Search Results (547)

Chemoresistance is a major challenge in the treatment of triple-negative breast cancer (TNBC). Multicellular spheroids are an attractive platform for investigating chemoresistance in TNBC, as they replicate the cues of the tumour microenvironment in vivo. We conducted a comprehensive literature search to summarise the multifactorial and interlinked mechanisms driving chemoresistance in TNBC spheroids. These mechanisms include spatial heterogeneity, hypoxia, extracellular matrix remodelling, tumour–stroma crosstalk, drug efflux, apoptotic resistance, and cancer stem cell signalling. Strategies for overcoming chemoresistance in TNBC spheroids include nanocarrier systems to overcome spatial diffusion limitations, pathway inhibition, and targeting tumour–microenvironment interactions. Despite their advantages, some spheroid models face challenges such as low reproducibility, a lack of heterogeneity, variability in size and shape, limited vascularisation, and constraints in long-term culture. Advanced culturing platforms such as clinostat bioreactors allow for extended culture periods, enabling mature spheroid drug testing. Furthermore, advanced analytical techniques provide spatially resolved spheroid data. These multifactorial and interlinked mechanisms reflect the tumour microenvironment in vivo that spheroids recapitulate, rendering them valuable models for studying chemoresistance. The incorporation of stromal components and advanced analytical workflows will enhance the utility and translational relevance of spheroids as reliable preclinical models for drug discovery in TNBC. Full article

Glioblastoma is the most common and aggressive malignant primary brain tumour. Patients with glioblastoma have a median survival of only around 14.6 months after diagnosis, despite the availability of various conventional multimodal treatments including chemotherapy, radiation therapy, and surgery. Therefore, photodynamic therapy (PDT) has emerged as an advanced, selective and more controlled therapeutic approach, which has minimal systemic toxicity and fewer side effects. PDT is a less invasive therapy that targets all cells or tissues that possess the photosensitizer (PS) itself, without affecting the surrounding healthy tissues. Polymeric NPs (PNPs) as carriers can improve the targeting ability and stability of PSs and co-deliver various anticancer agents to achieve combined cancer therapy. Because of their versatile tuneable features, these PNPs have the capacity to open tight junctions of the blood–brain barrier (BBB), easily transport drugs across the BBB, protect against enzymatic degradation, prolong the systemic circulation, and sustainably release the drug. Conjugated polymer NPs, poly(lactic-co-glycolic acid)-based NPs, lipid–polymer hybrid NPs, and polyethylene-glycolated PNPs have demonstrated great potential in PDT owing to their unique biocompatibility and optical properties. Although the combination of PDT and PNPs has great potential and can provide several benefits over conventional cancer therapies, there are several limitations that are hindering its translation into clinical use. This review aims to summarize the recent advances in the combined use of PNPs and PDT in the case of glioblastoma treatment. By evaluating various types of PDT and PNPs, this review emphasizes how these innovative approaches can play an important role in overcoming glioblastoma-associated critical challenges, including BBB and tumour heterogeneity. Furthermore, this review also discusses the challenges and future directions for PNPs and PDT, which provides insight into the potential solutions to various problems that are hindering their clinical translation in glioblastoma treatment. Full article

Breast cancer is one of the most commonly diagnosed malignant tumours in women worldwide. Although modern medicine has led to advanced diagnostic methods and therapies that allow for increasingly effective treatment, the mechanisms underlying breast cancer development and progression remain the subject of intensive research. In the pathogenesis of this cancer, significant importance is attributed to interactions between tumour cells and the tumour microenvironment, in which soluble immune system mediators—cytokines—play a key role, including IL-21 and IL-22. These interleukins, by modulating the immune response, can both promote and inhibit tumour progression, and analysing their concentrations may prove helpful in diagnosis, disease progression prognosis, and the development of new therapies, including immunotherapy. The aim of this study was to determine the concentrations of IL-21 and IL-22 in a group of patients with invasive cancer, depending on the biological type of the tumour and its malignancy grade. The study involved 60 women with breast cancer and 20 women with benign breast lesions, and the analysis of IL-21 and IL-22 protein concentrations was performed using the enzyme-linked immunosorbent assay (ELISA) method. The analysis shows that the concentrations of IL-21 and IL-22 do not differ significantly depending on the malignancy grade of the tumour. However, a statistically significant negative correlation between the concentrations of IL-21 and IL-22 was observed exclusively in the group of patients with benign breast lesions. Due to the high heterogeneity of breast cancers, further research with a larger study group is necessary to better understand these parameters and possibly apply them clinically in patients with breast cancer. Full article

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is associated with poor prognosis. Despite years of research and improvements in chemotherapy regimens, the 5-year survival rate of PDAC remains dismal. Therapies for PDAC often face resistance owing in large part to an extensive desmoplastic stromal matrix. Modelling PDAC ex vivo to investigate novel therapeutics is challenging due to the complex tumour microenvironment and its heterogeneity in native tumours. Development of novel therapies is needed to improve PDAC survival rates, for which disease models that recapitulate the tumour biology are expected to bear utility. This review focuses on the existing preclinical models for human PDAC and discusses advancements in tissue remodelling to guide translational PDAC research. Further emphasis is placed on photodynamic therapy (PDT) due to the ability of this treatment modality to not only directly kill cancer cells by minimally invasive means, but also to perturb the tumour microenvironment and elicit a post-therapeutic anti-tumour immune response. Accordingly, more complex preclinical models that feature multiple biologically relevant PDAC components are needed to develop translatable PDT regimens in a preclinical setting. Full article

Cancer metabolism is a hallmark of cancer. However, the impact of systemic metabolism and diet on tumour evolution is less understood. This study delves into the role of glucagon, as a component of the pancreatic microenvironment, in regulating features of pancreatic neuroendocrine tumour (pNET) cells and the metabolic remodelling occurring in the presence and absence of glucose. pNET cell lines (BON-1 and QGP-1) and the non-malignant pancreatic α-TC1 cell line were used as models. Results showed that pNET cells responded differently to glucose deprivation than α-TC1 cells. Specifically, pNET cells upregulated the GCGR in the absence of glucose, while α-TC1 cells did so in high-glucose conditions, allowing the glucagon-related pERK1/2 activation under these conditions in pNET cells. Glucagon enhanced cancerous features in pNET BON-1 cells under glucose-deprived and hyperglucagonemia-compatible concentrations. In the α-TC1 cell line, glucagon modulated cell features under high-glucose and physiological glucagon levels. NMR exometabolome analysis revealed differences in metabolic processes based on glucose availability and glucagon stimulation across cell lines, highlighting amino acid metabolism, glycolysis, and gluconeogenesis. The expression of metabolic genes was consistent with these findings. Interestingly, QGP-1 and α-TC1 cells produced glucose in no-glucose conditions, and glucagon upregulated glucose production in α-TC1 cells. This suggests that gluconeogenesis may be beneficial for some pNET subsets, pointing out novel metabolism-based strategies to manage pNETs, as well as a step forward in endocrinology and systemic metabolism. The association between GCGR expression and malignancy and a negative correlation between glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) expression was observed, indicating a biological role of glucagon in pNETs that deserves to be explored. Full article

Background and Objectives: Rectal cancer management increasingly relies on watch-and-wait strategies after neoadjuvant chemoradiotherapy (nCRT). Accurate, non-invasive prediction of pathological complete response (pCR) remains elusive. Emerging evidence suggests that gut-microbiome composition modulates radio-chemosensitivity. We systematically reviewed primary studies that correlated baseline or on-treatment gut-microbiome features with nCRT response in locally advanced rectal cancer (LARC). Methods: MEDLINE, Embase and PubMed were searched from inception to 30 April 2025. Eligibility required (i) prospective or retrospective human studies of LARC, (ii) faecal or mucosal microbiome profiling by 16S, metagenomics, or metatranscriptomics, and (iii) response assessment using tumour-regression grade or pCR. Narrative synthesis and random-effects proportion meta-analysis were performed where data were homogeneous. Results: Twelve studies (n = 1354 unique patients, median sample = 73, range 22–735) met inclusion. Four independent machine-learning models achieved an Area Under the Receiver Operating Characteristic curve AUROC ≥ 0.85 for pCR prediction. Consistently enriched taxa in responders included Lachnospiraceae bacterium, Blautia wexlerae, Roseburia spp., and Intestinimonas butyriciproducens. Non-responders showed over-representation of Fusobacterium nucleatum, Bacteroides fragilis, and Prevotella spp. Two studies linked butyrate-producing modules to radiosensitivity, whereas nucleotide-biosynthesis pathways conferred resistance. Pooled pCR rate in patients with a “butyrate-rich” baseline profile was 44% (95% CI 35–54) versus 21% (95% CI 15–29) in controls (I² = 18%). Conclusions: Despite heterogeneity, convergent functional and taxonomic signals underpin a microbiome-based radiosensitivity axis in LARC. Multi-centre validation cohorts and intervention trials manipulating these taxa, such as prebiotics or live-biotherapeutics, are warranted before clinical deployment. Full article

Systemic cancer progression culminating in metastatic disease is implicitly dependent on tumour cell interactions with the vascular system. Indeed, different facets of the micro- and macro-vasculature can be regarded as rate-limiting ‘vascular checkpoints’ in the process of cancer dissemination. The underlying complex communication networks drive tumour neovascularization, angiogenesis, immunoregulation, activation of the coagulation system, angiocrine interactions, and non-angiogenic vascular responses across multiple cancer types. Yet, each cancer may represent a unique vascular interaction scenario raising a prospect of targeted modulation of blood and lymphatic vessels for therapeutic purposes, beyond the traditional notion of tumour anti-angiogenesis. While the emphasis of studies aiming to understand this circuitry has traditionally been on soluble, or ‘mono-molecular’ mediators, the rise of the particulate secretome encompassing heterogeneous subpopulations of extracellular vesicles (EVs; including exosomes) and particles (EPs) brings another dimension into the tumour–vascular communication web during the process of metastasis. EVs and EPs are nanosized cellular fragments, the unique nature of which lies in their ability to encapsulate, protect and deliver to target cells a range of bioactive molecular entities (proteins, RNA, DNA) assembled in ways that enable them to exert a wide spectrum of biological activities. EVs and EPs penetrate through biological barriers and are capable of intracellular uptake. Their emerging vascular functions in metastatic or infiltrative cancers are exemplified by their roles in pre-metastatic niche formation, thrombosis, vasectasia or angiocrine regulation of cancer stem cells. Here, we survey some of the related evidence supporting the biological, diagnostic and interventional significance of EVs/EPs (EVPs) in disseminated neoplastic disease. Full article

Tumour-associated angiogenesis plays a key role at all stages of cancer development and progression by providing a nutrient supply, promoting the creation of protective niches for therapy-resistant cancer stem cells, and supporting the metastatic cascade. Therapeutic strategies aimed at vascular targeting, including vessel disruption and/or normalisation, have yielded promising but inconsistent results, pointing to the need to set up reliable models dissecting the steps of the angiogenic process, as well as the ways to interfere with them, to improve patients’ outcomes while limiting side effects. Murine models have successfully contributed to both translational and pre-clinical cancer research, but they are time-consuming, expensive, and cannot recapitulate the genetic heterogeneity of cancer inside its native microenvironment. Non-animal technologies (NATs) are rapidly emerging as invaluable human-centric tools to reproduce the complex and dynamic tumour ecosystem, particularly the tumour-associated vasculature. In the present review, we summarise the currently available NATs able to mimic the vascular structure and functions with progressively increasing complexity, starting from two-dimensional static cultures to the more sophisticated tri-dimensional dynamic ones, patient-derived cultures, the perfused engineered microvasculature, and in silico models. We emphasise the added value of a “one health” approach to cancer research, including studies on spontaneously occurring tumours in companion animals devoid of the ethical concerns associated with traditional animal studies. The limitations of the present tools regarding broader use in pre-clinical oncology, and their translational potential in terms of new target identification, drug development, and personalised therapy, are also discussed. Full article

Background: Prehabilitation is increasingly being used in patients undergoing multimodality treatment for oesophagogastric cancer (OGC). Most studies to date have been small, single-centre trials. This collaborative study sought to assess the overall impact of prehabilitation on patient outcomes following OGC surgery. Methods: Data came from four prospective prehabilitation trials conducted in the UK or Ireland in patients undergoing multimodality treatment for OGC. The studies included three randomised and one non-randomised clinical trial, each comparing a prehabilitation intervention group to controls. The prehabilitation interventions included aerobic training delivered by exercise physiologists alongside dietetic input throughout the treatment pathway. The primary outcome was survival (all-cause and disease-specific mortality). Secondary outcomes were differences in complications, cardio-respiratory fitness (changes in VO_{2 peak} and anaerobic threshold (AT)), chemotherapy completion rates, hospital length of stay, changes in body mass index, tumour regression and complication rates of anastomotic leak and pneumonia. Cox and logistic regression analysis provided hazard ratios (HR) and odds ratios (OR), respectively, with 95% confidence intervals (CI), adjusted for confounders. Results: Among 165 patients included, 88 patients were in the prehabilitation group and 77 patients were in the control group. All-cause and disease-specific mortality were not improved by prehabilitation (HR 0.67 95% CI 0.21–2.12 and HR 0.82 95% CI 0.42–1.57, respectively). The prehabilitation group experienced fewer major complications (20% vs. 36%, p = 0.034; adjusted OR of 0.54; 95%CI 0.26–1.13). There was a mitigated decline in VO_2 peak following neo-adjuvant therapy (delta prehabilitation −1.07 mL/kg/min vs. control −2.74 mL/kg/min; p = 0.035) and chemotherapy completion rates were significantly higher following prehabilitation (90% vs. 73%; p = 0.016). Hospital length of stay (10 vs. 12 days, p = 0.402) and neoadjuvant chemotherapy response (Mandard 1–3 41% vs. 35%; p = 0.494) favoured prehabilitation, albeit not statistically significantly. Conclusion: Despite some limitations in terms of heterogeneity of study methodology, this study suggests a number of meaningful clinical benefits from prehabilitation before surgery for OGC patients. Current initiatives to agree on national standards for delivering prehabilitation and the results of ongoing trials will help to further refine this important intervention and expand the evidence base to support the widespread adoption and implementation of prehabilitation programs. Full article

Background: Desmoid fibromatosis (DF) is a rare, locally aggressive soft tissue tumour with unpredictable clinical behaviour. Historically, treatment has involved surgery; however, contemporary guidelines, such as those from the Desmoid Tumour Working Group, advocate active surveillance. This article reviews current perspectives on DF, focusing on epidemiology, pathogenesis, treatment strategies, emerging research directions and cost effectiveness based on our experience at the West of Scotland Musculoskeletal Oncology Service, Glasgow Royal Infirmary (GRI). Methodology: We reviewed 101 patients diagnosed with desmoid fibromatosis between 2010 and 2024. A review of patient records was conducted to gather information on demographics, date of diagnosis, prior treatment, treatment initiation, intervention types, imaging intervals, follow-up duration, recurrence rate for surgery and other intervention, and discharge timelines. All data was systematically organized and analyzed to assess our outcomes. Results: Out of 101 patients with DF in the study, 66% were females. The most common site of primary tumour was lower extremity (39.6%) followed by near equal distribution in upper extremity and trunk. Out of the total cases, 72 (71.2%) were successfully managed with active surveillance involving serial imaging and clinical reviews in accordance with European guidelines. A total of 22 patients (21%) received treatment: 10 underwent surgery alone, 2 had surgery combined with radiotherapy, 8 received only radiotherapy, 1 was treated with hormonal therapy and 1 participated in a trial with Nirogacestat. Of the seven remaining patients, six had unplanned surgery outside followed by active surveillance at GRI. One patient was on alternative treatment modality, homeopathy. The average number of MRI scans per patient was 3.11, with many patients requiring significantly more imaging. MRI surveillance varies significantly in desmoid tumours due to their heterogeneous behaviour. Active or symptomatic tumours often require more frequent scans (every 3–6 months), while stable cases may need only imaging annually or just clinical monitoring. Recurrence was noted in eight patients, all of which were related to prior surgery. The total combined cost of imaging and appointments exceeds £6500 per patient in active surveillance. Conclusions: We conclude that most patients with desmoid fibromatosis in our cohort were effectively treated with active surveillance, consistent with current European guidelines. Surgical management of desmoid fibromatosis in our cohort is historic and has shown a significant recurrence risk. Our study proposes a revised follow-up protocol that significantly reduces costs without compromising on patient care. We suggest a two-year surveillance period for stable disease with patient-initiated return to reduce unnecessary clinic visits, imaging and healthcare costs. Full article

Renal cell carcinoma (RCC) is a major global health issue with an increasing incidence and mortality rate. Current diagnostic methods are either invasive or limited in their ability to accurately differentiate between benign and malignant tumours and to predict early treatment response. This can lead to incorrect diagnosis, delayed treatment, patient anxiety, and suboptimal outcomes. RCC subtypes are known to exhibit distinct metabolic alterations, for example in glucose metabolism. These metabolic phenotypes offer potential targets for non-invasive imaging techniques to improve diagnosis and treatment, but current clinically available metabolic imaging tools such as ¹⁸F-FDG-PET and ^99mTc-sestamibi SPECT have limitations. Therefore, new approaches are required to assess this metabolism, and novel metabolic MRI techniques including hyperpolarised [1-¹³C]pyruvate MRI and deuterium metabolic imaging offer promising alternatives. These techniques are non-radioactive, demonstrate spatial metabolic heterogeneity, and can probe metabolic flux beyond tracer uptake. This review aims to explore the potential of metabolic MRI in the clinical management of RCC by (1) summarising current clinical guidelines; (2) reviewing metabolic heterogeneity across RCC subtypes; (3) discussing the potential of metabolic MRI to advance the understanding of in vivo metabolism; (4) and finally suggesting future directions for research in this field. Full article

Breast cancer remains the most common malignancy in women, yet, many patients fail to achieve full remission despite significant advancements. This is largely due to tumour heterogeneity and the limitations of current experimental models in accurately replicating the complexity of in vivo tumour environment. In this study, we present a compartmentalised alginate hydrogel platform as an innovative in vitro tool for three-dimensional breast cancer cell culture. To mimic the heterogeneity of tumour tissues, we developed a core–shell structure (3.5% alginate core and 2% alginate shell) that mimic the stiffer, denser internal tumour matrix. The human triple-negative breast cancer cell line (MDA-MB-231) was embedded in core–shell alginate gels to assess viability, proliferation and hypoxic activity. Over one week, good cells proliferation and viability was observed, especially in the softer shell. Interestingly, cells within the stiffer core were more positive to hypoxic marker expression (HIF-1α) than those embedded in the shell, confirming the presence of a hypoxic niche, as observed in vivo. When cultured in the MIVO^® milli fluidic organ-on-chip resembling the physiological fluid flow conditions, cancer cells viability became comparable between core and shell hydrogel area, emphasising the importance of the fluid flow in nutrients diffusion within three-dimensional matrixes. Cisplatin chemotherapy treatment further highlighted these differences: under static conditions, cancer cell death was prominent in the softer shell, whereas cells in the stiffer core remained resistant to cisplatin. Conversely, drug diffusion was more homogeneous in the core–shell structured treated in the organ-on-chip, leading to a uniform reduction in cell viability. These findings suggest that integrating a compartmentalised core–shell cell laden alginate model with the millifluidic organ on chip offers a more physiologically relevant experimental approach to deepening cancer cell behaviour and drug response. Full article

Background/Objectives: Laryngeal cancer (LC), predominantly squamous cell carcinoma (SCC), represents a considerable health burden worldwide. Tumour subsite heterogeneity (supraglottic, glottic, subglottic) influences clinical behavior and outcomes. This review synthesizes current knowledge on epidemiology, risk factors, diagnostics, histological variants, biomarkers, treatment modalities, and survival. Results: This narrative review synthesizes current literature on the epidemiology, risk factors, diagnosis, histological variants, biomarkers, and prognosis of LC. The review highlights the critical influence of tumour sites (supraglottic, glottic, subglottic) on metastatic patterns and survival. Key risk factors of LC include tobacco and alcohol use, human papillomavirus (HPV) infection, and occupational exposures. The diagnostic process encompasses clinical examination, endoscopy, biopsy, and imaging. Several biomarkers that aid in diagnosis, treatment plan determination, and prognosis prediction have been established. These biomarkers include long noncoding RNAs, cell cycle regulators, apoptosis regulators, oncogenes, tumour suppressor genes, growth factor pathway components, angiogenic factors, structural proteins, sex hormone receptors, and immunological markers. Current treatment modalities range from organ-preserving surgery and radiotherapy to combined chemoradiotherapy and total laryngectomy. Finally, survival data are presented and stratified by stage and subsite. Conclusions: The review underscores the need for a multidisciplinary approach to LC management, integrating clinical, pathological, and molecular information to optimize patient outcomes. Full article

Objective: This study employed advanced biostatistical methods to investigate Interleukin-6 (IL-6), Tumour Necrosis Factor Alpha (TNF-α), and Myeloperoxidase (MPO) levels in serum and plasma samples from patients with severe osteoarthritis (OA) compared to volunteers. The primary aim was to evaluate the diagnostic potential of these biomarkers and address statistical challenges, including non-normal data distribution and non-aged-matched groups. Design: Using Enzyme-Linked Immunosorbent Assays (ELISAs), IL-6, TNF-α, and MPO concentrations were analysed in 58 OA patients and 28 volunteers. Statistical analyses included Shapiro–Wilk tests to assess normality, a Mann–Whitney U (MWU) test to compare biomarker levels, and sensitivity analyses using Rank-based ANCOVA, and regression models were used to address non-normal data distributions and to validate the findings under adjustments for age and gender. Levene’s test was used to evaluate the homogeneity of variables. Results: Serum TNF-α and plasma MPO were significantly higher in OA patients than in volunteers (p < 0.05), while IL-6 levels were non-significant (p = 0.160). MWU tests confirmed significant differences for TNF-α (p = 0.045) and MPO (p = 0.0001). Sensitivity analysis using Rank-based ANCOVA and regression models confirmed the robustness of these biomarkers, with TNF-α (p = 0.037) and MPO (p = 0.0099) retaining statistical significance after adjusting for covariates. IL-6 remained non-significant across all analyses. Conclusions: TNF-α and MPO emerged as statistically robust biomarkers for severe OA, with the serum samples better reflecting inflammation than plasma. These findings underscore the importance of using advanced biostatistical methods such as Rank-based ANCOVA and regression to validate biomarkers, particularly in heterogenous datasets. Future research should incorporate larger, more diverse cohorts and detailed demographic profiling to explore the early diagnostic potential of these biomarkers and further understand OA progression. Full article

Background/Objectives: CAR T cell therapy, as a rapidly advancing immuno-oncology modality, has achieved significant success in the treatment of leukaemia and lymphoma. However, its application in solid tumours remains limited. The challenges include the heterogeneity of tumours, local immunosuppression, poor trafficking and infiltration, life-threatening toxicity and the lack of precise representative immunocompetent research models. Considering its typically dense and immunosuppressive tumour microenvironment (TME) and early metastasis, pancreatic ductal adenocarcinoma (PDAC) was employed as a model to address the challenges that hinder CAR T cell therapies against solid tumours and to expand immunotherapeutic options for advanced disease. Methods: A novel murine A20FMDV2 (A20) CAR T cell targeting integrin αvβ6 (mA20CART) was developed, demonstrating efficient and specific on-target cytotoxicity. The mA20CART cell as a monotherapy for orthotopic pancreatic cancer in an immunocompetent model demonstrated modest efficacy. Therefore, a novel triple therapy regimen, combining mA20CART cells with oncolytic vaccinia virus encoding IL-21 and a TGF-β-blocking antibody was evaluated in vivo. Results: The triple therapy improved overall survival, improved the safety profile of the CAR T cell therapy, attenuated metastasis and enhanced T cell infiltration. Notably, the potency of mA20CART was dependent on IL-2 supplementation. Conclusions: This study presents an αvβ6-targeting murine CAR T cell, offering a novel approach to developing CAR T cell technologies for solid tumours and a potential adjuvant therapy for pancreatic cancer. Full article