Exercise reduces colorectal cancer risk, but its protective mechanisms in early carcinogenesis remain unclear. Male C57BL/6 mice (n = 10/group) were used in two experimental designs: (i) an acute molecular and epigenetic study to evaluate early changes 8h and 24h after a single Azoxymethane (AOM) dose; and (ii) a chronic carcinogenic model to assess the biological efficacy of exercise timing on premalignant lesions (Aberrant and mucin-depleted foci) after 6 weeks of AOM exposure. In both, mice underwent a 6-week progressive swimming protocol initiated either before (preconditioning) or concurrent with AOM. We demonstrate that 6-week exercise preconditioning, rather than concurrent training, conferred protection against mucin-depleted foci incidence (P = 0.03). Mechanistically, exercise preconditioning remodeled colon tissue to resist genotoxic stress, evidenced by an accelerated normalization of DNA repair kinetics (Mgmt expression returned to baseline by 24h vs sustained elevation in the AOM non-exercised group, P = 0.002). Exercise preconditioning also induced colon-specific epigenetic reprogramming, including Mgmt promoter hypermethylation (27% increase, P = 0.0043) and 3-fold reduction in expression of the mutagenic deaminase Apobec3 (P < 0.0001). These molecular changes occurred without altering global LINE-1 methylation or body composition, suggesting targeted tissue adaptation rather than systemic effects. These results demonstrate that exercise preconditioning, not concurrent training, provides colon preneoplastic prevention by enhancing DNA repair efficiency and suppressing Apobec3, a key driver of genomic instability and chronic mutational signatures, during the critical window of carcinogen attack.

Changes in lipid metabolism have been associated with the development of colorectal cancer (CRC), and they may serve as diagnostic markers to identify patients who have developed colorectal neoplasia. This study aimed to identify such biomarkers using untargeted lipidomics. Lipidomics were performed in serum from a racially diverse series of CRC cases and controls from Chicago and Tucson. In addition, enzymatic activity of secretory acid sphingomyelinase (aSMase; S-SMase) was measured in samples from the Tucson CRC series, and two series of adenoma patients. Untargeted lipidomics in the Chicago CRC series revealed significant alterations in sphingolipids. Targeted lipidomics revealed a robust signature of five sphingomyelins (SMs) that were significantly decreased in Chicago CRC patients compared to controls and were validated in the Tucson series. S-SMase activity, which degrades serum SMs, was elevated in CRC cases (0.13 ± 0.10 Cer/SM UACC CRC cases vs. 0.05 ± 0.04 Cer/SM controls; p<0.0001). In mostly white adenoma patients from Tucson, serum S-SMase activity could predict the presence of colorectal neoplasia (0.13 ± 0.07 Cer/SM in UACC adenoma cases vs. 0.03 ± 0.02 Cer/SM in controls; p<0.0001). However, S-SMase activity was not significantly different in Black adenoma patients from Chicago compared to controls. Together, these studies demonstrate for the first time the potential for S-SMase activity to serve as a biomarker for colorectal neoplasia in specific populations.

Early-onset colorectal cancer (EOCRC), defined as colorectal cancer in individuals under 50 years old, is a growing global epidemic, with incidence and mortality rates steadily increasing over the past several decades. Although EOCRC has been linked to established colorectal cancer risk factors, its underlying causes remain poorly understood. We propose that EOCRC may result from exposure to environmental factors, collectively known as the exposome, that have increased globally across EOCRC birth cohorts. Based on our current knowledge of EOCRC, the use of antibiotics is a potential exposome that may increase the risk for EOCRC. We hypothesized that exposure to antibiotics alters the gut microbiota resulting in dysbiosis that promotes inflammation in the distal colon and rectum, leading to increased risk of developing EOCRC. To test this, we examined the effects of repeated exposure to two commonly prescribed classes of pediatric antibiotics on gut microbiome composition, colonic inflammation, and tumor development following exposure to a carcinogen in a mouse model of EOCRC. A/J mice were subjected to multiple rounds of antibiotics followed by treatment with azoxymethane (AOM) to initiate tumor development, and assessment of colon tumor development. Antibiotic treatment induced dysbiosis and both local and systemic inflammation. Subsequent exposure to AOM showed that the two classes of antibiotics had different effects on tumor development in the distal colon and influenced the risk for EOCRC development in different ways.

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.

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.

Air pollution remains a global public health challenge, with nearly the entire global population (99%) breathing air that exceeds World Health Organization guideline limits-annual means of 5 μg/m3 for PM2.5 and 15 μg/m3 for PM10. Both household and ambient air pollution are classified as Group 1 carcinogens and contain hazardous components, including polycyclic aromatic hydrocarbons, heavy metals, and volatile organic compounds. Exposure contributes to a broad spectrum of systemic diseases and is responsible for more than 14% of global lung cancer deaths while also elevating risks for breast, gastrointestinal, and brain cancers. Mechanistically, air pollutants drive early lung carcinogenesis through intrinsic genomic instability, manifesting as DNA damage, telomere dysfunction, mitochondrial impairment, and specific mutational signatures, alongside epigenetic dysregulation. Concurrently, they foster a tumor-promoting niche via chronic inflammation mediated by CXCL13 and IL-1β and facilitate early immune evasion through activation of the PD-L1 and CD47-SIRPα axes. In addition, air pollution disrupts the respiratory-gut microbiome, reducing microbial diversity and promoting pathogenic enrichment. A range of early biomarkers-including genomic, epigenomic, inflammatory, and microbiome profiles-have been validated for preventive interventions, with multimarker combinations demonstrating improved efficacy. Multiple chemopreventive targets have also been identified to counteract oxidative stress, inflammation, and immune evasion. Looking ahead, research priorities should include exploring gene-environment interactions, clinically validating biomarkers and therapeutic targets, translating basic discoveries into clinical practice, and developing precision prevention strategies for high-risk populations. Ultimately, integrating biomarker-guided early detection with multi-target chemoprevention will be essential to reducing the global burden of air pollution-induced early-onset lung cancer.

The incidence of early-onset cancers (diagnosis before 50 years of age) has been steadily increasing globally, presenting a significant public health challenge. While genetic predispositions play a role, most cancers cannot be traced to heritable components. Furthermore, the rapid rise in the incidence rates of these cancers strongly suggests the influence of environmental factors that constitute the "exposome." This perspective article integrates recent findings linking climate change and broader planetary health challenges to pervasive inflammation in the development of chronic diseases, especially cancer. We propose that the complex interplay of anthropogenic climate change, biodiversity loss, environmental degradation, disruption of ecological systems, exposure to environmental pathogens and toxins, industrialized food systems, and consumption of suboptimal, proinflammatory diets containing high concentrations of ultra-processed foods, creates a procarcinogenic exposome that may be particularly important during critical developmental windows, leading to increased susceptibility to carcinogenesis relatively early in life. Framed through a planetary health perspective, this article synthesizes evidence on how large-scale ecological disruption alters the human exposome and contributes to chronic inflammation, metabolic dysregulation, immune dysfunction, and cellular damage, all recognized drivers of cancer development. Although our primary focus is on early-onset cancers, many of these mechanisms are relevant across the cancer continuum and may influence carcinogenesis throughout the life course. We highlight the need for transdisciplinary research and integrated solutions that address both individual behaviors and systemic environmental and policy changes to mitigate the growing burden of early-onset cancers.

Environmental exposures, such as per-and polyfluoroalkyl substances (PFAS), are suspected to play a role in the significant increase in incidence of some early-onset cancers. PFAS are chemicals of concern due to their persistence in the environment, long biological half-lives, and potential carcinogenic properties. Exposure during sensitive windows of development may exert durable effects on cancer-related biological pathways leading to greater risks of early-onset cancers. This review summarizes the current evidence of PFAS exposure and early-onset carcinogenesis, with an emphasis on potential exposure routes, early-onset cancer development in humans linked with PFAS exposure, and mechanistic pathways. Emerging evidence supports a potential role for PFAS exposure in carcinogenesis during early life, particularly through prenatal and early postnatal windows of susceptibility. While epidemiologic studies increasingly link PFAS to several types of cancer, the evidence specifically addressing early-onset cancers remains limited and heterogeneous. Future research should prioritize prospective, longitudinal cohort studies with repeated exposure measurements spanning prenatal, infancy, and childhood periods, coupled with long-term follow-up into early adulthood to capture early-onset cancer outcomes.

Although most common cancers occur in adulthood, evidence supports that the etiological relevant time period for many cancers can often extend into childhood and adolescence. This fact is especially noteworthy given the recent rise in early-onset cancers, generally defined as cancers before age 50. Two factors could contribute to strong early life influences on cancer. First, an organ may have a specific susceptibility to irreversible genetic damage from exposure at an early life stage. Second, cells with genetic damage established earlier in life will have sufficient time available to transform into cancer because many cancers require multiple decades to fully develop after initiation, and cancers from cell initiated later in life may be averted by competing causes of death. This paper reviews the main types of evidence supporting that both reasons why early-life exposures are likely to be important. First, a brief summary of the multistage process of cancer is provided, followed by insights from the initiation-promotion model of cancer, and then evidence that some tissues may be especially prone to carcinogenic damage at early ages. The review then ends with some emerging data supporting that lifestyle exposures act primarily during adolescence for breast cancer (especially premenopausal/early onset breast cancer) because of greater carcinogenic susceptibility of breast tissue during this time period; in contrast, for colorectal cancer, lifestyle factors are operative throughout life, but early life is particularly important because early tissue damage allows longer time for cancers (especially early-onset colorectal cancer) to have sufficient time to develop.

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.