Search Results (1,284)

Clear-cell renal cell carcinoma (ccRCC) accounts for the majority of kidney cancer diagnoses and exhibits widely variable clinical behaviour. The dataset described here was generated to support the discovery of robust biomarkers of tumour cell-cycle arrest and to inform the risk-stratified management of ccRCC. We assembled four independent cohorts including 480 patients from the UK arm of the SORCE adjuvant trial, 300 patients from a surgically treated series in Korea, 120 patients from a retrospective Scottish cohort, and a paired primary–metastatic cohort comprising 62 patients. Formalin-fixed paraffin-embedded nephrectomy specimens were processed for routine hematoxylin and eosin (H&E) histology, and for multiplex immunofluorescence (mIF). The mIF panels detect the cyclin-dependent kinase inhibitor p21^CDKN1a, the DNA replication licencing factor MCM2, endoglin/CD105, Lamin B1 and nuclear DNA (Hoechst). Whole-slide images (WSIs) were acquired at high resolution, and artificial-intelligence pipelines were used to segment nuclei, classify individual cells into arrested phenotypes, and calculate the fraction of cells. Accompanying metadata include demographics, tumour stage, grade, Leibovich score, treatment arm (sorafenib/placebo), relapse events, and disease-free survival. All images and derived tables are released under a CC0 licence via the BioImage Archive, ensuring unrestricted reuse. This multi-cohort dataset provides a rich resource for studying cell-cycle arrest and proliferation markers, training image-analysis algorithms, and developing prognostic signatures in RCC. Full article

This review describes the immunosuppressive effect of secreted phosphoprotein 1 (SPP1)+ tumor-associated macrophages (TAMs) in coordinating the tumor microenvironment (TME) as a functionally unique myeloid cell subgroup. SPP1+ TAMs transcend the traditional M1/M2 paradigm and represent a group of cells that are widely found in various cancer types. SPP1+ TAMs have the characteristics of high expression of SPP1 and promoting immune escape, matrix remodeling and metastasis. We clarify the dual developmental source of SPP1+ TAMs, and introduce the activation process of SPP1+ TAMs through recruitment, polarization and epigenetic locking. After SPP1+ TAMs are activated, they are strategically enriched in the tumor core and tumor marginal area to play their functions. Functionally, SPP1+ TAMs mainly promote the progression of tumors through three mechanisms: (1) Interacting with cancer-associated fibroblasts (CAFs): constructing an immunoexcluded fibrotic niche; (2) Multiple regulation of immune cells; (3) Promoting tumor metastasis and the construction of pre-metastatic niche (PMN). Overall, this review aims to provide a comprehensive overview of the mechanisms mediated by SPP1+ TAMs in the TME, and emphasize their unique role in cancer progression. At the same time, the treatment strategies targeting them are further explored, highlighting their potential as precise therapeutic targets for tumor treatment. Full article

A group of experts of different specialties involved in the care of prostate cancer (PCa) patients participated in the ENFOCA2 project, promoted by the Spanish Oncology Genitourinary Group (SOGUG), with the aim to review, discuss, and summarize current relevant aspects related to screening, diagnosis, imaging, risk-based approach, and molecular characterization of PCa. A multidisciplinary team (MDT) approach is essential to ensure that patients receive evidence-based care, promoting shared decision-making, and tailoring treatment to the patient’s unique values and preferences. Population-based screening based on risk-stratified algorithms is needed to overcome the limitations of opportunistic screening for detecting clinically significant PCa. Next-generation imaging (NGI) methods, such as prostate-specific membrane antigen (PSMA) PET/CT alone or combined with multiparametric MRI (mpMRI), have a promising role in different scenarios of the diagnostic process due to their high sensitivity. The diagnostic yield of mpMRI should be improved, especially for assessing extraprostatic extension. The use of specific molecular probes as imaging markers for MRI could improve the staging of metastatic disease. Protocols for germline testing developed by international societies, such as the European Association of Urology (EAU) and the National Comprehensive Cancer Network (NCCN), should be adapted at local levels, with BRCA1/2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2, EPCAM, and HOXB13 as the genes to be investigated. Genomic classifier tools help identifying aggressiveness of cancers and aid in personalized treatment decision-making. Joint efforts of multidisciplinary physicians are crucial to improve health outcomes for patients with PCa across the spectrum of this disease. Full article

Liver cancer, also known as hepatocellular carcinoma (HCC), remains a major global health concern, with high mortality driven by late-stage diagnosis, limited treatment efficacy, and frequent therapeutic resistance. Matrix metalloproteinases (MMPs), a large family of zinc-dependent endopeptidases, are central to the biological processes that drive liver tumor initiation and progression. By degrading and reorganizing extracellular matrix components, MMPs facilitate tumor expansion, tissue invasion, and metastatic dissemination. In addition, these enzymes regulate the availability of growth factors, cytokines, and chemokines, thereby influencing angiogenesis, inflammation, immune cell recruitment, and the development of an immunosuppressive tumor microenvironment. Aberrant expression or activity of multiple MMP family members is consistently associated with aggressive clinicopathologic features, including vascular invasion, increased metastatic potential, and reduced patient survival, highlighting their promise as prognostic markers and actionable therapeutic targets. Past attempts to modulate MMP activity were hindered by broad inhibition profiles and dose-limiting toxicities, underscoring the need for improved specificity and delivery strategies. Recent advances in molecular design, biologics engineering, and nanotechnology have revitalized interest in MMP targeting by enabling more selective, context-dependent modulation of proteolytic activity. Preclinical studies demonstrate that carefully tuned MMP inhibition can limit tumor invasion, enhance anti-angiogenic responses, and potentially improve the efficacy of existing systemic therapies, including immuno-oncology agents. This review synthesizes current knowledge on the multifaceted roles of MMPs in HCC pathobiology and evaluates emerging therapeutic strategies that may finally unlock the clinical potential of targeting these proteases. Full article

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of the MET proto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, including MET gene amplification, transcriptional upregulation of MET or HGF, MET fusion genes, and MET exon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC. Full article

Calcium deposition within soft tissues is a significant pathological process, bearing significant implications for animal and human health. It is classified into four categories, including dystrophic, metastatic, idiopathic, and iatrogenic. It involves multiple molecular mechanisms. Vascular calcification includes medial artery mineralization, siderocalcinosis in equine cerebral arteries, and vitamin D-induced arterial mineralization in multiple species. Renal and urinary mineralization occurs with kidney disease, uremic gastropathy, and ethylene glycol toxicity. Calcinosis cutis is associated with renal insufficiency and systemic fungal infections and is commonly observed in dogs with hyperadrenocorticism, while calcinosis circumscripta occurs at pressure points secondarily to trauma. Multiple pathogens are responsible for soft tissue calcification; they can be zoonotic and include Mycobacterium spp., Brucella spp., Toxoplasma gondii, and Echinococcus granulosus, underscoring the translational role of veterinary medicine surveillance from a public health standpoint. In addition, the placental chorioallantois is frequently affected by idiopathic or infection-induced calcification, highlighting the convergence of metabolic dysregulation and infectious mechanisms. Tissue calcifications provide valuable insights into disease mechanisms and diagnostic challenges, with comparative pathology serving as a powerful tool to enhance our understanding of these processes from a One Health standpoint. Full article

Background/Objectives: Brain metastases (BM) are a major challenge in the treatment of non-small cell lung cancer (NSCLC), particularly among patients with anaplastic lymphoma kinase rearrangements (ALK+ NSCLC), where incidence can reach up to 60% during the course of the disease. This study used in silico systems biology and artificial intelligence-based modeling to investigate the mechanistic effects of brigatinib, a second-generation ALK inhibitor, on metastatic processes in both primary tumors (PT) and established BM. Methods: We applied the Therapeutic Performance Mapping System (TPMS) technology, which integrates systems biology and artificial intelligence, to simulate the impact of brigatinib on metastasis-associated pathways in PT and BM of ALK+ NSCLC patients. Results: In these simulations, brigatinib was predicted to modulate a broad set of proteins implicated in metastasis in both PT and BM, acting mainly through IGF1R, EGFR, FLT3, and ROS1, in addition to its known target ALK. Conclusions: These results suggest brigatinib’s potential to impact key pathways involved in metastatic progression and intracranial disease control. Overall, this study provides insights into brigatinib’s multifaceted role in targeting metastatic processes in ALK+ NSCLC, underscoring its potential benefits in both PT and BM. Nonetheless, further experimental and clinical studies would confirm our results and the potential of in silico models reported here. Full article

Uveal melanoma (UVM) is a rare cancer that represents the second most common melanoma (after the cutaneous) and the most common primary intraocular malignancy in adults. Despite recent advances in the understanding of UVM pathogenesis, its prognosis remains unchanged, with half of patients dying because of liver metastasis. Erythropoietin-producing human hepatocellular receptors (EPHs) constitute the largest known family of tyrosine receptors, and, along with their ligands, EFNs, regulate key physiological processes and are implicated in cancer pathogenesis. In this study, we used open-access web bioinformatics platforms to explore and analyze big datasets provided by The Cancer Genome Atlas (TCGA) UVM cohort of patients. We profiled the genomic alterations present in a subset of UVM patients, highlighting a likely pathogenic deep deletion of EPHA7. Survival analysis showed that overexpression levels of EPHA4, EPHA5, EPHA8, EPHB2, and EFNB2 are significantly associated with poor overall survival. Additionally, high expression levels of EPHA4, EPHA5, EPHA7, EPHA8, EPHB2, EFNA2, and EFNB2 correlate with reduced progression-free interval and disease-free survival. Finally, we identified the EPHs (EPHA2, EPHA4, EPHA8, and EPHB4) and EFNs (EFNA1, EFNA3, EFNA4, and EFNB2) that are significantly overexpressed in the aggressive epithelioid histological subtype and revealed that the majority of EPHs/EFNs are overexpressed in metastatic disease. In conclusion, our results highlight that a subset of EPHs and EFNs may be associated with worse clinical outcomes (EPHA4, EPHA5, EPHA7, EPHA8, EPHB2, EFNA2, and EFNB2), and an aggressive histological subtype (EPHA2, EPHA4, EPHA8, EPHB4, EFNA1, EFNA3, EFNA4, and EFNB2). The potential correlation of these genes with clinicopathological parameters of UVM need to be evaluated and validated with bioinformatic and experimental approaches in well-characterized cohorts of UVM patients. Full article

Background/Objectives: Peritoneal carcinomatosis is the leading cause of death in advanced ovarian cancer (AOC). Mesothelial cells lining the peritoneum modulate tumor implantation, yet the role of their apoptosis in metastasis development remains unclear. This study investigated the relationship between mesothelial cell apoptosis and metastatic spread in ovarian cancer (OC). Methods: The study included 26 patients with AOC, 11 with early-stage OC (EOC), and 13 healthy controls. Apoptotic activity in parietal peritoneal wall and omental mesothelial cells was assessed using the TUNEL technique. Metastases were classified as pushing or infiltrating. Associations with the peritoneal cancer index (PCI), BRCA mutation, and homologous recombination deficiency (HRD) status were analyzed. Results: Mesothelial cells adjacent to AOC metastases exhibited significantly higher apoptotic activity compared to controls (p < 0.05). Apoptosis was greater near infiltrating metastases than near pushing ones in both parietal (p < 0.01) and omental (p = 0.04) sites. The infiltration pattern was consistent between omental and parietal metastases (R = 0.588, p < 0.01). No significant differences in apoptosis were found between EOC and healthy controls, or in tumor and stromal cells between invasion types. Mesothelial apoptosis was independent of PCI, BRCA mutation, and HRD status. Conclusions: Our study suggests that mesothelial cell apoptosis may be associated with peritoneal spread in OC. Mesothelial cell apoptosis is more pronounced near infiltrative-type lesions, independent of BRCA/HRD status. These findings highlight mesothelial apoptosis as a relevant process in peritoneal dissemination. Further studies are needed to clarify its role in ovarian cancer progression. Full article

The PICO framework determines the scope of the Joint Clinical Assessment (JCA) under the EU HTA Regulation (EU HTAR), with PICO consolidation being a critical final step of the scoping process. Due to limited clarity on how consolidation works in practice, Health Technology Developers (HTDs) may simulate PICO scoping as a strategic tool to guide the development of robust JCA submissions. A review of 14 publications, representing 35 individual PICO exercises across 20 indications (74% in oncology), showed an average of 7 countries participating per exercise and 8 consolidated PICOs per analysis. A separate PICO scoping simulation focused on a first-line immuno-oncology treatment for metastatic non-small cell lung cancer (mNSCLC) generated 67 PICOs, reflecting the anticipated perspectives of 25 countries, largely driven by biomarker and histology-based sub-populations. The limited number of published examples and country participation restricts the ability to draw clear conclusions or confidently predict the output of PICO scoping in a real life JCA processes. The simulation also raised questions about whether all sub-populations should be included or consolidated further. Overall, there is a need for greater clarity in the JCA PICO scoping process, in particular the consolidation step, to facilitate high-quality evidence generation and support the EU HTAR to meet its goals of efficiency, transparency, and equity in health technology evaluation across Europe, along with more consistent patient access. Full article

Background/Objectives: Colorectal cancer (CRC) is the third most commonly occurring cancer. Apoptosis is a fundamental cellular process of programmed cell death, and although many pathways for inducing apoptosis may exist, only the intrinsic and the extrinsic pathways have been demonstrated in detail. This study investigated the expression of BAD, BID, BCL2, MDM2, p53, Ki-67, and PUMA in primary CRC, paired lymph node metastases, and adjacent normal mucosa and explored their associations with clinicopathologic features and patient outcomes. Methods: One hundred thirty patients who underwent surgery for resectable CRC were included in the study. FFPE tumor tissue samples were prospectively collected and used for the construction of the TMA blocks from the primary tumor, paired lymph node metastasis, and paired normal mucosa. Immunohistochemistry for BAD, BID, BCL2, MDM2, p53, Ki-67, and PUMA antibodies was performed. Results: Univariate analysis showed reduced cancer-specific (CSS), disease-free (DFS), and overall survival (OS) in patients with lymphatic invasion, ≥4 positive lymph nodes, poorly differentiated tumors, older age (≥65), right-sided tumors, stage IIIC disease, or no chemotherapy. Multivariate analysis identified lymphovascular invasion, ≥4 metastatic nodes, and high Ki-67 as independent predictors of worse DFS and CSS, with low BAD expression additionally predicting DFS. For OS, adverse predictors included nodal burden, tumor location, absence of chemotherapy, and high p53, MDM2, and Ki-67 expression. Notably, combined high PUMA and low p53 expression independently predicted poorer CSS and OS. Conclusions: High expression of PUMA combined with low expression of p53 and a high expression of Ki-67 were independent unfavorable prognostic indicators for both OS and CSS. Further studies are required to clarify the prognostic and therapeutic role of these markers in CRC. Full article

Ferroptosis is an iron-dependent form of regulated cell death (RCD) characterized by intracellular iron homeostasis disruption and lipid peroxide accumulation. It is involved in many pathological processes, including malignant tumors, cardiovascular diseases, inflammatory diseases, and mitochondrial disorders. Cysteine desulfurase (NFS1), a key enzyme in mitochondrial iron-sulfur (Fe-S) cluster biosynthesis, participates in regulating cellular ferroptosis by maintaining Fe-S cluster homeostasis and modulating the ACO1/IRP1 axis, the Xc⁻–glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis, and the p53/STAT signaling pathway. When the function of NFS1 is abnormal, the intracellular free iron level is elevated, followed by reactive oxygen species (ROS) accumulation and lipid peroxidation. NFS1 expression exhibits significant variation across different tissues. Upregulation of NFS1 in tumors can enhance tumor cell resistance to ferroptosis; thus, it can promote tumor growth, drug resistance, and metastatic ability. Conversely, downregulation of NFS1 in cardiomyocytes and neurons exacerbates ferroptosis and causes functional impairment. Here, we systematically review recent advances in the molecular mechanisms of NFS1-mediated ferroptosis and its role in various disease models, intending to clarify key components in the upstream regulatory network of ferroptosis and explore the application value of NFS1 as a potential therapeutic target. The review shows that NFS1 plays an important role in cellular fate regulation, which has significant clinical application potential in the treatment of cancer and interventions for neurological and cardiovascular diseases. Therefore, it can provide a new theoretical basis and research direction for subsequent mechanism research and targeted therapeutic strategy development. Full article

Neutrophil extracellular traps (NETs)—webs of DNA and granular proteins expelled by neutrophils—have been implicated in hepatocellular carcinoma (HCC) progression. NETs promote tumor angiogenesis, facilitate invasion/metastasis, and enable immune evasion. Recent data suggest that perioperative factors, including anesthetic techniques, may modulate NET formation (NETosis), thus potentially influencing oncologic outcomes. We conducted a literature review of experimental and clinical studies on NETosis pathophysiology and involvement in HCC and how anesthetic techniques may modulate NET formation and, implicitly, cancer outcomes. NET biomarkers such as citrullinated histone H3 (CitH3), cell-free DNA (cfDNA), and myeloperoxidase–DNA complexes (MPO-DNA) are elevated in HCC patients and correlate with tumor spread, showing diagnostic and prognostic potential. Perioperative anesthetic choices may influence NET activity and immune function. Regional anesthesia and local anesthetics (e.g., lidocaine infusion) attenuate the surgical stress response and preserve anti-tumor immunity. Notably, lidocaine may modulate NET formation and, in a few studies published so far, was shown to reduce postoperative NET markers and other pro-metastatic factors (MMP-9, VEGF) in cancer surgery. In conclusion, NETosis is a process that is strongly implicated in HCC biology. Data published so far suggest that the clinical significance of NETosis may lie in its potential as a marker for disease evaluation and progression, including during the perioperative period. Preliminary results suggest that lidocaine may have a role in decreasing NETosis. Future large randomized trials are needed to exactly quantify these effects. Targeting NETs may be another way to influence HCC outcomes. Full article

Background: Malignant ovarian tumours are most often detected at an advanced stage, when peritoneal dissemination across abdominal organs is already present. Metastasis in ovarian cancer arises from complex interactions between cancer cells and diverse components of the tumour microenvironment (TME), including extracellular matrix elements, fibroblasts, adipocytes, mesenchymal cells and leukocytes. This dynamic niche drives tumour progression, invasiveness and immunosuppression through cytokine- and chemokine-mediated signalling. A deeper understanding of these interactions may enable targeted modulation of the TME and help limit metastatic spread. Methods: In this study, using immunoenzymatic assays and a computational digital twin—a mechanistic, ODE-based in silico model that replicates key cellular and microenvironmental processes—we investigated whether and how caffeic acid phenethyl ester (CAPE) influences TME activation, cytokine and growth factor levels, and extracellular matrix remodelling. Results: Our findings show that CAPE modulates both pro- and antitumourigenic signalling pathways across immune, stromal and hypoxia-related axes, suggesting its potential to reshape the ovarian cancer microenvironment and improve therapeutic outcomes in this challenging malignancy. Conclusions: Taken together, these results indicate that CAPE may serve as a multifaceted modulator capable of simultaneously targeting tumour cells and their microenvironment, offering a promising avenue for enhancing therapeutic strategies in ovarian cancer. Full article

Prostate cancer (PCa) exhibits a unique propensity to metastasize to bone, where it predominantly generates osteoblastic lesions. The formation of these lesions is a complex and dynamic process driven by reciprocal interactions between tumor cells and the bone microenvironment. Emerging evidence indicates that extracellular vesicles (EVs) play pivotal roles in the establishment of metastatic colonies and disease progression, as well as in local tumor–bone interactions. Through their diverse cargos, including proteins, lipids, and non-coding RNAs, EVs mediate bidirectional communication that regulates osteoclastogenesis, osteoblast activation, and osteocyte function, ultimately reshaping the bone niche to favor tumor growth. Importantly, EVs exhibit dual and context-dependent functions, acting either as promoters or suppressors of malignancy depending on the cellular source and microenvironmental context. These insights highlight EVs not only as mechanistic drivers of PCa bone metastases but also as promising therapeutic targets. Approaches aimed at modulating EV biogenesis, eliminating deleterious EVs, or harnessing EVs as drug delivery vehicles hold significant potential for advancing treatment strategies against PCa bone metastases. Full article