Elizabeth Angela Murphy

Obesity is a well‐established risk factor for numerous cancers, with body habitus, especially central adiposity, contributing to increased cancer incidence and worse prognosis. Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), initially developed to treat Type 2 diabetes, have rapidly gained prominence as powerful anti‐obesity agents due to their ability to induce significant weight loss and potential to improve metabolic health. These medications act by reducing appetite, enhancing insulin sensitivity, lowering systemic inflammation, and preferentially targeting fat mass for reduction. This review explores the growing body of evidence linking GLP‐1 RA therapy to potential changes in cancer risk among individuals with obesity. To date, data suggest that GLP‐1 RAs do not increase overall cancer risk and may reduce the risk of certain obesity‐related cancers, likely by interrupting obesity‐driven metabolic dysregulation. Still, questions remain about the beneficial effects of weight loss and the sustainability of health benefits if weight is regained after stopping treatment. We examine how GLP‐1 RAs' anti‐inflammatory and metabolic effects might mediate reductions in cancer risk, review emerging data regarding both protective signals and specific safety concerns (e.g., increased risk of medullary thyroid carcinoma), and emphasize the critical role of combining pharmacotherapy with lifestyle interventions to maintain muscle mass and long‐term weight loss. Ultimately, given the strong link between obesity and cancer, GLP‐1 RAs represent a promising new class of agents that may not only help to manage obesity but also serve as effective chemopreventive tools against obesity‐associated cancers.

Early-onset cancers (EOCs), defined as cancers diagnosed before the age of 50, are increasing globally. This rise cannot be fully explained by improved detection, suggesting the involvement of evolving environmental and lifestyle-related risk factors. In parallel, the global prevalence of obesity has increased substantially, particularly among younger populations. Obesity is increasingly recognized not simply as excess adiposity, but as a systemic metabolic state characterized by insulin resistance, hyperinsulinemia, chronic low-grade inflammation, altered lipid metabolism, hormonal dysregulation, microbiome disruption, and epigenetic remodeling. These perturbations create a pro-tumorigenic environment that may promote early tumor initiation and progression. Importantly, when metabolic dysfunction arises during critical developmental windows, including in utero, childhood, adolescence, and early adulthood, it may establish long-lasting biological programs that influence growth signaling, immune function, and tissue homeostasis. In this context, increasing attention has shifted toward the “exposome,” defined as the totality of environmental exposures encountered across the lifespan and their interactions with biological susceptibility. These exposures may contribute to obesity-associated metabolic dysfunction and interact with one another to influence cancer risk, underscoring the multifactorial nature of EOC development. In this review, we integrate epidemiologic and mechanistic evidence linking obesity and metabolic dysfunction to EOCs, with a focus on colorectal and breast cancers. We highlight key biological pathways, including metabolic signaling, inflammation, microbiome alterations, endocrine disruption, and epigenetic reprogramming, and discuss emerging strategies for prevention and early risk stratification. Understanding the interplay between metabolic health and the exposome may provide critical insights into the prevention of EOCs in younger populations.

This study identifies panaxynol, a bioactive compound from American ginseng, as a novel therapeutic candidate for chemotherapy-induced intestinal mucositis. In a murine 5-fluorouracil model, panaxynol attenuated mucosal injury, reduced cytopenia, suppressed proinflammatory immune cells, and altered gut microbial community structure. Importantly, panaxynol exhibited sex-dependent effects, with stronger immunological and microbial modulation in males. These findings highlight panaxynol’s pleiotropic protective actions and underscore the importance of sex as a biological variable in mucositis therapeutics.

Objectives: The study aimed to examine the association between a dietary index for gut microbiota (DI-GM) and the risk of incident colorectal cancer (CRC). Clarifying the role of diet-induced alterations in the composition and function of gut microbiota on the development of CRC can contribute to prevention efforts. Methods: Participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial enrolled in the intervention arm and who completed baseline assessments were included in the analysis (n = 55,685). The DI-GM is a literature-derived index used to score diet quality in terms of maintaining healthy gut microbiota. A time-dependent Cox model stratified by follow-up years (adjusted = 0.82, 95% CI: 0.63, 1.07) compared with those with lower diet quality (DI-GM scores below the 67th percentile), though effect estimates were imprecise. During ≥ 5 years of follow-up, there was no association between incident CRC and DI-GM (HR_adjusted = 1.01, 95% CI: 0.80, 1.26). Conclusions: Diet quality measured using the DI-GM was associated with the risk of CRC in the first five years of follow-up in a large prospective cohort study. A diet that enhances the composition and function of gut microbiota may contribute to reduction in CRC risk.

Mixed dementia, most often caused by the coexistence of Alzheimer’s disease and vascular dementia pathologies, presents unique preventive and therapeutic challenges that may be addressed through dietary and nutraceutical interventions. Current evidence demonstrates that diets emphasizing polyphenol-rich foods like olive oil, berries, and leafy greens exert neuroprotective effects by reducing oxidative stress, inflammation, and amyloid pathology while improving cerebrovascular function. Specific bioactive compounds, including resveratrol, curcumin, quercetin, epigallocatechin gallate, N-acetylcysteine, and Huperzine A, among some others, have demonstrated therapeutic potential through their multimodal mechanisms targeting the pathogenic pathways of Alzheimer’s disease and vascular dementia, including Aβ and tau pathology, neuroinflammation, oxidative stress, and neurovascular dysfunction. However, our limited appreciation of the pharmacokinetics and pharmacodynamics of natural compounds and the inadequate extent of clinical studies underscore the need for further research. This review synthesizes current knowledge on diet and nutraceutical compounds that may be of value in the prevention and treatment of mixed Alzheimer’s disease and vascular dementia. We focus on their molecular mechanisms of action relevant to the dual pathophysiological basis of mixed Alzheimer’s disease and vascular dementia.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are inflammatory conditions with substantial rates of morbidity and mortality, but no effective treatments. The lack of effective treatments and unacceptably high mortality rates for ARDS are partly due to an incomplete understanding of the mechanisms that control ALI/ARDS and subsequent vascular repair. Transforming growth factors (TGFs) are a class of growth factors that regulate the vascular response to inflammation, including migration, proliferation, and differentiation of cells comprising the lung vasculature. Here we review studies that describe the impact of the TGF family on inflammatory lung injury and subsequent vascular repair and fibrosis. We highlight gaps in understanding TGF isoform-specific roles in ALI/ARDS and outline directions for future research in the field of TGF-dependent regulation of inflammatory lung injury and vascular repair. Functional roles of the TGFs have been investigated in ALI/ARDS pathogenesis and pulmonary fibrosis, with a predominance for studies showing a proinjurious and profibrotic impact of TGF-β1. Studies have also shown that TGF-α is positively associated with inflammatory lung injury and fibrosis. However, the contributions of TGF-β2 and TGF-β3 to ALI/ARDS are unclear, and the contributions of all the TGF isoforms to vascular repair after ALI/ARDS are not well characterized. Improved understanding of the regulation of inflammatory lung injury and repair by the TGFs could lead to the development of a safe and effective treatment strategy for patients with ALI/ARDS.

We examined the effects of the cannabis plant with high cannabidiol (CBD) content or high Δ⁹-tetrahydrocannabinol (THC) content on metabolic and immune dysregulation in obese mice. Both CBD and THC mitigated the obesity-induced increase in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and metabolic dysfunction-associated steatohepatitis (MASH). Furthermore, the increase in macrophages, in particular M1-like proinflammatory macrophages, in the adipose tissue and liver was rescued by high CBD and high THC.

Skeletal muscle fibrosis contributes to disproportionate muscle weakness with cancer cachexia. Our novel findings demonstrate an inflammatory and profibrotic cachectic muscle microenvironment, demonstrated by increased fibro-adipogenic progenitor cells, neutrophils, and profibrotic macrophages. Using scanning and transmission electron microscopy, we show expansion and thickening of the extracellular matrix within the endomysium and perimysium. We also identified clusters of infiltrating cells localized to regions of excessive ECM deposition, which were not present in weight-stable tumor-bearing controls.

Obesity is a global menace that has impacted more than 14% of adults worldwide and more than a third of Americans. Importantly, obesity is associated with an increased risk of more than 13 types of cancer and worse outcomes, including increased mortality. This review focuses on the importance of considering obesity and metabolic dysfunction in cancer risk as part of the NCI’s funded consortium known as the Metabolic Dysfunction and Cancer Risk Program. It describes previous and ongoing mouse models used in studies conducted by Metabolic Dysfunction and Cancer Risk Program consortium members, as well as other relevant studies. Most cancer studies examine tumor progression, metastasis, or recurrence, which are consequences following tumor onset; however, this approach does not consider risk per se. To truly model cancer risk, parameters to measure include the quantification of cancer onset, measured as incidence or latency. Investigators must be cognizant of many factors in study design, including the choice of cancer model and genetic strain. Preclinical approaches addressing risk typically include genetically engineered mouse models or the administration of irritants or carcinogens. We also discuss the transplantation of cells or tumors such as allografts or xenografts, with a focus on tumor rejection or regression to approximate cancer risk, not cancer progression. Herein, we highlight two cancers, breast and colorectal cancers, in which risk is associated with obesity and discussed varied murine model approaches, as well as key findings that explore cancer risk, prevention, or interception.

The current study aimed to examine the impact of obesity on tumorigenesis and 5FU safety and efficacy with two established murine models of colorectal cancer. Diet-induced obesity increased tumor burden in both models, and 5FU’s antitumor efficacy remained and extended survival with both tumor models. Obese mice demonstrated increased 5FU-induced immune cell cytotoxicity following multiple cycles of 5FU with distinct changes to liver macrophages, suggesting an increased propensity for liver metastasis.