Abstract 4234: Effects of age-diet interactions on colorectal cancer (CRC) progression in mice
Authors: Lo Jae Ho , Soni Shivani , Yang Yan , Smbatyan Goar , Wan Junxiang , Millstein Joshua , Yen Kelvin , Mehta Hemal H. , Miller Brendan , Battaglin Francesca , Mittal Pooja , Gonzalez Lesly Torres , Zhang Wu , Cohen Pinchas , Lenz Heinz Josef 
Published: April 2023

Abstract
Background. CRC is the third leading cause of cancer related deaths worldwide with age and diet are among the strongest risk factors. CRC characteristics appear to be distinct between younger and older patients. We evaluated the effects of age on CRC tumor biology using syngeneic mice models with a focus on a) specific differences in tumor growth patterns and the role of the tumor microenvironment (TME) in young versus old mice harboring CRC allografts; b) differential dietary effects in young versus old hosts.
Methods. 1 × 106 MC38 cells were subcutaneously implanted into the right flank of young (6 weeks) or old (24 months) C57BL/6 male mice. Mice were randomized into 3 diet groups: A. Standard Chow (SC); B. Calorie Restriction (CR: 30% reduction in total calories); C. High Fat (HF). Parameters studied were daily food intake, body weight, tumor growth and survival. Once endpoint reached, tumors were isolated and processed for RNA sequencing. Cytokine analysis was done on plasma using multiplex immunoassays on the Meso Scale Discovery platform.
Results. Both old and young mice showed significant reduction in tumor growth while on the CR protocol when compared to other dietary groups. Young mice fed with HF diet had increased tumor growth as compared to old. Cytokine analysis showed that the pro tumorigenic IFNγ, TNF α, IL10, IL-12p70, and 1L6 were higher in old mice relative to young. Caloric restriction irrespective of age led to significant reductions in IFNγ, TNFα, and 1L6 compared to other diets. Irrespective of diet, IL10, known for its immunosuppressive role in CRC, was significantly lower in young versus old mice. Proinflammatory IL-5 was significantly higher in young fed a HF diet compared to the other groups. RNA sequencing of the allograft tumors at the end of the study revealed that differentially expressed genes (DEGs) between young and old mice tumors were dramatically influenced by diet. The most affected gene expression pathways were antigen processing and presentation, MHC-II complex assembly and T cell activation. Diet affected the tumor expression of key oncogenes associated with immune escape, cell proliferation, invasion, metastasis, chemotaxis, ECM remodeling and chemosensitivity which were upregulated in old mice and HF diet.
Conclusion. Based on transcriptomic profiles and comprehensive cytokine analysis, our data shows that age-diet interactions significantly influence the host TME leading to differential gene expression in the tumor. Our findings will advance current understanding of the mechanisms by which aging and diet impact CRC onset, progression, metastasis, and therapeutic response but warrants further investigation.
Citation Format: Jae Ho Lo, Shivani Soni, Yan Yang, Goar Smbatyan, Junxiang Wan, Joshua Millstein, Kelvin Yen, Hemal H. Mehta, Brendan Miller, Francesca Battaglin, Pooja Mittal, Lesly Torres Gonzalez, Wu Zhang, Pinchas Cohen, Heinz Josef Lenz. Effects of age-diet interactions on colorectal cancer (CRC) progression in mice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4234.