Metastasis is the main cause of cancer-related deaths and the biggest challenge in improving cancer prognosis. Platelet-tumor cell aggregates are a prerequisite for hematogenous metastasis. However, the internal relation and molecular mechanism of platelets and their receptor glycoprotein (GP) Ibα in platelet-tumor cell interaction and metastasis remain elusive. Here, we find that in the absence of the full-length GPIbα or its cytoplasmic tail, platelets maintain a more resting state and exhibit reduced tumor cell-induced platelet activation. The deficiency of the cytoplasmic tail of GPIbα inhibits tumor cell-platelet interaction, platelet-induced tumor cell migration and invasion, and metastasis. Using a state-of-the-art spinning disk intravital microscopy, we observe a rapid accumulation of platelets on tumor cells, forming numerous tumor cell-platelet aggregates in vivo. We also find that the cytoplasmic tail of GPIbα regulates the tumor cell-induced platelet protein kinase C-α (PKCα) activation, and both the pharmacological inhibition and genetic ablation of platelet PKCα attenuate tumor cell-induced platelet activation, tumor cell-platelet interaction, tumor cell migration and invasion, and metastasis. Overall, our findings reveal for the first time that GPIbα promotes experimental metastasis through its cytoplasmic tail-regulated platelet activation, and suggest a potential target to regulate tumor hematogenous metastasis.

Previous studies have produced conflicting results regarding whether aspirin affects survival in colorectal cancer (CRC) patients. This study examines the relationship between regular aspirin use and survival in CRC patients within a nationwide cohort.

All patients diagnosed with CRC in Iceland from 2000 to 2019 were identified through the Icelandic Cancer Registry. Clinical variables, including medications, were extracted from medical records. Overall survival (OS) and cancer-specific survival (CSS) were calculated. The follow-up period ended on 1 October 2022. The Charlson comorbidity index was used to assess comorbidity burden, and propensity score matching was employed to balance patient characteristics.

Of the 2,561 eligible patients, 22% (n = 559) had been taking aspirin before their CRC diagnosis. Aspirin users were generally older and more frequently male (63% vs. 51%), with a higher comorbidity burden (15% vs. 4.7%). The median follow-up period was 51 months (IQR 14-110). Aspirin users were less likely to receive a stage IV diagnosis. After matching, overall survival (OS) was comparable between aspirin and non-users (HR: 0.94, 95% CI (0.83-1.06), p = 0.30). However, cancer-specific survival (CSS) was significantly better for aspirin users (HR: 0.79, 95% CI (0.65-0.95), p = 0.01). This benefit was not observed in patients with stages I-III CRC or those diagnosed due to gastrointestinal bleeding.

Aspirin use was linked to improved CSS but not OS. The findings suggest aspirin's potential role in slowing or hindering progression to stage IV cancer.

Disease recurrence is the primary cause of death in patients with gastric cancer who have undergone complete surgical resection. No prognostic factors for recurrence, other than the Tumor, Node, and Metastasis stage, have been established. However, recurrence rates differ even within the same Tumor, Node, and Metastasis stage. Therefore, we aimed to develop a new prognostic confidence measure for gastric cancer recurrence and demonstrate its practical utility.

This was a retrospective study based on the medical records of the Chungnam National University Hospital, Republic of Korea. We enrolled patients diagnosed with stage II/III gastric cancer who underwent complete surgical resection and adjuvant chemotherapy over the past 12 years. The association between seven variables, including the systemic inflammation response index (SIRI) and gastric cancer recurrence, was analyzed.

A total of 296 patients were enrolled in this study. Although other factors did not exhibit significant correlations, SIRI showed a significant positive correlation with gastric cancer recurrence risk, confirmed through Cox regression testing (hazard ratio, 1.231; 95% confidence interval, 1.04-1.45). Linear regression analysis revealed a significant association between higher SIRI values and shorter recurrence time (p = 0.044; β = -0.225).

In this study, other than SIRI, effective prognostic factors related to gastric cancer recurrence were not verified, thus indicating SIRI as a potential independent prognostic factor.

Although cancer chemopreventive agents have been confirmed to effectively protect high-risk populations from cancer invasion or recurrence, only over ten drugs have been approved by the U.S. Food and Drug Administration. Therefore, screening potent cancer chemopreventive agents is crucial to reduce the constantly increasing incidence and mortality rate of cancer. Considering the lengthy prevention process, an ideal chemopreventive agent should be nontoxic, inexpensive, and oral. Natural compounds have become a natural treasure reservoir for cancer chemoprevention because of their superior ease of availability, cost-effectiveness, and safety. The benefits of natural compounds as chemopreventive agents in cancer prevention have been confirmed in various studies. In light of this, the present review is intended to fully delineate the entire scope of cancer chemoprevention, and primarily focuses on various aspects of cancer chemoprevention based on natural compounds, specifically focusing on the mechanism of action of natural compounds in cancer prevention, and discussing in detail how they exert cancer prevention effects by affecting classical signaling pathways, immune checkpoints, and gut microbiome. We also introduce novel cancer chemoprevention strategies and summarize the role of natural compounds in improving chemotherapy regimens. Furthermore, we describe strategies for discovering anticancer compounds with low abundance and high activity, revealing the broad prospects of natural compounds in drug discovery for cancer chemoprevention. Moreover, we associate cancer chemoprevention with precision medicine, and discuss the challenges encountered in cancer chemoprevention. Finally, we emphasize the transformative potential of natural compounds in advancing the field of cancer chemoprevention and their ability to introduce more effective and less toxic preventive options for oncology.

Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally1,2. Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours3. There is interest in therapeutically exploiting this immune vulnerability to prevent recurrence in patients with early cancer at risk of metastasis. Here we show that inhibitors of cyclooxygenase 1 (COX-1), including aspirin, enhance immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A2 (TXA2). TXA2 acts on T cells to trigger an immunosuppressive pathway that is dependent on the guanine exchange factor ARHGEF1, suppressing T cell receptor-driven kinase signalling, proliferation and effector functions. T cell-specific conditional deletion of Arhgef1 in mice increases T cell activation at the metastatic site, provoking immune-mediated rejection of lung and liver metastases. Consequently, restricting the availability of TXA2 using aspirin, selective COX-1 inhibitors or platelet-specific deletion of COX-1 reduces the rate of metastasis in a manner that is dependent on T cell-intrinsic expression of ARHGEF1 and signalling by TXA2 in vivo. These findings reveal a novel immunosuppressive pathway that limits T cell immunity to cancer metastasis, providing mechanistic insights into the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies.

In the era of immunotherapy, the lymphatic system has garnered significant attention from researchers. Increasing evidence highlights the complex regulation of lymphatic vessels (LVs) within the tumor microenvironment, unveiling a paradox in tumor progression: while LVs enhance immune surveillance, they simultaneously foster immune suppression. This review summarizes the regulatory factors of lymphangiogenesis, discusses the intricate effects of LVs on immunotherapy, and emphasizes the potential connection between lymphangiogenesis and tertiary lymphoid structure. Additionally, current therapeutic strategies targeting lymphangiogenesis are critically evaluated, with a forward-looking perspective on future research directions and regulatory approaches to achieve precise targeting and optimize immunotherapy paradigms.

The malignant tumor is a serious disease threatening human life. Increasing studies have confirmed that the tumor microenvironment (TME) is composed of a variety of complex components that precisely regulate the interaction of tumor cells with other components, allowing tumor cells to continue to proliferate, resist apoptosis, evade immune surveillance and clearance, and metastasis. However, the characteristics of each component and their interrelationships remain to be deeply understood. To target TME, it is necessary to deeply understand the role of various components of TME in tumor growth and search for potential therapeutic targets. Herein, we innovatively classify the TME into physical microenvironment (such as oxygen, pH, etc.), mechanical microenvironment (such as extracellular matrix, blood vessels, etc.), metabolic microenvironment (such as glucose, lipids, etc.), inflammatory microenvironment and immune microenvironment. We introduce a concise but comprehensive classification of the TME; depict the characteristics of each component in TME; summarize the existing methods for detecting each component in TME; highlight the current strategies and potential therapeutic targets for TME; discuss current challenges in presenting TME and its clinical applications; and provide our prospect on the future research direction and clinical benefits of TME.

Aspirin, a non-steroidal anti-inflammatory drug and platelet inhibitor, has been shown to reduce cancer incidence, lower metastatic rates and improve survival in certain cancer types. However, data on the effect of aspirin on prognosis in pancreatic ductal adenocarcinoma (PDAC) are limited. Therefore, we conducted a retrospective, single-center study to evaluate the impact of aspirin use on disease characteristics and survival in PDAC patients.

The study analyzed data from all consecutively treated PDAC patients over a 6-year period. Operability, Tumor-Node-Metastasis (TNM) stage, and survival endpoints were compared between patients who had used aspirin for 2 or more years prior to their diagnosis (ASA ≥ 2) and those who did not (ASA 0).

A total of 182 patients were included. In the ASA ≥ 2 group, significantly fewer patients had metastatic disease at diagnosis, and a significantly larger proportion presented in the operable stages, compared to the ASA 0 group. No significant differences were observed between the two groups in the T or N stages, overall survival, disease-free survival, or time to progression-free survival.

Although long-term aspirin use did not influence survival endpoints, it was associated with a significantly lower probability of demonstrable distant metastases at diagnosis and a higher rate of resectable disease. This finding warrants further research to explore new therapeutic approaches for the treatment of PDAC.

Cancer is a systemic disease with complications beyond the primary tumor site. Among them, thrombosis is the second leading cause of death in patients with certain cancers (e.g., pancreatic ductal adenocarcinoma [PDAC]) and advanced-stage disease. Here, we demonstrate that pro-thrombotic small extracellular vesicles (sEVs) are secreted by C-X-C motif chemokine 13 (CXCL13)-reprogrammed interstitial macrophages in the non-metastatic lung microenvironment of multiple cancers, a niche that we define as the pro-thrombotic niche (PTN). These sEVs package clustered integrin β2 that dimerizes with integrin αX and interacts with platelet-bound glycoprotein (GP)Ib to induce platelet aggregation. Blocking integrin β2 decreases both sEV-induced thrombosis and lung metastasis. Importantly, sEV-β2 levels are elevated in the plasma of PDAC patients prior to thrombotic events compared with patients with no history of thrombosis. We show that lung PTN establishment is a systemic consequence of cancer progression and identify sEV-β2 as a prognostic biomarker of thrombosis risk as well as a target to prevent thrombosis and metastasis.

This review examines the current evidence and management strategies for stable coronary artery disease (CAD) and acute coronary syndrome (ACS) in patients with cancer. We outline the unique challenges, optimal treatment approaches, and outcomes in this growing population.

First-line medications for CAD management are consistently underutilized in cancer patients despite serving as standard of care. As a corollary, medical optimization in CAD management in general is less likely to occur in patients with cancer. Early invasive strategies in ACS show improved survival, yet cancer patients receive percutaneous coronary intervention less frequently than non-cancer patients. Optimization of medical management should be prioritized in stable CAD; revascularization with PCI is first line for most patients presenting with ACS. Modification of risk factors contributing to both CAD and cancer is of utmost importance. Cancer survivors should receive vigilant, long-term monitoring for the development of signs of CAD.

Acetylsalicylic acid (ASA), commonly known as aspirin, is an organic compound with the formula C9H8O4 obtained from the natural compound salicylic acid, recognized for its analgesic, anti-inflammatory, antipyretic, and anticancer properties. Its role in medicine and plant biology is well-established, but its emerging potential in cancer treatment has garnered increased attention. This review aims to provide a comprehensive overview of the therapeutic applications of ASA as an anticancer agent, focusing on its mechanisms, effectiveness, and role as an adjuvant therapy, preventive compound, and radioprotective agent. Recent research papers, including mechanistic studies, preclinical investigations, and clinical trials related to the effects of ASA on various cancer types, were reviewed. The review places particular emphasis on the enhancement of traditional chemotherapy drugs by ASA and considers toxicological aspects. The analysis of recent studies highlights the potential of ASA to improve the effectiveness of chemotherapy and its role in cancer inhibition through specific molecular pathways. Mechanistic insights suggest that ASA may influence cellular processes that contribute to cancer growth suppression and increased sensitivity to conventional treatments. ASA exhibits promising potential as an adjunct therapy in cancer treatment, with evidence supporting its benefits in improving therapeutic outcomes when used alongside conventional chemotherapy. Further studies are needed to clarify its mechanisms and ensure its safe and effective application in clinical settings.

Aspirin is a simple, globally available medication that has been shown to reduce the incidence of colorectal cancer. We aimed to evaluate the safety and efficacy of aspirin in the secondary prevention of colorectal cancer.

This phase 3, randomised, double-blind, placebo-controlled trial was conducted at 66 centres across 11 countries and territories (ten in Asia-Pacific; one in the Middle East). The trial included patients aged 18 years and older with Dukes' C or high-risk Dukes' B colon cancer or Dukes' B or C rectal cancer who had undergone resection and had completed standard adjuvant therapy (at least 3 months of chemotherapy). Patients with contraindications to aspirin, familial syndromes of colorectal cancer, recent other cancers, and clinically significant history of cardiovascular disease or stroke were excluded. Patients were randomly assigned (1:1) to aspirin 200 mg daily or placebo for 3 years, and were followed up for 5 years. Randomisation was stratified by study centre, tumour site and stage, and inclusion of oxaliplatin in adjuvant chemotherapy. The patients, study team, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival. The primary analysis used a stratified Cox model in those commencing study treatment (modified intention-to-treat population), analysing all events to March 31, 2023. Safety was analysed in the same population. This trial is registered at ClinicalTrials.gov (NCT00565708). The primary analysis has been completed, but translational studies of putative aspirin sensitivity biomarkers are ongoing.

Between Feb 25, 2009, and June 30, 2021, 1587 patients underwent randomisation, of whom 1550 were included in the modified intention-to-treat analysis: 791 (51%) in the aspirin group and 759 (49%) in the placebo group. Of these patients, the median age was 57 years (IQR 48-65); 897 (58%) were male and 653 (42%) female; 271 (17%) had Dukes' B colon cancer, 770 (50%) Dukes' C colon cancer, and 509 (33%) rectal cancer. Median follow-up at data cutoff was 59·2 months (IQR 36·7-60·0). 5-year disease-free survival was 77·0% (95% CI 73·6-80·0) in the aspirin group and 74·8% (71·3-77·9) in the placebo group (hazard ratio of 0·91 [95% CI 0·73-1·13]; p=0·38). Any-grade adverse events were reported in 390 (49%) of 791 patients in the aspirin group versus 386 (51%) of 759 in the placebo group. Serious adverse events were reported in 95 (12%) patients in the aspirin group versus 107 (14%) in the placebo group. There were no treatment-related deaths in either group. Among adverse events of special interest, there were no cases of acute myocardial infarction in the aspirin group versus two in the placebo group; no ischaemic cerebrovascular events in the aspirin group versus two in the placebo group; and three major gastrointestinal bleeds in the aspirin group versus one in the placebo group.

In patients with colorectal cancer, aspirin 200 mg daily for 3 years after completion of standard adjuvant therapy was well tolerated but did not significantly improve disease-free survival.

SingHealth Foundation, National Medical Research Council Singapore, National Cancer Centre Research Fund, Rising Tide Foundation, Lee Foundation, Lee Kim Tah Foundation, Duke-NUS Khoo Bridge Funding Award, Terry-Fox Run, Silent Foundation, Cancer Australia, Bowel Cancer Australia, and Cancer Council NSW.

Aspirin, a non-steroidal anti-inflammatory drug (NSAID), has garnered significant attention for its anti-cancer potential. This review explores the pharmacological properties, chemical dynamics, and evolving therapeutic applications of aspirin, with an emphasis on its integration into advanced cancer therapies. Aspirin demonstrates broad-spectrum efficacy across diverse cancer types by modulating signaling pathways such as COX-dependent and COX-independent mechanisms, including Wnt, NF-κB, β-catenin/TCF, and IL-6/STAT3. Recent advancements highlight the role of nanotechnology in enhancing aspirin's targeted delivery, therapeutic effectiveness, and patient outcomes. Nanoparticle-based formulations, including liposomes, solid lipid nanoparticles, and mesoporous silica nanoparticles, offer improved solubility, stability, and bioavailability, enabling controlled drug release and tumor-specific targeting. These innovations reduce systemic toxicity and enhance therapeutic effects, paving the way for aspirin's integration into personalized cancer treatments. Ongoing clinical studies reinforce its safety profile, underscoring aspirin's role in cancer pharmacotherapy. This review calls for continued research into aspirin's repurposing in combination therapies and novel delivery systems to maximize its therapeutic potential.

Metastasis is the major cause of thyroid cancer morbidity and mortality. However, the mechanisms are still poorly understood.

We performed genome-wide transcriptome analysis comparing gene expression profile of metastatic thyroid cancer cells (Met) with primary tumor cells established from transgenic mouse models of papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC).

Genes involved in tumor microenvironment (TME), inflammation, and immune escape were significantly overexpressed in Met cells. Notably, IL-6-mediated inflammatory and PD-L1 pathways were highly active in Met cells with increased secretion of pro-inflammatory and pro-metastatic cytokines such as CCL2, CCL11, IL5, IL6, and CXCL5. Furthermore, Met cells showed robust overexpression of Tbxas1, a thromboxane A synthase 1 gene that catalyzes the conversion of prostaglandin H2 to thromboxane A2 (TXA2), a potent inducer of platelet aggregation. Application of aspirin, a TXA2 inhibitor, significantly reduced lung metastases. Mertk, a member of the TAM (Tyro, Axl, Mertk) family of RTKs, was also overexpressed in Met cells, which led to increased MAPK activation, epithelial-mesenchymal transition (EMT), and enrichment of cancer stem cells. Braf-mutant Met cells developed resistance to BRAFV600E inhibitor PLX4720, but remained sensitive to β-catenin inhibitor PKF118-310.

We have identified several overexpressed genes/pathways in thyroid cancer metastasis, making them attractive therapeutic targets. Given the complexity of metastasis involving multiple pathways (PD-L1, Mertk, IL6, COX-1/Tbxas1-TXA2), simultaneously targeting more than one of these pathways may be warranted to achieve better therapeutic effect for metastatic thyroid cancer.

Aspirin [1], also known as acetylsalicylic acid, is a common non-steroidal anti-inflammatory drug (NSAID). The available evidence shows that aspirin can effectively prevent and treat diseases such as rectal, gastric, ovarian, prostate, and lung cancer. Aspirin has been extensively studied for the prevention and treatment of colorectal cancer. In recent years, studies have found that the potential mechanism of aspirin in the prevention and treatment of cancer may lie in immune regulation, the role of DNA repair pathways, the regulation of cell metabolism, anti-inflammatory effects and antiplatelet effects.

It is widely accepted that cancer mostly arises from random spontaneous mutations triggered by environmental factors. Our theory challenges the idea of the random somatic mutation theory (SMT). The SMT does not fit well with Charles Darwin's theory of evolution in that the same relatively few mutations would occur so frequently and that these mutations would lead to death rather than survival of the fittest. However, it would fit well under the theory of evolution, if we were to look at it from the vantage point of pathogens and their supporting microbial communities colonizing humans and mutating host cells for their own benefit, as it does give them an evolutionary advantage and they are capable of selecting genes to mutate and of inserting their own DNA or RNA into hosts. In this article, we provide evidence that tumors are actually complex microbial communities composed of various microorganisms living within biofilms encapsulated by a hard matrix; that these microorganisms are what cause the genetic mutations seen in cancer and control angiogenesis; that these pathogens spread by hiding in tumor cells and M2 or M2-like macrophages and other phagocytic immune cells and traveling inside them to distant sites camouflaged by platelets, which they also reprogram, and prepare the distant site for metastasis; that risk factors for cancer are sources of energy that pathogens are able to utilize; and that, in accordance with our previous unifying theory of disease, pathogens utilize melanin for energy for building and sustaining tumors and metastasis. We propose a paradigm shift in our understanding of what cancer is, and, thereby, a different trajectory for avenues of treatment and prevention.

The association between aspirin and hepatocellular carcinoma (HCC) has been reported to prevent carcinogenesis caused by hepatitis B or C virus infection. The objective of this study was to investigate the prognostic impact of aspirin in patients who underwent liver resection for HCC.

Data for 1032 patients who underwent primary resection for HCC between 2000 and 2019 were reviewed. There were 87 patients (8.4%) who took aspirin (aspirin group) and 945 (91.6%) who did not (non-aspirin group). Short-term outcomes, recurrence-free survival (RFS), and overall survival (OS) were compared between two groups in the matched cohort using propensity-score matching.

The median patient follow-up was 42.6 months (95% confidence interval 3.12-136.8 months). There was no significant difference in short-term outcomes, including bleeding events. RFS and OS after liver resection in the aspirin group were significantly better than those in the non-aspirin group in the unmatched cohort [5-year RFS rate: 50.3% vs 31.4%, hazard ratio (HR) 0.55, P = 0.0002; 5-year OS rate: 82.9% vs 70.2%, HR 0.46, P = 0.002]. In the matched cohort, RFS and OS after liver resection in the aspirin group were also significantly better than those in the non-aspirin group (5-year RFS rate: 50.3% vs 32.0%, HR 0.60, P = 0.003; 5-year OS rate: 82.9% vs 74.6%, HR 0.56, P = 0.03).

Use of aspirin was associated with better prognosis for patients who underwent primary resection for HCC.

Background: Breast cancer is a leading cause of cancer-related mortality in women. Aspirin, an affordable anti-inflammatory drug, may have anticancer effects, but its impact on survival outcomes after breast cancer diagnosis remains unclear. This meta-analysis evaluates the role of post-diagnostic aspirin use in breast cancer management. Methods: A systematic review and meta-analysis were conducted using PubMed, EMBASE, and Cochrane Library databases. Twenty studies involving 141,251 participants were included. Survival outcomes assessed were disease-free survival (DFS), overall survival (OS), and breast cancer-specific mortality. Trial sequential analysis (TSA) was used to evaluate the sufficiency of cumulative evidence. Results: Post-diagnostic aspirin use was not significantly associated with DFS (HR: 0.88; 95% CI: 0.69-1.11) or OS (HR: 0.89; 95% CI: 0.74-1.07). However, a significant reduction in breast cancer-specific mortality was observed (HR: 0.77; 95% CI: 0.63-0.93). TSA confirmed that the evidence supporting this association is sufficient. Conclusions: Post-diagnostic aspirin use significantly reduces breast cancer-specific mortality, but it does not improve DFS or OS. These findings underscore the potential therapeutic role of aspirin in breast cancer management. Further randomized controlled trials are needed to validate these results and determine optimal dosing regimens for post-diagnostic use.

Inflammation is strongly linked to cancer and is essential for the growth and development of tumors. Targeting inflammation and the mediators involved in the inflammatory process could therefore provide a suitable method for cancer prevention and therapy. Numerous studies have shown that inflammation can predispose tumors. Non-steroidal anti-inflammatory drugs (NSAIDs) can affect the tumor microenvironment through increasing apoptosis and chemo-sensitivity while decreasing cell migration. Since the development of novel drugs requires a significant amount of money and time and poses a significant challenge for drug discovery, there has been a recent increase in interest in drug repositioning or repurposing. The growing body of research suggests that drug repurposing is essential for the quicker and less expensive development of anticancer therapies. In order to set the course for potential future repositioning of NSAIDs for clinical deployment in the treatment of cancer, the antiproliferative activity of derivatives of Indomethacin and Naproxen as well as their mechanism of action and structural activity relationships (SARs) published in the time frame from 2017 to 2024 are summarized in this review.

Cervical cancer ranks as the fourth most common and fatal cancer among women worldwide. Studies have demonstrated a strong association between purinergic platelet signaling and tumor progression in this type of cancer. The literature shows that neoplastic cells, when in the bloodstream, secrete adenosine triphosphate (ATP) and adenosine nucleotide diphosphate (ADP) that act on their corresponding platelet P2Y and P2X receptors. The interaction of these nucleotides with their receptors results in platelet activation and degranulation, ensuing several consequences, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, matrix metalloproteinases, ADP, and ATP. These molecules play essential roles in angiogenesis and tumor metastasis in cervical cancer. Several purinergic receptors are found in endothelial cells. Their activation, especially P2Y2, by the nucleotides released by platelets can induce relaxation of the endothelial barrier and consequent extravasation of tumor cells, promoting the development of metastases. Cancer cells that enter the bloodstream during the metastatic process are also subject to high shear stress and immune surveillance. In this context, activated platelets bind to circulating tumor cells and protect them against shear stress and the host's immune system, especially against natural killer cells, facilitating their spread throughout the body. Furthermore, activation of the P2Y12 receptor present on the platelet surface promotes the release of VEGF, the main inducer of angiogenesis in cervical cancer, in addition to increasing the concentration of several other pro-angiogenic molecules. Therefore, this review will address the role of platelet purinergic signaling in tumor progression of cervical cancer and propose possible therapeutic targets.

Previous studies have reported inconsistent associations between platelet count (PLT) and cancer survival. However, whether there is linear causal effect merits in-depth investigations. We conducted a cohort study using the UK Biobank and a two-sample Mendelian randomization (MR) analysis. PLT levels were measured prior to cancer diagnosis. We adopted overall survival (OS) as the primary outcome. Cox models were utilized to estimate the effects of PLTs on survival outcomes at multiple lag times for cancer diagnosis. We employed 34 genetic variants as PLT proxies for MR analysis. Linear and non-linear effects were modeled. Prognostic effects of gene expression harboring the instrumental variants were also investigated. A total of 65 471 cancer patients were included. We identified a significant association between elevated PLTs (per 100 × 109/L) and inferior OS (HR: 1.07; 95% CI: 1.04-1.10; p < .001). Similar significant associations were observed for several cancer types. We further observed a U-shaped relationship between PLTs and cancer survival (p < .001). Our MR analysis found null evidence to support a causal association between PLTs and overall cancer survival (HR: 1.000; 95% CI: 0.998-1.001; p = .678), although non-linear MR analysis unveiled a potential greater detrimental effect at lower PLT range. Expression of eleven PLT-related genes were associated with cancer survival. Early detection of escalated PLTs indicated possible occult cancer development and inferior subsequent survival outcomes. The observed associations could potentially be non-linear. However, PLT is less likely to be a promising therapeutic target.

Platelets (PLTs) facilitate tumor progression and the spread of metastasis. They also interact with cancer cells in various cancer types. Furthermore, PLTs form complexes with gastric cancer (GC) cells via direct contact and promote their malignant behaviors. The objective of the present study was to explore the molecular mechanisms driving these interactions and to evaluate the potential for preventing peritoneal dissemination by inhibiting PLT activation in GC cells. The present study examined the roles of PLT activation pathways in the increased malignancy of GC cells facilitated by PLT-cancer cells. Transforming growth factor-β receptor kinase inhibitor (TRKI), Src family kinase inhibitor (PP2) and Syk inhibitor (R406) were used to identify the molecules influencing these interactions. Their therapeutic effects were verified via cell experiments and validated using a mouse GC peritoneal dissemination model. Notably, only the PLT activation pathway-related inhibitors TRKI and PP2, but not R406, inhibited the PLT-enhanced migration and invasion of GC cells. In vivo analyses revealed that PLT-enhanced peritoneal dissemination was suppressed by PP2. Overall, the present study revealed the important role of the Srk family in the interactions between PLTs and GC cells, suggesting kinase inhibitors as promising therapeutic agents to mitigate the progression of peritoneal metastasis in patients with GC.

In cancer, activation of platelets by tumor cells is critical to disease progression. Development of precise antiplatelet targeting may improve outcomes from anticancer therapy. Alongside a distinct shift in functionality such as pro-metastatic and pro-coagulant properties, platelet production is often accelerated significantly early in carcinogenesis and the cancer-associated thrombocytosis increases the risk of metastasis formation and thromboembolic events. Tumor-activated platelets facilitate the proliferation of migrating tumor cells and shield them from immune surveillance and physical stress during circulation. Additionally, platelet-tumor cell interactions promote tumor cell intravasation, intravascular arrest, and extravasation through a repertoire of adhesion molecules, growth factors and angiogenic factors. Particularly, the presence of circulating tumor cell (CTC) clusters in association with platelets is a negative prognostic indicator. The contribution of platelets to the metastatic process is an area of intense investigation and this review provides an overview of the advances in understanding platelet-tumor cell interactions and their contribution to disease progression. Also, we review the potential of targeting platelets to interfere with the metastatic process.

Despite the success of anti-programmed cell death-1 (anti-PD-1) immunotherapy, many cancer patients remain unresponsive, and reliable predictive biomarkers are lacking. Here, we show that aberrant expression of the pyrimidinergic receptor P2RY6 is frequent in human cancers and causes immune evasion. In mouse syngeneic and human xenograft tumor models, ectopic expression of P2RY6 shapes an immunosuppressive tumor microenvironment (TME) to enhance tumor growth and resistance to immunotherapy, whereas deletion of P2RY6 from tumors with high P2RY6 expression inflames the TME to inhibit tumor growth. As a G protein-coupled receptor, P2RY6 activates Gq/phospholipase C-β signaling and stimulates the synthesis of prostaglandin E2, which is a key mediator of immunosuppression in the TME. In contrast to the essential role of P2RY6 in tumors, global deletion of P2ry6 from mice does not compromise viability. Our study thus nominates P2RY6 as a precision immunotherapy target for patients with high tumor-intrinsic P2RY6 expression.

Based on a wealth of evidence, aspirin is one of the cornerstones of secondary prevention of cardiovascular disease. However, despite several studies showing efficacy also in primary prevention, an unopposed excess risk of bleeding leading to a very thin safety margin is evident in subjects without a clear acute cardiovascular event. Overall, the variability in recommendations from different scientific societies for aspirin use in primary prevention is a classic example of failure of simple risk stratification models based on competing risks (atherothrombosis vs. bleeding), perceived to be opposed but intertwined at the pathophysiological level. Notably, cardiovascular risk is dynamic in nature and cannot be accurately captured by scores, which do not always consider risk enhancers. Furthermore, the widespread use of other potent medications in primary prevention, such as lipid-lowering and anti-hypertensive drugs, might be reducing the benefit of aspirin in recent trials. Some authors, drawing from specific pathophysiological data, have suggested that specific subgroups might benefit more from aspirin. This includes patients with diabetes and those with obesity; sex-based differences are considered as well. Moreover, molecular analysis of platelet reactivity has been proposed. A beneficial effect of aspirin has also been demonstrated for the prevention of cancer, especially colorectal. This review explores evidence and controversies concerning the use of aspirin in primary prevention, considering new perspectives in order to provide a comprehensive individualized approach.

To examine the association between low-dose aspirin use and risk of colorectal cancer (CRC).

In this nationwide cohort study, we identified individuals aged 50 years or older residing for 6 months or more in Norway in 2004-2018 and obtained data from national registers on drug prescriptions, cancer occurrence, and sociodemographic factors. Multivariable Cox regression models were used to estimate the association between low-dose aspirin use and CRC risk. In addition, we calculated the number of CRC potentially averted by low-dose aspirin use.

We included 2,186,390 individuals. During the median follow-up of 10.9 years, 579,196 (26.5%) used low-dose aspirin, and 38,577 (1.8%) were diagnosed with CRC. Current use of aspirin vs never use was associated with lower CRC risk (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.84-0.90). The association was more pronounced for metastatic CRC (HR 0.79; 95% CI 0.74-0.84) than regionally advanced (HR 0.89; 95% CI 0.85-0.92) and localized CRC (HR 0.93; 95% CI 0.87-1.00; P heterogeneity = 0.001). A significant trend was found between duration of current use and CRC risk: HR 0.91 (95% CI 0.86-0.95) for <3 years, HR 0.85 (0.80-0.91) for ≥3 and <5 years, and HR 0.84 (0.80-0.88) for ≥5 years of use vs never use ( P trend < 0.001). For past use, HR were 0.89 (95% CI 0.84-0.94) for <3 years, 0.90 (0.83-0.99) for ≥3 and <5 years, and 0.98 (0.91-1.06) for ≥5 years since last use vs never use ( P -trend < 0.001). We estimated that aspirin use averted 1,073 cases of CRC (95% CI 818-1,338) in the study period.

In this nationwide cohort, use of low-dose aspirin was associated with a lower risk of CRC.

Studies have demonstrated the influence of immunity and inflammation on the development of tumors. Although single biomarkers of immunity and inflammation have been shown to be clinically predictive, the use of biomarkers integrating both to predict prognosis in patients with gastric cancer remains to be investigated.

To investigate the prognostic and clinical significance of inflammatory biomarkers and lymphocytes in patients undergoing surgical treatment for gastric cancer.

Univariate COX regression analysis was performed to identify potential prognostic factors for patients with gastric cancer undergoing surgical treatment. Least absolute shrinkage and selection operator-COX (LASSO-COX) regression analysis was performed to integrate these factors and formulate a new prognostic immunoinflammatory index (PII). The correlation between PII and clinical characteristics was statistically analyzed. Nomograms incorporating the PII score were devised and validated based on the time-dependent area under the curve and decision curve analysis.

Patients exhibiting elevated neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and systemic immune inflammatory index displayed inferior progression-free survival (PFS) and overall survival (OS). Conversely, low levels of CD3(+), CD3(+) CD8(+), CD4(+)CD8(+), and CD3(+)CD16(+)CD56(+) T lymphocytes were associated with improved PFS and OS, while high CD19(+) T lymphocyte levels were linked to worse PFS and OS. The PII score demonstrated associations with tumor characteristics (primary tumor site and tumor size), establishing itself as an independent prognostic factor for both PFS and OS. Time-dependent area under the curve and decision curve analysis affirmed the effectiveness of the PII-based nomogram as a robust prognostic predictive model.

PII may be a reliable predictor of prognosis in patients with gastric cancer undergoing surgical treatment, and it offers insights into cancer-related immune-inflammatory responses, with potential significance in clinical practice.

Portal vein tumor thrombosis (PVTT) is one of the hallmarks of advanced Hepatocellular carcinoma (HCC). Platelet (PLT) function parameters and CD8+T cells (CD8+Ts) play an important role in HCC progression and metastasis. This study is committed to establishing an efficient prognosis prediction model and exploring the combined effect of PLT and CD8+Ts on PVTT prognosis.

This retrospective study collected 932 HCC patients with PVTT from 2007 to 2017 and randomly divided them into a training cohort (n = 656) and a validation cohort (n = 276). We performed multivariable Cox and Elastic-net regression analysis, constructed a nomogram and used Kaplan-Meier survival curves to compare overall survival and progression-free survival rates in different substrata. Relationships between indicators involved were also analyzed.

We found tumor number, size, treatment, PLT, γ-glutamyl transferase, alpha-fetoprotein, mean platelet volume, and CD8+Ts were related to the 5-year OS of patients with PVTT, and established a nomogram. The area under the receiver operating characteristic curve (AUCs) for predicting the 1-year OS rates were 0.767 and 0.794 in training and validation cohorts. The calibration curve and decision curve indicated its predictive consistency and strong clinical utility. We also found those with low PLT (<100*10^9/L) and high CD8+Ts (>320 cells/μL) had a better prognosis.

We established a well-performing prognostic model for PVTT based on platelet functional parameters and CD8+Ts, and found that PT-8 formed by PLT and CD8+Ts was an excellent predictor of the prognosis of PVTT.

Observational studies of survivors of breast cancer and prospective trials of aspirin for cardiovascular disease suggest improved breast cancer survival among aspirin users, but prospective studies of aspirin to prevent breast cancer recurrence are lacking.

To determine whether aspirin decreases the risk of invasive cancer events among survivors of breast cancer.

A011502, a phase 3, randomized, placebo-controlled, double-blind trial conducted in the United States and Canada with 3020 participants who had high-risk nonmetastatic breast cancer, enrolled participants from 534 sites from January 6, 2017, through December 4, 2020, with follow-up to March 4, 2023.

Participants were randomized (stratified for hormone receptor status [positive vs negative], body mass index [≤30 vs >30], stage II vs III, and time since diagnosis [<18 vs ≥18 months]) to receive 300 mg of aspirin (n = 1510) or placebo once daily (n = 1510) for 5 years.

The primary outcome was invasive disease-free survival. Overall survival was a key secondary outcome.

A total of 3020 participants were randomized when the data and safety monitoring committee recommended suspending the study at the first interim analysis because the hazard ratio had crossed the prespecified futility bound. By median follow-up of 33.8 months (range, 0.1-72.6 months), 253 invasive disease-free survival events were observed (141 in the aspirin group and 112 in the placebo group), yielding a hazard ratio of 1.27 (95% CI, 0.99-1.63; P = .06). All invasive disease-free survival events, including death, invasive progression (both distant and locoregional), and new primary events, were numerically higher in the aspirin group, although the differences were not statistically significant. There was no difference in overall survival (hazard ratio, 1.19; 95% CI, 0.82-1.72). Rates of grades 3 and 4 adverse events were similar in both groups.

Among participants with high-risk nonmetastatic breast cancer, daily aspirin therapy did not improve risk of breast cancer recurrence or survival in early follow-up. Despite its promise and wide availability, aspirin should not be recommended as an adjuvant breast cancer treatment.

ClinicalTrials.gov Identifier: NCT02927249.