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 wild-type 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. Osteopontin is a multifunctional protein whose importance in exercise-induced muscle regeneration has come to light. For the pediatric muscle cancer, rhabdomyosarcoma, Osteopontin may play a role in the progression of the embryonal subtype of rhabdomyosarcoma.
Abstract Cancer is conventionally defined when malignant transformation can be demonstrated, yet carcinogenesis is increasingly understood as a multistep biological process extending from exposure and tissue response through clonal evolution and, in some individuals, clinically apparent malignancy. The modern exposome provides a framework for considering environmental, endogenous, metabolic, infectious, occupational, and social influences that accumulate and interact across the life course. These influences can converge on chronic inflammation, oxidative stress, immune dysregulation, metabolic dysfunction, genomic instability, and epigenetic remodeling. Importantly, these processes are not specific to cancer and may accompany many chronic diseases. Their relevance to carcinogenesis therefore depends on persistence, tissue context, interaction with inherited and acquired susceptibility, and trajectories that favor clonal selection and malignant progression. This review develops a measurement-centered framework for identifying biological states that may precede clinically detectable cancer. The framework integrates quantitative assessment of tissue physiology, longitudinal biomarkers, genetic and epigenetic information, and external and internal exposure measures. It distinguishes transient physiological variation from persistent biological deviation by emphasizing magnitude, duration, reproducibility, and trajectory rather than isolated abnormal measurements. The proposed approach does not define cancer by a pre-malignant measurement or imply deterministic progression. Instead, it identifies a research pathway in which validated quantitative measurements could characterize biological states, support causal investigation, and permit longitudinal evaluation of preventive interventions before overt malignancy. Translation will require rigorous analytical and clinical validation, causal inference, longitudinal outcome studies, assessment of overdiagnosis and clinical benefit, and demonstration that measurement improves outcomes rather than merely increasing detection.
Abstract 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.
Abstract Early-onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) 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 CRC 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 of 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.
