The impact of diet-induced obesity on 5 fluorouracil-induced tumor and liver immune cell cytotoxicity.

Abstract

Obesity increases the risk for developing several cancers, including colorectal cancer (CRC), and is associated with liver perturbations, which likely impacts treatment tolerance. 5 fluorouracil (5FU) remains a first line treatment for CRC, but efficacy is hampered by interpatient variable responsiveness and off-target toxicities. The current study examined the impact of diet-induced obesity (DIO) on 5FU cytopenia and efficacy using two established CRC models: MC38 (C57BL/6) and C26 (CD2F1). DIO increased tumor size in both MC38 and C26. DIO reduced liver dihydropyrimidine dehydrogenase (dpyd) expression, the enzyme that catalyzes 5FU's catabolism to become inactive, in MC38 mice, but not in C26. 5FU remained efficacious against early MC38 and C26 tumor growth; however, 5FU-induced tumor and liver immune cell death was exacerbated following three cycles of 5FU with MC38. DIO caused dramatic changes to liver Kupffer cells (KCs), wherein there were increased prometastatic, immunosuppressive KCs in Obese Control and MC38. 5FU, however, depleted these KCs and increased inflammatory KCs in both Lean and Obese MC38. DIO yielded a milder obesity phenotype in CD2F1 mice, and 5FU-induced cytopenia was not different between Lean and Obese. DIO increased total liver KCs; however, C26 tumors increased liver KCs, which were normalized with 5FU treatment, irrespective of DIO. Although 5FU remained efficacious in both models of CRC and did not reduce survival, multiple cycles of 5FU monotherapy increased liver and tumor immune cell death in DIO mice. Altogether, obesity was not protective but rather exacerbated chemotherapy-induced cytotoxicity and promoted a prometastatic liver environment.NEW & NOTEWORTHY 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.