Search Results (253)

Introduction: Radiotracer-based nuclear imaging, including positron emission tomography (PET) and single-photon emission computed tomography (SPECT), can complement conventional cross-sectional imaging in renal cell carcinoma (RCC) by providing biological characterisation of tumour metabolism, angiogenesis, hypoxia, and the tumour microenvironment. While computed tomography (CT) and magnetic resonance imaging (MRI) remain the diagnostic standard, accumulating evidence suggests that selected nuclear imaging techniques may offer incremental value in specific clinical scenarios. Methods: A narrative literature review was performed using PubMed, Embase, and Web of Science to identify preclinical, retrospective, and prospective studies evaluating PET and SPECT radiotracers in localised and metastatic RCC. Priority was given to meta-analyses, multicentre prospective trials, and studies with histopathological correlation. Results: [¹⁸F]fluorodeoxyglucose (FDG) PET/CT demonstrates limited sensitivity for primary renal tumours (pooled sensitivity of approximately 60%) but performs substantially better in metastatic and recurrent disease (pooled sensitivity and specificity of approximately 85–90%), where uptake correlates with tumour grade, progression-free survival, and overall survival. [^99mTc]sestamibi SPECT/CT differentiates oncocytoma and hybrid oncocytic/chromophobe tumours from malignant RCC with pooled sensitivity and specificity of around 85–90%, supporting its role in evaluating indeterminate renal masses rather than staging. Prostate-specific membrane antigen (PSMA) PET/CT shows high detection rates in clear-cell RCC, particularly in metastatic disease, with reported sensitivities of approximately 85–90% and management changes in up to 40–50% of selected cohorts. Carbonic anhydrase IX (CAIX)-targeted PET/CT enables the biologically specific visualisation of clear-cell RCC, achieving sensitivities and specificities in the range of 85–90% in prospective phase II and III trials for primary tumour characterisation. Fibroblast activation protein inhibitor (FAPI) PET/CT demonstrates high tumour-to-background uptake in early RCC studies, but evidence remains preliminary, with small cohorts and recognised non-specific uptake in benign inflammatory and fibrotic conditions. Conclusions: Radiotracer-based nuclear imaging provides complementary, biology-driven insights in RCC that extend beyond anatomical assessment. While most modalities remain adjunctive or investigational and are not recommended for routine use, selective application in carefully chosen clinical scenarios may enhance tumour characterisation, prognostication, and personalised treatment planning. Full article

Background: Suppressor of Cytokine Signalling 6 (SOCS6) is a cytokine signalling suppressor that regulates receptor tyrosine kinase pathways by promoting degradation of signalling proteins, thereby controlling cell growth and survival. One of these tyrosine kinase receptors, Erythropoietin Receptor (EPOR), plays a critical role in CRC progression by enhancing tumour metabolism, angiogenesis, proliferation, and growth. This study investigates the molecular mechanisms governing SOCS6’s role in CRC pathogenesis using in vitro cell models and examines its interaction with EPOR expression following gene knockdown. Methods: Bioinformatics interaction between SOCS6 and EPOR were investigated using molecular visualization. HT-29 and COLO 320DM colorectal cancer cells were transfected with SOCS6 siRNA followed by measurement of SOCS6 and EPOR expression levels by qRT-PCR. The selected knockdown concentration was used in functional assays assessing cell viability, colony formation, migration, apoptosis, and invasion. Results: Bioinformatic results showed interaction between SOCS6 and EPOR through polar bonds. Furthermore, SOCS6 silencing increased cell viability and colony formation in both cell lines and significantly enhanced migration in COLO 320DM cells. Active caspase-3 levels were elevated markedly in HT-29 cells post SOCS6 knockdown, consistent with caspase-3’s reported oncogenic role in CRC. Moreover, EPOR knockdown selectively altered SOCS6 expression in HT-29 cells, indicating a regulatory feedback loop. EPOR silencing elevated cell viability at 24 h in both cell lines but caused a significant decrease in COLO 320DM cells at 72 h. Conclusions: These findings identify the SOCS6–EPOR axis as a potential target for personalized CRC therapy, supporting SOCS6’s tumour-suppressive and diagnostic roles. Full article

Gliomas, particularly glioblastoma multiforme, remain among the most lethal brain tumours despite multimodal therapy. Increasing evidence indicates that systemic factors, including the gut microbiota, may influence glioma progression through immune, metabolic, and neurochemical pathways. We conducted a comprehensive systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines to synthesize recent evidence on the role of gut and intratumoral microbiota in glioma biology. Peer-reviewed studies published within the last five years were identified through structured searches of major biomedical databases, and original studies using human cohorts, animal models, or Mendelian randomization approaches were included. The 17 studies met the eligibility criteria. Glioma was consistently associated with gut dysbiosis characterized by a reduced Firmicutes:Bacteroidetes ratio and enrichment of Verrucomicrobia, particularly Akkermansia, alongside decreased short-chain fatty acids and altered neurotransmitter profiles, contributing to neuroinflammation, immune suppression, and blood–brain barrier dysfunction. Antigenic mimicry by Bacteroidetes-derived peptides may impair antitumour T-cell responses, while intratumoral Fusobacteriota and Proteobacteria appear to promote angiogenesis and pro-inflammatory chemokine expression. In contrast, SCFA-producing taxa such as Ruminococcaceae and probiotic genera including Lactobacillus and Bifidobacterium show protective associations. Evidence is limited by small cohorts and methodological heterogeneity. Standardized humanized models and integrated multi-omics approaches are required to clarify causal mechanisms and support microbiome-targeted therapies in glioma. Full article

The field of nanotechnology has witnessed a paradigm shift towards eco-friendly and sustainable synthesis methods for nanoparticles due to increasing concerns over environmental toxicity and resource sustainability. Among various metal oxide nanoparticles, zirconium dioxide (ZrO₂) nanoparticles have garnered significant attention owing to their exceptional thermal stability, biocompatibility, mechanical strength, and catalytic properties. Doping ZrO₂ with transition metals such as copper (Cu) further enhances its physicochemical attributes, including antibacterial activity, redox behaviour, and electronic properties, rendering it suitable for a diverse range of biomedical and industrial applications. In the present study, we report the green synthesis of copper-doped ZrO₂ nanoparticles (Cu-ZrO₂-CO NPs) using an aqueous extract of Calendula officinalis (marigold) flowers as a natural reducing and stabilizing agent. The complete characterization was performed using UV–vis spectrophotometry, dynamic light scattering (DLS), zeta potential, FTIR, SEM, EDAX, and XRD, revealing its size to be around 20–40 nm and zeta potential as −20 mV, indicating nano size and stability. The biocompatibility of the as-synthesized nanoparticle was analyzed in vitro using fibroblast cell viability and haemolysis assay, and in vivo using brine shrimp assay. The nanoparticles were safe up to a dose of 50 μg/mL, showing more than 95% cell viability and less than 2% haemolysis, which is within an acceptable range. Finally, the anticancer activity was explored for A549 cells by MTT assay and live-dead assay, with an IC50 value of 38.63 μg/mL. The chorioallantoic membrane (CAM) model was used to assess the anti-angiogenesis potential of the Cu-ZrO₂-CO NPs. The results showed that the nanoparticles could kill the cancer cells via apoptosis, and one of the reasons for the anticancer effect was angiogenesis inhibition. Further research is needed using other cancer cell lines and animal tumour models. Full article

Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play a dual role in cancer biology. While the SASP can suppress tumors by facilitating immunosurveillance, it can also promote tumor progression by fostering a pro-inflammatory milieu, stimulating angiogenesis, enhancing invasiveness, and enabling immune evasion. In Head and Neck Cancers (HNCs), a highly heterogeneous group of malignancies, SASP has emerged as a critical player in disease progression and treatment resistance. Persistent DNA damage response (DDR) signaling drives SASP and thereby contributes to the progression of head and neck cancer by modulating the tumour microenvironment. It influences the tumor microenvironment (TME) by facilitating epithelial-to-mesenchymal transition (EMT), promoting cancer stem cell-like properties, and impairing the efficacy of radiotherapy, chemotherapy, and immune checkpoint inhibitors. These effects underscore the need for targeted interventions to regulate SASP activity. This review presents a comprehensive overview of the molecular mechanisms underlying SASP generation and its effects on HNCs. We discuss the dual roles of SASP in tumor suppression and progression, its contribution to therapy resistance, and emerging therapeutic strategies, including novel senolytic and senomorphic drugs. Finally, we highlight key challenges and future directions for translating SASP-targeted therapies into clinical practice, emphasizing the need for biomarker discovery, and a deeper understanding of SASP heterogeneity. By targeting the SASP, there is potential to enhance therapeutic outcomes and improve the management of HNCs. Full article

Proteoglycans (PGs) are highly glycosylated proteins of great importance both structurally and for signalling in the extracellular matrix (ECM) as well as cell surfaces. In breast cancer (BC), they control the structure of tissue architecture, cellular communication pathways and tumour–stroma interactions, thus affecting adhesion, migration, angiogenesis, immune evasion, and metastasis. Their structural heterogeneity supports either subtype- or context-dependent functions. This review combines current studies of PGs in BC according to their classification into intracellular, cell-surface, pericellular, extracellular, and small leucine-rich PGs and a range of non-classical PGs. A literature-driven approach to focus on molecular mechanisms and clinical correlations will demonstrate how PGs respond with collagens, growth factors, cytokines, and proteolytic enzymes in order to modulate the ECM and affect therapy resistance. Indeed, PGs including syndecans, glypicans, perlecan, versican, biglycan and decorin showed the potential to be promoters or suppressors of cancer, with local effects on invasion, and have a significant modulating effect on BC subtypes or the prognosis and therapeutic response and may potentially serve as new biomarkers for stratification and liquid biopsy candidates. Furthermore, PGs appear to modulate the tumour immune landscape, are involved in the development of metastatic niches, and underlie signalling pathways like Wnt or TGFβ in a subtype-dependent manner, extending their translational prospects and therapeutic utility. PGs, taken together, seem to be major modulators of BC, with particular relevance for precision medicine. Full article

Background: Chemoresistance, particularly to cisplatin, remains a significant challenge in treating high-risk neuroblastoma, resulting in a mere 20% five-year overall survival rate. Tumour-derived small extracellular vesicles (sEVs) have been implicated in cancer progression by promoting angiogenesis, invasion, and proliferation in recipient cells. This study investigated alterations in the protein cargo of sEVs secreted by cisplatin-sensitive and resistant neuroblastoma cells and their impact on reprogramming non-cancerous recipient cells. Methods: sEVs from cisplatin-resistant (KellyCis83) and its cisplatin-sensitive parental cell line (Kelly) were isolated and characterised, followed by proteomic profiling and Gene Set Enrichment Analysis. Functional assays using human umbilical vein endothelial cells (HUVECs) evaluated the effects of sEVs on proliferation, migration, tube formation, and metabolism. The clinical relevance of the shortlisted sEV glycolytic proteins was evaluated using the R2 Genomics Analysis and Visualisation Platform. Results: Proteomic analysis revealed dysregulated metabolic pathways in KellyCis83 sEVs. While Kelly’s and KellyCis83’s sEV-induced aerobic glycolytic rates were similar, oxidative phosphorylation (OXPHOS) was significantly reduced in HUVECs treated with Kelly’s sEVs compared to KellyCis83’s sEVs, which might have been due to an altered balance of glycolytic enzymes in sEVs. Under angiogenic-factor-deprived conditions, the uptake of sEVs by HUVECs reduced their proliferation and increased anchorage-dependent differentiation. Our study demonstrated the enrichment of the MYCN oncogene and clinically relevant glycolytic proteins in neuroblastoma cell-derived sEVs. Conclusions: This study reports a potential mechanism by which sEVs derived from cisplatin-resistant neuroblastoma cells modulate endothelial cell function through alterations in metabolic pathways and provides an opportunity to explore exosomal MYCN and glycolytic proteins as circulating biomarkers for progression and treatment response signatures, using less invasive methods and enabling personalised treatment approaches for neuroblastoma patients. Full article

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that has become central to prostate cancer (PCa) diagnostics and treatment. Beyond its enzymatic role in folate and glutamate metabolism, PSMA is upregulated in advanced PCa, where it contributes to angiogenesis, tumour progression, and therapeutic resistance. This review integrates current understanding of PSMA biology with an emphasis on the role of PSMA expression and the hallmarks of cancer-proliferative signalling, metabolic adaptation, and evasion of cell death. While PSMA has revolutionised theranostic strategies in PCa, its utility as a sole biomarker is limited in select cases such as neuroendocrine differentiation and discordant disease biology. To address these challenges, we highlight emerging biomarkers and novel imaging markers that complement PSMA, including genomic alterations, circulating tumour markers, and exosomal microRNAs. Advances in radiomics and dual-tracer positron emission tomography (PET) further refine patient selection by capturing aggressive low-PSMA phenotypes. Furthermore, PSMA-PET is showing promise in other malignancies, including renal cell carcinoma (RCC) and glioblastoma multiforme (GBM), where neovasculature expression may extend its theranostic applications beyond PCa. By situating PSMA within this broader biomarker landscape, we outline opportunities for theranostic integration, including predictive models, combination therapies and expansion into non-prostate malignancies. Understanding the biology of PSMA in conjunction with novel biomarkers provides a framework for optimising theranostic applications and advancing personalised cancer care. Full article

The tumour microenvironment in pancreatic ductal adenocarcinoma (PDA) regulates vascular function and therapeutic response. P21-activated kinases (PAKs) regulate cytoskeletal dynamics and angiogenesis; however, their roles in vascular reprogramming and chemotherapy responses remain unclear. This study examined the effects of a PAK1 knockdown (PAK1KD) and a PAK4 knockout (PAK4KO) on vascular remodelling in PDA. Human PANC-1 wild-type (WT), PAK1KD, and PAK4KO cells were injected subcutaneously into the flanks of SCID mice followed gemcitabine treatment. The tumour growth, vascular density, pericyte coverage, adhesion molecules, and hypoxia were determined. A proteomics study was used to identify the molecular changes involved in the vascular pathways. PAK1KD suppressed tumour growth and angiogenesis, promoted vascular normalisation, reduced hypoxia, and increased stromal ICAM-1. PAK4KO inhibited tumour growth, enlarged vessels, enhanced angiogenesis, and reduced hypoxia. PAK4KO did not affect adhesion molecules in the absence of gemcitabine, but markedly upregulated ICAM-1 and VCAM-1 with gemcitabine. Additionally, PAK4KO promoted vascular mimicry (VM) with a compromised integrity in tumour-derived vessels, but enhanced the integrity in endothelial-derived vessels. The proteomics study confirmed the enrichment of molecules in fibronectin and the VEGF pathway in PAK4KO cancer cells, along with the upregulation of EphA2, RhoA, ROCK1, ROCK2, and components of the EPH-ephrin signalling pathway, linking to enhanced VM. Neither PAK1KD nor PAK4KO increased the gemcitabine efficacy. In conclusion, PAK1KD and PAK4KO suppressed tumour growth with distinct vascular effects, but failed to enhance the gemcitabine responses, suggesting that PAK targeting reprograms the PDA vasculature, but offers limited benefit in chemotherapy-resistant models. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed to treat type 2 diabetes mellitus, are now being investigated as agents in oncology. Recent preclinical studies have demonstrated their antitumor activity in several solid malignancies, including pancreatic, colorectal, breast, and prostate. Importantly, GLP-1 RAs modulate key signalling pathways such as PI3K/Akt, PKA, and AMPK, and exert anti-inflammatory effects by reducing cytokine production and macrophage infiltration. Preclinical data support their antineoplastic activity in vitro and in vivo, particularly by inhibiting tumour growth and metastasis. Nevertheless, there are ongoing concerns about tumorigenic effects in certain cancer types. This review critically examines the molecular mechanisms by which GLP-1 RAs influence cancer cell proliferation, apoptosis, angiogenesis, and inflammation, and emphasizes the need for further clinical studies to determine their therapeutic relevance. It also proposes assessing GLP-1 RAs as adjuncts in the management of solid tumours. Full article

ADAM10 is a transmembrane metalloprotease that regulates diverse signalling functions via the shedding of membrane protein ectodomains, and is implicated in tumour development, including glioblastoma multiforme (GBM) and gastrointestinal (GI) cancers, where high ADAM10 expression is associated with poor prognosis. We assessed the role of ADAM10 by gene knockout (KO) in U251 GBM cells, and its effects on protein shedding and protein expression on cell proliferation and on the growth of tumour xenografts in mice. The growth of tumours was severely delayed, relative to modest effects on proliferation in vitro, suggesting roles particularly in the context of the tumour microenvironment (TME). Proteomics analysis of KO cell-conditioned medium showed decreased levels of known ADAM10 targets such as Notch and Eph receptors and ligands, as well as other proteins involved in cell–cell adhesion, migration, signalling, metabolism, differentiation, and development, including angiogenesis. KO cell and tumour lysate analysis also showed modulation of proteins associated with metabolic and catalytic activity, cell–matrix organisation and differentiation. Similar effects were also observed in the SW620 colon cancer model, indicating broader significance. Furthermore, expression of the associated protein sets also correlated with ADAM10 expression in human GBM and colon cancer specimens (TCGA datasets), indicating clinical relevance. Collagens and proteins associated with matrix deposition and fibril organisation were notably reduced in ADAM10 KO GBM tumours, and histology confirmed decreased collagen fibrils and blood vessels. Unexpectedly, increased chondrocyte differentiation was evident in ADAM10 KO U251 tumours, suggesting a role for ADAM10 in maintaining an undifferentiated phenotype in vivo. Together, our data indicate the importance of ADAM10 in diverse signalling mechanisms in tumours and the TME that promote tumour development. Full article

Background/Objectives: The tumour microenvironment in pancreatic ductal adenocarcinoma (PDA) is highly complex, influencing both vascular function and therapy response. P21-activated kinases (PAKs) are key regulators of the cellular and immune system, but the specific roles of PAK1 and PAK4 in pancreatic tumour vasculature and chemotherapy sensitivity are unclear. This study investigated the effects of PAK1 and PAK4 on tumour vasculature and therapeutic response in an immunocompromised mouse model. Methods: KPC-derived wild type (WT), PAK1 knockout (KO), PAK4KO, or PAK1&4KO pancreatic cancer cells were injected subcutaneously into SCID mice, followed by gemcitabine treatment. Tumour growth, vessel density, pericyte coverage, and endothelial adhesion molecule expression were analysed by histology and immunostaining. A proteomic study was used to identify protein changes. Results: PAK1KO significantly reduced tumour growth, enhanced vascular normalisation, upregulated stromal ICAM-1 and VCAM-1, but reduced gemcitabine efficacy. PAK4KO did not inhibit tumour growth but increased vessel diameter and enhanced gemcitabine efficacy. Proteomics study indicated that PAK1KO downregulated proteins involved in the VEGF pathway, while PAK4KO upregulated most proteins involved in the VEGF pathway and downregulated DNA repair proteins, contributing to improved chemotherapy sensitivity. The double knockout of PAK1 and PAK4 did not inhibit tumour growth, although it stimulated vascular normalisation, indicating an outcome balanced between PAK1 and PAK4. Conclusions: PAK1 and PAK4 differentially regulated pancreatic tumour vasculature and chemotherapy response. PAK1KO suppressed tumour growth by reducing angiogenesis and enhancing vascular normalisation, whereas PAK4KO enhanced gemcitabine efficacy through vessel dilation. Full article

Glioblastoma (GB) is an aggressive brain cancer with high microvascular proliferation. The pathological angiogenesis leads to accelerated tumour invasion and diffused infiltration into the surrounding brain tissues, with a tragically short survival rate. Various transmembrane proteins, which are embedded on the glioblastoma cancer cell surface, interact with diverse extracellular ligands/molecules present in the tumor micro-environment. These ligands play a crucial role in the development, progression, and therapeutic resistance. In the present study, we systematically screened multiple transmembrane protein receptors, and their extracellular ligands involved/implicated in GB cancer cell progression. Additionally, we analyzed the homotypic and heterotypic protein associations within glioblastoma cancer cells to better understand their role in tumor development. Ten well-known and clinically approved GB cancer drugs were selected and retrieved from online databases for molecular docking analyses with extracellular proteins. Among the different ligands analyzed, computational analysis revealed a strong interaction between fibronectin (PDB ID: 3VI4) and the majority of GB surface receptors. Furthermore, molecular docking studies between GB-approved drugs and fibronectin demonstrated the strongest binding interaction with Irinotecan, followed by Etoposide, Vincristine, etc. In conclusion, identification of ligand-drugs interactions provides valuable insights into the mechanisms underlying GB cancer cell development and potential avenues for therapeutic inhibition strategies. Our study demonstrated that Irinotecan, Etoposide, and Vincristine exhibit strong binding interactions with fibronectin, effectively disrupting its interaction with surface receptor(s). Since fibronectin receptor interactions play a crucial role in GB tumor progression, these findings suggest that targeting fibronectin could present a promising strategy to inhibit GB cell proliferation and invasion. Full article

Background: p73, a member of the p53 family of transcription factors, plays important roles in DNA repair, cell proliferation, angiogenesis, invasion, metastasis, immune evasion, and cytotoxic therapy response. The clinicopathological significance of p73 in breast cancer, particularly in the context of TP53 mutation, remains largely unknown. Methods: Clinicopathological significance of p73 and p53 protein expression was evaluated in 1369 invasive BC and 317 ductal carcinomas in situ (DCIS), including in p53 wild-type or p53 mutant tumours. p73 transcripts and splice variants were investigated in breast cancer genomes (TCGA). Results: High cytoplasmic p73 was significantly associated with high tumour grades, high pleomorphism scores, high mitotic scores, high risk Nottingham prognostic index, negative expression of oestrogen receptors (ERs), triple negative phenotypes (all p values ≤ 0.01), and poor breast cancer specific survival (BCSS) (p = 0.013). In TP53 mutant breast cancers, high p73 was significantly associated with aggressive histopathological features (all p ≤ 0.001) and poor BCSS (p = 0.001) but not in p53 wild-type tumours. Conclusions: Cytoplasmic p73 may be a marker of aggressive phenotype and worse prognosis, particularly in p53 mutant breast cancer. p73, in conjunction with altered p53 expression, may be involved in breast cancer pathogenesis. Full article

We review the latest development in non-angiogenic tumours. We focused on the last 3 years except the rarer tumours, for which the papers are older. Following the explanation of the modified hallmark of cancer, inducing angiogenesis and/or accessing vessels, the authors review primary and metastatic tumours growing into lung, liver and brain, plus oral cancer, lymphomas and node metastasis. Also progress in treatment, not many unfortunately, and techniques in non-angiogenic tumours are discussed. Full article