Abstract 6952: The role of interleukin-11 (IL11) in cancer-associated cachexia (CAC)

Abstract

Abstract Cancer-associated cachexia (CAC), characterized by loss of skeletal muscle and involuntary body weight loss, is responsible for increased chemotherapy toxicity, reduced quality of life, and impaired survival in cancer patients. While interleukin-11 (IL11), one of the IL6 family cytokines, was originally thought to be involved in hematopoiesis, studies increasingly suggest its involvement in tumorigenesis including chemoresistance, metastasis, and survival of cancer cells. However, the precise role of IL11 in CAC has not been determined. Our lab has previously shown that IL11 treatment suppressed the myogenic differentiation of C2C12 myoblasts, suggesting that IL11 may interfere with differentiation and subsequent regeneration of muscle. In this study, we investigated the role of IL11 in cancer-induced muscle wasting using cell culture and mouse models. The mRNA expression of IL11 was highly up-regulated in C26 and Lewis lung carcinoma (LLC) cells, two well-known cachectic mouse cancer cell lines, while its expression was low in a non-cachectic MC38 mouse colon cancer cell line. Knockdown of IL11 in C26 cells using two independent lentiviral shRNAs significantly reduced the mRNA levels of the cytokines involved in CAC including GDF15, LIF, and VEGFA, while the mRNA level of IL6 was not significantly altered. Additionally, IL11 knockdown significantly reduced the mRNA and protein levels of ATF4, CHOP, and TRIB3, suggesting that IL11 may be responsible for the activation of unfolded protein response, an adaptive mechanism for growth, survival, and angiogenesis of cancer. Knockdown of IL11 in C26 and LLC cell lines also significantly reduced the volume of tumors in syngeneic mouse models, while over-expression of IL11 in MC38 cells increased tumor size. Moreover, the knockdown of IL11 in cachectic cancer cells partially prevented the loss of muscle and body weight in tumor-bearing mice, although the amelioration of muscle loss by IL11 knockdown may be associated with the decreased tumor burden. Together, these results indicate that IL11 may contribute to muscle wasting and provide novel insight into the previously unestablished role of IL11 in CAC. Citation Format: Kimberly Drinkwater, Ashlyn Meyers, Samin Kargari, Natalie Crisan, Aaron Mody, Minsub Shim. The role of interleukin-11 (IL11) in cancer-associated cachexia (CAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6952.