Abstract The 4-nitroquinoline-1-oxide (4NQO) model closely recapitulates oral squamous cell carcinoma (OSCC) progression but is limited by cumulative toxicity in conventional protocols. This study aimed to develop a modified 4NQO regimen with defined carcinogen-free intervals and evaluate the chemopreventive potential of black tea-derived polyphenols. C57BL/6 mice were subjected to conventional and modified 4NQO regimens (50 and 100 ppm). Tumour incidence, multiplicity, and volume were assessed alongside histopathology. Systemic toxicity was monitored using body weight, fluid intake, and serum biochemistry. Chemoprevention was evaluated using thearubigins and decaffeinated extracts (1.5% and 10%) administered during pre- and concurrent intervention phases. Molecular analyses included western blotting and qualitative immunohistochemistry. The modified regimen improved body weight maintenance without compromising tumour incidence or progression. No significant differences in tumour burden were observed between the 50 and 100 ppm groups. Histopathological analysis confirmed the presence of lesions across the disease spectrum in all carcinogen-treated groups. In chemoprevention studies, tumour incidence remained unchanged; however, the 10% decaffeinated extract significantly reduced tumour volume, while thearubigins showed a non-significant trend. Molecular analyses revealed no statistically significant differences, though directional changes were observed. The modified protocol enables defined intervention windows, addressing limitations of continuous carcinogen exposure, and the reduction in tumour volume without changes in incidence suggests an effect on tumour progression rather than initiation. Collectively, the modified 4NQO model provides a robust platform for stage-specific chemoprevention evaluation, with black tea polyphenols, particularly decaffeinated extracts, demonstrating modest progression-modulating effects that warrant further investigation.
Abstract The classification of foods according to their degree of processing, and particularly the concept of ultra-processed foods (UPFs), is relatively new. Consumption of UPFs has increased markedly worldwide in recent decades. Their growing consumption has coincided with a rising global burden of cancer, including marked increases in several cancers diagnosed before age 50 years. In this comprehensive review, we summarize trends in ultra-processed food consumption and the sociodemographic, psychological, and behavioral characteristics associated with higher intake. We further review the epidemiological evidence linking UPFs with cancer incidence and mortality, with particular attention to the limited but emerging evidence relevant to early-onset cancer. Potential mechanisms linking UPFs to cancer include unfavorable nutrient displacement, changes in body composition and fat deposition, and increased exposure to additives, processing byproducts, and other chemicals. These influences may converge on a range of biological pathways, including metabolic dysfunction, chronic inflammation, immune dysregulation, gut microbiome disruption, DNA damage and genomic instability, and epigenetic alterations. Substantial uncertainties remain, including heterogeneous exposure definitions and classification practices, limitations in dietary assessment and temporal exposure capture, residual confounding, and the complexity of putative biological mechanisms. We conclude by highlighting key research challenges and future directions, along with considerations related to policy, regulation, and industry practices.
Abstract Neural regulation of cancer extends beyond anatomical innervation: tumours receive systemic neural and neuroendocrine inputs and locally produce and decode neurotransmitters and neuropeptides. We propose the Tumour Neurotone (TN) as a tumour-level state of neurochemical regulation generated by the combined actions of these signals across malignant, immune, stromal and vascular compartments, shaping proliferative signalling, metabolic adaptation, immune escape, tissue remodelling, dissemination and treatment response. Biologically, a TN state reflects the context-dependent, spatially organised and relatively persistent configuration of neuroactive ligand availability; cell-type-specific signalling competence, including receptors, transporters and metabolic enzymes; proximal pathway engagement; and downstream cellular responses. TN is therefore not synonymous with tumour innervation, nerve density, an instantaneous neurochemical profile, neuroimmune crosstalk or the broader field of cancer neuroscience; it is a narrower state model intended to capture functional organisation beyond any single neurotransmitter pathway. We synthesise evidence across proliferative signalling, metabolic plasticity, immune regulation, sensory–neuropeptide circuits, neural remodelling, bioelectrical communication, vasculo–stromal organisation and circadian timing. Although many constituent mechanisms are causally supported, the existence and predictive value of integrated TN states have not yet been validated clinically. We therefore specify three criteria for assigning a TN state: temporal reproducibility, predictive value beyond individual components and established tumour covariates, and coherent change after targeted perturbation. We also provide a longitudinal experimental workflow, framework-specific predictions and falsification criteria, and an evidence-graded appraisal of neuromodulatory interventions.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma found in children, with distinct biological subtypes. We found that the protein Osteopontin (Ostp) is highly expressed in our genetically engineered mouse models (GEMM) of RMS alveolar and embryonal subtypes. Through GEMM studies and allograft mouse studies we explored how Ostp expression affects the onset and growth of tumors in vivo. Ostp loss in alveolar RMS tumors and the tumor microenvironment of genetically-engineered mice changed the character of the tumors (decreasing multiplicity, decreasing limb predominance, and decreasing tumor stage) without changing tumor-free survival or histological appearance. Similarly, tumor growth rates and metastasis were not different for Ostp expressing and Ostp null tumors in orthotopic allograft studies. Conversely, loss of Ostp expression increased tumor incidence in embryonal RMS GEMMs animals compared to mice on an Ostp wildtype background, although the sample size was small. When combined with the clinical correlation of human Osteopontin gene expression and altered patient survival, Ostp in embryonal RMS may be a topic of further interest and investigation.
Triple-negative breast cancer (TNBC) presents significant clinical challenges due to its aggressive phenotype and the limited availability of molecularly targeted therapies. In this study, we investigated the therapeutic potential of targeting PHB2 in TNBC by combining bioinformatics analysis with comprehensive in vitro and in vivo experiments (CCK-8, colony formation and Transwell migration assays) to evaluate the clinical significance of PHB2 and its role in regulating the malignant phenotypes of TNBC cells. To dissect the underlying molecular circuitry, we measured glycolytic flux through glucose uptake and lactate production assays, mapped transcription-factor occupancy by chromatin immunoprecipitation (ChIP), and assessed promoter activity using dual-luciferase reporters. We demonstrate that elevated PHB2 expression leads to unfavorable prognosis in TNBC. Mechanistically, PHB2 drives glycolytic reprogramming by enhancing FOXM1-mediated transcriptional activation of LDHB, a key enzyme in anaerobic glycolysis. These findings highlight PHB2 as a critical regulator of metabolic adaptation and aggressiveness in TNBC, positioning it as a promising candidate for targeted therapy.
