. Currently, TVS and CA125 measurement are among the most extensively studied approaches for OC detection and screening. TVS enables visualization of ovarian morphology and detection of suspicious lesions, whereas CA125 has limited specificity. O-RADS was developed to standardize ultrasound assessment and risk stratification; however, studies have reported lower specificity than alternative models such as IOTA ADNEX, which incorporates multiple clinical and ultrasound variables. Despite their clinical utility, neither TVS nor CA125 is sufficiently accurate for population-based screening because ultrasound is operator-dependent and may miss early lesions, while CA125 lacks adequate specificity [ 6 , 67 ]. Combining multiple diagnostic approaches is currently considered the most promising strategy for OC detection. Beyond ROMA, which integrates CA125 and HE4 with menopausal status to improve diagnostic accuracy, additional algorithms and novel biomarkers related to inflammation, oxidative stress, and PLT activity are being investigated to further refine risk assessment and improve both the sensitivity and specificity of early diagnosis. In addition to biomarker-based strategies, ongoing studies emphasize the importance of regular gynecological examinations and patient awareness. Early detection depends not only on laboratory tests but also on careful clinical assessment and recognition of subtle symptoms. Despite advances in imaging and laboratory diagnostics, OC remains difficult to detect at an early stages because of its nonspecific clinical presentation. Consequently, efforts to combine imaging, biomarkers, and risk algorithms aim to increase the proportion of patients diagnosed with curable disease and improve survival outcomes [ 68 ]. In summary, CA125 and HE4 remain the primary biomarkers in OC diagnostics, and their combination within the ROMA algorithm improves specificity and clinical utility, although important limitations persist. Despite advances, most cases are still diagnosed at advanced stages, underscoring the need for improved screening strategies and novel biomarkers. The limitations of currently available biomarkers have stimulated the search for molecular indicators associated with chronic inflammation, oxidative stress, lipid mediator signaling, and PLT activation. These pathways, discussed in the preceding sections, represent promising sources of novel diagnostic and prognostic biomarkers. Rather than replacing established biomarkers, eicosanoid profiling may complement current diagnostic algorithms. A multiplex biomarker panel integrating CA125, HE4, and selected PLT- and inflammation-derived lipid mediators may improve discrimination between benign inflammatory conditions and early-stage EOC [ 14 , 69 ]. Among the most promising candidates are TxB₂, reflecting PLT activation, prostacyclin metabolites indicative of endothelial responses, and LOX-derived HETEs (12-HETE and 15-HETE), which are associated with inflammation, tumor invasion, and features associated with tumor progression (Fig.  1 ) [ 14 , 16 , 41 , 54 ]. Because these lipid mediators reflect PLT activation, inflammation and tumor-host interactions, they may provide complementary information beyond conventional markers of tumor burden. Whether such profiles can discriminate early-stage OC from benign conditions or provide information on tumor aggressiveness and metastatic potential remains to be determined in prospective clinical studies. In particular, composite PLT activation signatures incorporating the TxB₂/PGI₂ balance together with LOX-derived HETEs warrant investigation as complementary biomarkers within multiplex diagnostic panels. Although prospective clinical validation is still required, recent advances in multiplex biomarker profiling and lipidomics support the potential integration of eicosanoid signatures into future diagnostic algorithms to improve both early detection and biological characterization of OC [ 46 , 70 ].

Oxidative stress is a key contributor to genomic instability and carcinogenesis through the accumulation of DNA damage, protein modifications, and lipid peroxidation. Importantly, reactive oxygen species (ROS) can PLA₂, resulting in AA release from membrane phospholipids. In PLTs, this mechanism enhances thromboxane A₂ (TxA 2 ) synthesis and amplifies PLT activation, thereby linking oxidative stress with altered eicosanoid production in OC [ 16 ]. Experimental and clinical evidence demonstrates the significant role of ROS and reactive nitrogen species (RNS) in the initiation and progression of malignant transformation [ 17 ]. Chronic inflammation is closely associated with redox imbalance, leading to excessive production of pro-inflammatory mediators and consequently contributing to endothelial dysfunction within the vascular system [ 18 , 19 ]. Although oxidative stress is associated with carcinogenesis, it is not specific to cancer and therefore serves, at best, as a non-specific marker of neoplastic change. Excessive ROS disrupt intracellular redox homeostasis and contribute to DNA, protein, and lipid damage, thereby promoting genomic instability and cancer progression. Cancer cells can adapt to elevated oxidative stress by enhancing antioxidant defense mechanisms, supportive tumor survival and progression [ 20 , 21 ]. ROS can also activate signaling pathways involved in tumor progression, including MAPK/ c-Jun N-terminal Kinase (JNK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thereby promoting cell survival, proliferation, and inflammatory responses [ 21 , 22 , 23 ]. Importantly, oxidative stress may also contribute to PLT activation and altered eicosanoid metabolism. ROS stimulate PLA₂, increasing AA release from membrane phospholipids. In PLTs, AA serves as a substrate for cycloxygenase-1(COX-1)-dependent TxA₂ synthesis, providing a mechanistic link between oxidative stress, PLT activation, and dysregulated thromboxane biosynthesis in OC [ 16 ]. Chronic pelvic inflammation has been associated with an increased risk of OC, supporting a role for persistent inflammatory signaling in ovarian carcinogenesis [ 24 , 25 ]. Ovulation itself represents a physiological inflammatory-like event characterized by the release of chemokines, growth factors, and reactive oxygen species, as well as increased cyclooxygenase-2 (COX-2) activity, which may contribute to repeated inflammatory exposure within the pelvic environment [ 26 ]. However, the contribution of additional reproductive factors, including ovarian stimulation, remains controversial. During OC development and progression, inflammatory cytokines and chemokines, particularly interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and interleukin 8 (IL-8), contribute to tumor growth, immune evasion, metastasis, and therapeutic resistance [ 27 , 28 , 29 ]. Elevated IL-6 levels have been associated with advanced disease and poorer clinical outcomes, further supporting its role in the tumor-promoting inflammatory microenvironment [ 29 ]. Inflammatory signaling may also enhance PLT activation and thromboxane biosynthesis, providing a mechanistic link between the inflammatory tumor microenvironment and PLT-derived eicosanoid pathways [ 22 , 30 ]. Although inflammatory biomarkers are not cancer-specific, their integration with established tumor markers may provide complementary diagnostic, monitoring, and prognostic information. The association between chronic inflammation, cytokine release, and thrombosis suggests that thrombosis-related biomarkers may have potential as adjunctive tools for improving OC diagnostics and risk stratification [ 31 ]. Cancer-associated hypercoagulability has important clinical implications, as thrombotic events are associated with disease progression and poorer outcomes. Patients at risk of forming clots often experience faster cancer progression and poorer prognosis [ 32 ]. Cancer-associated thrombosis (CAT) arises from the interplay of endothelial dysfunction, hypercoagulability, PLT activation, and inflammatory signaling [ 31 ]. Tumor cells express tissue factor (TF), release TF-positive extracellular vesicles, and generate thrombin through activation of the coagulation cascade. Thrombin subsequently activates PLT via protease-activated receptors (PAR-1/PAR-4), inducing PLA₂ activation, AA release, and TxA₂ synthesis. These mechanisms provide a direct molecular link between OC-associated hypercoagulability, PLT activation and dysregulated eicosanoid production [ 33 , 34 ]. Idiopathic deep vein thrombosis (DVT) may occasionally be associated with underlying malignancy, including OC, reflecting the prothrombotic state characteristic of cancer-associated coagulopathy [ 35 , 36 ]. As TxA₂ is rapidly hydrolyzed to its more stable metabolite TxB₂, circulating TxB₂ may serve as an indicator of increased PLT activation [ 37 , 38 ]. Early studies reported elevated TxB₂ levels in patients with OC, providing initial evidence of altered thromboxane biosynthesis in this population [ 39 , 40 ]. However, despite its mechanistic rationale as a candidate biomarker of PLT activation, contemporary evidence remains insufficient to establish the diagnostic performance and clinical utility of TxB₂ in OC, underscoring the need for prospective validation studies. Eicosanoids are lipid-derived mediators involved in inflammation, hemostasis, and cancer biology. Most eicosanoids are derived from membrane phospholipid-associated AA, which is released by PLA₂ and subsequently metabolized through COX, lipoxygenase (LOX), or cytochrome P450 (CYP450) pathways [ 41 , 34 ]. Eicosanoids can be classified into three main groups based on their biosynthetic pathways: COX-dependent, LOX-dependent, and cytochrome P450-dependent metabolites (Fig.  1 ) [ 42 ]. Among these mediators, TxA₂ is of particular relevance to PLT biology because of its potent pro-aggregatory effects. TxA₂ is rapidly hydrolyzed to the more stable metabolite TxB₂, which can be measured as an indicator of thromboxane biosynthesis and PLT activation [ 16 , 38 ]. In contrast, prostacyclin (PGI₂), predominantly produced by vascular cells, exerts vasodilatory and anti-aggregatory effects, illustrating the opposing roles of PLT- and vascular-derived eicosanoids in hemostatic regulation [ 27 ]. Fig. 1 Arachidonic Acid (AA) pathway and its products involved in carcinogenesis and platelet activation. PLA 2 – phospholipase A 2 , CYP – Cytochrome P450, COX – Cyclooxygenase, LOX – Lipooxygenase, HETEs – Hydroxyeicosatetraenoic acids; blue: CYP-dependent, green: LOX-dependent, red: COX-dependent; illustrated by authors Arachidonic Acid (AA) pathway and its products involved in carcinogenesis and platelet activation. PLA 2 – phospholipase A 2 , CYP – Cytochrome P450, COX – Cyclooxygenase, LOX – Lipooxygenase, HETEs – Hydroxyeicosatetraenoic acids; blue: CYP-dependent, green: LOX-dependent, red: COX-dependent; illustrated by authors TxB₂ measurement is widely used in PLT research to assess thromboxane biosynthesis and COX-1 activity, including the pharmacodynamic effects of antiplatelet therapy [ 43 , 44 , 45 ]. However, despite the established use of TxB₂ as a marker of PLT activation, its diagnostic value in OC remains insufficiently characterized. Recent lipidomic studies have identified distinct circulating lipid profiles in patients with OC, supporting the potential of lipid-derived mediators as minimally invasive biomarkers and providing a broader context for investigating PLT-derived eicosanoids in OC [ 46 ]. PLTs contribute to tumor growth, dissemination, and immune evasion through bidirectional interactions with cancer cells. In OC, experimental studies have shown that PLT–tumor cell interactions can enhance TF expression, metastatic cell phenotypes, and cancer cell migration [ 33 ]. Cancer cells can also activate PLTs through TF-dependent coagulation and thrombin generation, further promoting PLT activation and tumor–PLT aggregate formation [ 47 , 48 ]. Activated PLTs form aggregates with tumor cells, creating a protective barrier that may facilitate immune evasion, metastatic dissemination, and resistance to therapeutic interventions [ 49 ]. Several PLT receptors, including glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC2), contribute to PLT–tumor interactions and aggregate formation, particularly through recognition of extracellular matrix components and podoplanin-expressing tumor cells [ 50 , 51 ]. Importantly, PLT activation is accompanied by TxA₂ biosynthesis and its subsequent conversion to TxB₂, providing a measurable link between PLT–tumor interactions and PLT-derived eicosanoid production. These mechanisms support the biological rationale for investigating TxB₂ as a potential biomarker of PLT activation in OC. Elevated PLT counts have been linked to worse outcomes in many cancers, including gynecological cancers [ 52 ]. Beyond PLT number, PLT activation may provide additional information on tumor-associated hemostatic alterations. Tumor–PLT interactions can enhance PLT activation and thromboxane biosynthesis, potentially resulting in increased TxB₂ level [ 53 ]. However, TxB₂ is not exclusively PLT-derived and may also reflect COX activity in other cells, particularly under inflammatory and oxidative stress conditions [ 41 ]. Therefore, elevated TxB₂ should be interpreted as a marker of thromboxane biosynthesis and PLT activation rather than a cancer-specific biomarker. PLT-derived eicosanoids contribute to tumor progression by regulating tumor cell proliferation, migration, angiogenesis, and immune responses. Among these mediators, TxA₂ and prostaglandin E₂ (PGE₂) have been implicated in pro-tumor signaling, while other lipid mediators generated through LOX and CYP450 pathways, including hydroxyeicosatetraenoic acids (HETEs: 5-HETE, 12-HETE, 20-HETE), may also contribute to tumor-promoting processes [ 54 , 41 ]. In PLTs, COX-1 is the predominant source of thromboxane, whereas COX-2 is induced during inflammation and contributes to tumor-associated inflammatory signaling. The balance between TxA₂ and PGI 2 is pivotal for maintaining vascular homeostasis. In cancer, chronic inflammation, or heart disease, PLT activity is often excessive, which disrupts this balance [ 27 ]. The role of platelet COX-1–dependent thromboxane signaling in tumor biology has also prompted interest in aspirin as a potential chemopreventive agent. Epidemiological and experimental evidence suggests that regular aspirin use may be associated with a modest reduction in OC risk, potentially through inhibition of PLT COX-1 and thromboxane biosynthesis [ 55 , 14 , 56 ]. However, current evidence remains insufficient to support aspirin for primary OC prevention. Nevertheless, these findings provide indirect support for the relevance of PLT-derived thromboxane signaling in OC biology (Fig.  2 ). Fig. 2 Biochemical pathways involved in ovarian cancer carcinogenesis and progression in early-stage and advanced disease. AA – Arachidonic Acid, COX – Cyclooxygenase, IL – Interleukin, TNF-α – Tumor Necrosis Factor, TxB 2 – Thromboxane B 2 , PGE 2 - Prostaglandin E 2 , HETEs- Hydroxyeicosatetraenoic Acids, PLT – Platelets, TCIPA – Tumor Cell Induced Platelets Aggregation; orange boxes and labels emphasize the link between chronic inflammation, oxidative stress, and increased eicosanoid production during different stages of ovarian cancer progression and metastasis Biochemical pathways involved in ovarian cancer carcinogenesis and progression in early-stage and advanced disease. AA – Arachidonic Acid, COX – Cyclooxygenase, IL – Interleukin, TNF-α – Tumor Necrosis Factor, TxB 2 – Thromboxane B 2 , PGE 2 - Prostaglandin E 2 , HETEs- Hydroxyeicosatetraenoic Acids, PLT – Platelets, TCIPA – Tumor Cell Induced Platelets Aggregation; orange boxes and labels emphasize the link between chronic inflammation, oxidative stress, and increased eicosanoid production during different stages of ovarian cancer progression and metastasis Lipidomics provides a complementary approach to investigating circulating lipid alterations as potential biomarkers in gynecological malignancies [ 57 ]. In OC, serum lipidomic studies have identified alterations across multiple lipid classes, including phospholipids, ceramides, sphingomyelins, and triacylglycerols, with some changes detectable in early-stage disease [ 58 ]. These findings support the broader concept that tumor-associated alterations in lipid metabolism may be detectable in the circulation. Within this context, PLT-derived TxB₂ warrants investigation as a complementary biomarker of tumor-associated PLT activation, particularly in combination with established OC markers. Overall, the interplay between PLT activation, eicosanoid production, and endothelial dysfunction may contribute to a tumor-promoting microenvironment. These mechanisms provide a biological rationale for investigating PLT-derived eicosanoids, particularly TxB₂, as potential biomarkers and therapeutic targets in OC, while their clinical utility remains to be established.

Attempts have been made to improve the detection of OC by developing multiplex assays that combine several biomarkers. Combining biomarkers can increase both sensitivity and specificity compared to using a single marker. Many molecules involved in inflammation, angiogenesis, and blood clotting have been studied for their potential association with OC at different stages. Several models using four to six biomarkers were tested and showed better detection of OC than single biomarkers [ 71 ]. Among the numerous candidates evaluated, osteopontin has received particular attention. Osteopontin is a protein synthesized in osteoblasts, but it also participates in many cellular pathways, including those related to cancer development. Attempts have been made to include osteopontin in OC diagnosis by correlating it with CA125 and HE4. Although some studies showed that combining osteopontin with CA125 and HE4 improved sensitivity, meta-analyses found that specificity was still insufficient for routine clinical use [ 72 ]. Osteopontin is considered to be a marker of angiogenesis and may help estimate tumor stage and metastatic potential. Despite promising results in early detection, its performance has not been strong enough to recommend it as a standard diagnostic biomarker. Despite extensive evaluation in large randomized trials such as UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, neither multimodal screening strategies nor combinations of imaging, longitudinal CA125 algorithms, genetic testing, and emerging molecular biomarkers demonstrated a significant reduction in OC mortality. Among the investigated biomarkers were aldehyde dehydrogenase 1 (ALDH1), Glutathione S-transferase Pi 1 (GSTP1) genes polymorphisms, folate receptor α and circulating DNA-based markers. Despite these efforts, these trials did not demonstrate a reduction in OC mortality. This suggests that, although multiple biomarkers or tests may improve detection, they are still not sufficient to significantly improve patient outcomes when used alone [ 73 , 74 ]. MicroRNAs (miRNAs) represent another promising area of research in OC diagnostics. MiRNAs are short non-coding RNA molecules that regulate gene expression and play important roles in cell proliferation, differentiation, apoptosis, and metastasis. They are also involved in early stages of tumor development, making them attractive candidates for early detection of OC [ 75 ]. MiRNAs were first discovered in 1993 and consist of 18–25 nucleotides. Under normal conditions, many circulating miRNAs act as tumor suppressors, controlling pathways that prevent uncontrolled cell growth. In cancer patients, the expression of specific miRNAs, such as members of the Let-7 family, is often reduced. This downregulation is linked to increased activity of oncogenes like KRAS , which promote tumor growth and progression [ 76 , 77 ]. Meta-analyses have highlighted other miRNAs, including miRNA-30 and miRNA-200, as potential biomarkers of OC. Higher expression of these miRNAs has been associated with better prognosis and lower risk of tumor progression [ 78 ]. Some miRNAs, including miRNA-199a and miRNA-125b, regulate the expression of human epidermal growth factor receptor 2 ( HER2) and human epidermal growth factor receptor 3 ( HER3) under normal conditions. However, in the presence of oxidative stress, their regulatory function is disrupted. This leads to increased oncogene expression, higher risk of cancer development, and more aggressive progression [ 77 ]. MiRNAs are stable in blood and other body fluids, making them suitable for liquid biopsy and non-invasive monitoring. Tumor cells interact with PLT, endothelial cells, and plasma proteins, leading to imbalances in coagulation and hemostasis. Since abnormalities in blood clotting are associated with cancer progression, angiogenesis, inflammation, and metastasis, miRNAs may help assess these changes and serve as useful diagnostic markers [ 78 ]. Despite promising results, the diagnostic performance of individual miRNAs varies considerably between studies, likely due to differences in study design, patient populations, and analytical methods. Consistent with the inflammatory mechanisms discussed previously, inflammatory biomarkers may also enhance OC diagnosis. A single marker, such as CA125, is not sufficient for reliable detection, especially in early-stage disease. Researchers have proposed combining CA125 with inflammatory markers to improve diagnostic accuracy. For example, platelet distribution width (PDW) has been suggested as a complementary marker [ 79 ]. Other inflammatory markers associated with CA125 include the neutrophil-to-lymphocyte ratio (NLR), which has been linked to immune profiles and prognosis in OC [ 52 ]. Some diagnostic algorithms using these markers have been able to detect OC in patients with advanced disease and metastases, but their performance in early-stage disease remains limited [ 80 ]. While several studies report elevated levels of inflammatory markers such as IL-6 in advanced OC, their diagnostic utility in early-stage disease remains limited and inconsistent across cohorts. PLT also play an important role in OC progression and may serve as additional diagnostic tools. Tumor-cell induced platelet aggregation (TCIPA) triggers the release of pro-angiogenic and pro-tumorigenic factors, depending on the type of stimulus, including TxA 2 , prostaglandins, platelet-derived growth factor (PDGF). These PLT-derived molecules support tumor growth, protect cancer cells from the immune system, and help the tumor spread. By analyzing PLT activity and the molecules they release, it may be possible to better understand the stage of tumor development and aggressiveness. Despite the clear involvement of PLT in cancer biology, no standardized clinical method is currently available to measure tumor-associated PLT activity. Combining PLT-derived markers with established biomarkers like CA125 and HE4 could improve detection and monitoring of OC patients [ 80 ]. TxB₂ represents a biologically plausible candidate biomarker of PLT activation, and altered AA metabolism in OC. However, its clinical utility for early detection, tumor stratification or prognostic assessment remains to be established. Although direct evidence supports the involvement of TxB₂ in OC, the available data are largely derived from historical studies and remain insufficient for robust diagnostic validation [ 39 , 40 ]. Evidence from other malignancies, including colorectal and lung adenocarcinoma, supports the biological relevance of thromboxane metabolites in cancer-associated PLT activation; however, these findings cannot be directly extrapolated to OC [ 81 , 82 ]. Since eicosanoids pathway is involved in multiple stages of cancer development, its products, such as TxB₂, represent potential candidates for disease monitoring; however their association with OC stage requires further validation [ 83 ]. TxB₂ levels in biological samples can be measured using enzyme-linked immunosorbent assay (ELISA) or chromatographic techniques, including gas chromatography (GC) and high-performance liquid chromatography (HPLC). Currently, liquid chromatography-mass spectrometry (LC-MS) is increasingly preferred due to its ability to simultaneously quantify multiple eicosanoids with high precision, even in small sample volumes [ 84 ]. These analytes can be assessed in plasma and urine, supporting the feasibility of minimally invasive sampling; however, their suitability for routine clinical diagnostics requires further analytical and clinical validation. In addition to TxB₂, other eicosanoids involved in angiogenesis and metastasis can be measured simultanously, supporting assessment of tumor progression and disease stage [ 85 ]. Although LC-MS offers high analytical specificity and enables multiplexed eicosanoid profiling, its routine clinical implementation may currently be limited by instrumentation costs, specialized infrastructure, technical expertise, and the need for standardized analytical protocols. Some in-vitro studies have demonstrated that predominance of TxA 2 in human OC may contribute tumor growth and dissemination [ 40 ]. Clinical observations have reported increased PLT capacity to generate TxA 2 and elevated levels of TxB 2 in OC serum [ 39 ]. Moreover, TxB₂ levels were reported to be significantly higher in metastatic OC tissue than in localized OC, borderline malignant tumors, benign ovarian tumors, or normal ovarian tissue [ 86 ]. Although evidence evaluating 11-dehydro-TxB₂ as a circulating biomarker in OC patients remains particularly limited, studies in other malignancies indicate that 11-dehydro-TxB₂ may serve as a marker of tumor-associated PLT activation. For example, Joharatnam-Hogan et al. reported associations between 11-dehydro-TxB₂ levels and tumor characteristics in colorectal and gastro-oesophageal cancers [ 87 ]. However, available OC studies did not systematically evaluate TxB₂ levels according to FIGO stage, histological subtype, treatment response, or survival outcomes. Nor did they establish diagnostic performance parameters such as sensitivity, specificity, area under the receiver operating characteristic curve (AUC), or clinically validated cut-off values. To date, we have not identified recent studies from the past two decades specifically investigating eicosanoid profiles or the clinical significance of TxB₂ in OC patients. This lack of current evidence highlights an important knowledge gap and supports the need for dedicated clinical and experimental studies to validate the potential role of thromboxane metabolites as biomarkers or mechanistic mediators in OC progression. Early diagnosis of OC remains a major challenge. Multiplex biomarker panels, miRNAs, inflammatory markers, and PLT-derived molecules all have potential to improve detection. Current approaches such as CA125, HE4 and ROMA are useful but not sufficient, especially for early-stage disease. Continued research into combining multiple biomarkers and exploring new molecular targets is essential to develop more accurate and sensitive diagnostic tools. A better understanding of tumor biology, PLT interactions, and inflammatory processes will help guide the design of new algorithms that can detect OC earlier and improve patient outcomes. Future prospective studies should evaluate TxB₂ and other PLT-derived eicosanoids alongside established OC biomarkers to determine whether they provide additional diagnostic or prognostic value. Such studies should include adequately powered cohorts representing healthy individuals, benign gynecological conditions, and different OC stages and histological subtypes, and should establish standardized analytical procedures and clinically relevant cut-off values.

OC remains one of the most lethal gynecological malignancies, largely due to late-stage diagnosis. Current diagnostic tools, including CA125, HE4, and the ROMA algorithm, provide clinically useful information but remain insufficient for reliable early detection and accurate assessment of disease progression. This review highlights PLT-derived eicosanoids, particularly TxB₂, as an emerging and underexplored class of potential biomarkers in OC. Current understanding of the molecular mechanisms underlying OC suggests that PLT-derived eicosanoids, particularly TxB₂, play important roles in inflammation, angiogenesis, and metastatic progression. Together with inflammatory biomarkers and microRNAs, these mediators may provide complementary information on different stages of OC development and could be integrated with established biomarkers into multiparametric diagnostic models. Collectively, the available evidence supports a potential role for inflammation-associated mediators, PLT-derived eicosanoids, and regulatory microRNAs as interconnected components of the molecular network underlying OC initiation and progression. Their integration into multiparametric models may improve early detection while providing additional insight into tumor biology. However, the clinical utility of TxB₂ and other eicosanoids remains to be established. Future studies should therefore focus on validation in large prospective cohorts, standardization of analytical methods, and clarification of interactions within inflammatory and AA signaling pathways to facilitate clinical translation.

Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies worldwide, primarily due to its asymptomatic early course and frequent diagnosis at advanced stages. According to the latest GLOBOCAN 2024 estimates, approximately 324,000 new cases and 207,000 deaths from OC were estimated worldwide in 2024 [ 1 ]. In Poland, ovarian cancer is one of the leading causes of death among women with gynecological malignancies, with approximately 3600 new cases and 3100 deaths reported annually [ 2 ]. Despite advances in diagnosis and treatment, OC continues to be associated with poor survival because most patients are diagnosed at an advanced stage. Moreover, demographic changes, including population growth and aging, are expected to further increase its global burden [ 1 ]. Among gynecological malignancies, OC remains one of the most lethal worldwide. OC is the fifth leading cause of cancer-related death among women in Western countries [ 3 ]. According to the European Cancer Information System (ECIS), OC accounts for approximately 5% of newly diagnosed cancers in women [ 4 ]. The disease is most frequently detected at an advanced stage, often incidentally during routine gynecological examinations, which largely contributes to its high mortality rate. The risk of OC increases with age, particularly among women aged 40 years and older, with the average age at diagnosis being approximately 63 years [ 5 ]. OC is often named as a “silent killer” due to its asymptomatic or non-specific clinical presentation in the early stages. When symptoms do occur, they are typically vague and easily overlooked, resulting in delayed diagnosis. Although ultrasound-based risk stratification systems such as Ovarian-Adnexal Reporting and Data System (O-RADS) improve the characterization of adnexal masses, their role is primarily to distinguish benign from malignant lesions rather than to achieve population-level early detection of OC [ 6 ]. Consequently, most patients are diagnosed with advanced-stage disease, which is associated with poor long-term survival and limited treatment options [ 7 ]. The 10-year survival of patients with advanced OC (FIGO stages III and IV) remains at approximately 10–15% and has not improved substantially over the past 20 years. These observations highlight a critical unmet medical need for improved diagnostic strategies that enable earlier detection of OC and contribute to improved patient outcomes [ 8 ]. Due to the high mortality of OC and its strong association with late-stage diagnosis, a precise understanding of disease heterogeneity is essential for improving diagnostic and therapeutic strategies. OC is not a single malignant disease but rather a heterogeneous group of entities that differ in histopathological and molecular characteristics. Dysregulation of oxidative stress, inflammatory signaling, platelet (PLT) and platelet-derived pathways may contribute to tumor initiation, progression, angiogenesis, immune evasion, and metastatic dissemination. These pathways also provide a promising source of novel diagnostic and prognostic biomarkers. Among these processes, PLT activation and platelet-derived eicosanoid pathways attract increasing interest as potential sources of circulating biomarkers. Although current clinical management and prognostic assessment rely primarily on histological subtype and disease stage, these approaches do not fully capture the molecular complexity of OC. Therefore, an overview of OC classification provides a necessary framework for understanding the biological complexity of the disease and the limitations of existing diagnostic approaches, which in turn underscores the need for more refined and biologically informative biomarkers.