Murine Models of Obesity-Related Cancer Risk

Abstract

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.

Figure 1.

Obesity and metabolic dysregulation in cancer risk. The processes of tumor initiation, promotion, progression, and metastasis are goverened by many factors, including hormones, adipokines, microbiome, cytokines, and chemokines, as well as metabolites. Dynamic changes in various cancer-associated factors are being studied for impacts on the process of tumor initiation, with the goal to identify biomarkers of risk and progression which highlight the relationship between risk factors and cancer initiation. Biomarkers and mediators discussed in this review include genomic instability and DNA damage, oxidative stress, activation of oncogenes or oncogenic signaling pathways, loss of tumor suppressors, metabolic advantages, inflammation, immunosuppression and antitumor immunity, and oxidative stress. CRP, C-reactive protein. [Created in BioRender. Hayes, L. (2025). https://BioRender.com/peqf8md.]