Poster Presentation NSW State Cancer Conference 2023

Overexpression of mitochondrial catalase in adipose tissue improves survival and cardiac cachexia in AOM-DSS model of colitis-associated colorectal cancer. (#283)

Amanda Croft 1 2 , Conagh Kelly 1 2 , Dongqing Kelly Chen 1 2 , Lucy Murtha 1 2 , Stuart Sugito 3 , Tatt Jhong Haw 1 2 , Andrew Boyle 1 2 3 , Aaron Sverdlov 1 2 3 , Doan Ngo 1 2
  1. Hunter Medical Research Institute, New Lambton Hgts, NSW, Australia
  2. University of Newcastle, Callaghan, NSW, Australia
  3. Hunter New England Health, New Lambton Hgts, NSW, Australia

 Background: A debilitating result of colorectal cancer (CRC) is cachexia, involving fat and muscle wasting, leading to cardiac atrophy and heart failure. Adipose tissue undergoes extensive remodelling, including inflammation, oxidative stress and lipolysis that all contribute to cardiac cachexia and predict overall survival in CRC patients. We hypothesise that improving adipose tissue health by adipose-targeted overexpression of mitochondrial catalase (mCAT) can prevent cardiac cachexia and overall survival in an animal model of colitis-induced CRC.  

Purpose: We aimed to test if targeting adipose tissue oxidative stress by adipose-targeted mCAT overexpression can affect CRC survival while conferring cardio-protection during CRC development. 

Methods: AdipoQ-mCAT transgenic (TG) mice were generated by crossing AdipoQ-Cre with floxed mCAT mice. Colitis-associated CRC was induced by the azoxymethane/dextran sodium sulphate (AOM/DSS) protocol in TG and age-matched wild-type (WT) mice. On Day 0, 10mg/kg AOM was injected i.p., then 3 x 1-week cycles of 2% w/v DSS were given in drinking water. Tumours were observed by endoscopy at Days 24, 48 and 70. At Day 49, echocardiography was performed on cancer-bearing mice and age-matched cancer-free mice, according to the European Association of Cardiovascular Imaging guidelines. RNA from AT and hearts was analysed by qPCR.  

Results: TG mice had better survival rates (80% vs 32%; p = 0.0053), gained more weight (p<0.0001) and had reduced tumour number and burden (p<0.05) vs WTs. Inflammatory and cachectic markers increased in AT of WT cancer-bearing mice (FC vs. WT cancer-free mice: CD68, 2.2-fold; F4/80, 2.6-fold; TNFA, 3.9-fold; Ghrelin, 2.1-fold; UCP2, 4.7-fold), which were reversed in TG mice. Echocardiography showed reduced wall thickness and LV mass in WT cancer-bearing mice (vs. WT cancer-free mice: IVSd, p<0.0001; LVPWd, p<0.0001; LV mass, p<0.0001), which were partially reversed in TG cancer-bearing mice (vs. WT cancer-bearing mice: IVSd, p<0.01; LVPWd, p<0.05; LV mass, p<0.01). Heart tissue of WT cancer-bearing mice had significant changes to cardiac remodelling, inflammation, cell growth and metabolism genes (FC vs. WT cancer-free mice: COL1A1, -1.6-fold; COL3A1, -1.7-fold; C6, 3.7-fold; S100A8, 16.1-fold; FSTL1, -1.5-fold; GDF11, -1.6-fold; PPARGC1A, 1.4-fold; RARRES1, -1.7-fold), consistent with cardiac cachexia; however, these changes were reversed in TG cancer-bearing mice.  

Conclusion: Adipose-targeted overexpression of mCAT reduced inflammatory and cachectic markers in AT. Compared to WTs, TG mice had improved survival, reduced tumour burden and attenuation of cardiac structural and gene expression changes associated with cardiac cachexia. Therefore, adipose tissue health may play an important role in CRC and associated CV disease.

  1. Argilés, J.M., Stemmler, B., López-Soriano, F.J. et al. Inter-tissue communication in cancer cachexia. Nat Rev Endocrinol 15, 9–20 (2019).
  2. Seongkyun Lim, Jacob L. Brown, Tyrone A. Washington, Nicholas P. Greene, Development and progression of cancer cachexia: Perspectives from bench to bedside,Sports Medicine and Health Science, 2 (4):177-185.