Combinatorial Normalization of Liver-Derived Cytokine Pathways Alleviates Hepatic Tumor-Associated Cachexia in Zebrafish
- 15 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (4), 873-884
- https://doi.org/10.1158/0008-5472.can-20-2818
Abstract
The role and significance of liver-derived cytokines in cancer-associated cachexia syndrome (CACS) remain elusive. Here we report that combinatorial counterbalances of the leptin and Igf1 signaling pathways in hepatocellular carcinoma (HCC) models significantly relieves cachexia. Double transgenic zebrafish models of HCC that stably displayed focal lesions, anorexia, and wasting of adipose and muscle tissues were first generated. Knockout of lepr or mc4r from these zebrafish partially restored appetite and exerted moderate or no effect on tissue wasting. However, genetic replenishment of Igf1 in a lepr mutant background effectively relieved the cachexia-like phenotype without affecting tumor growth. Similarly, administration of napabucasin, a Stat3/Socs3 inhibitor, on the zebrafish HCC model, mammalian cell lines with exogenous IGF1, and two mouse xenograft models restored insulin sensitivity and rescued the wasting of non-tumoros tissues. Together these results describe the synergistic impact of leptin and Igf1 normalization in treating certain HCC-associated cachexia as a practical strategy.Keywords
Funding Information
- National Key Research and Development Program of China (2020YFA0803202)
- National Natural Science Foundation of China (81402582, 81500671, 81802333)
- Natural Science Foundation of Shanghai (14YF1400600, 18ZR1404500)
This publication has 31 references indexed in Scilit:
- AgRP and POMC Neurons Are Hypophysiotropic and Coordinately Regulate Multiple Endocrine Axes in a Larval TeleostCell Metabolism, 2012
- The significance of serum levels of adiponectin, leptin, and hyaluronic acid in hepatocellular carcinoma of cirrhotic and noncirrhotic patientsHuman & Experimental Toxicology, 2012
- A transgenic zebrafish liver tumor model with inducible Myc expression reveals conserved Myc signatures with mammalian liver tumorsDisease Models & Mechanisms, 2012
- Muscle atrophy in experimental cancer cachexia: Is the IGF‐1 signaling pathway involved?International Journal of Cancer, 2010
- PI3 Kinase Regulation of Skeletal Muscle Hypertrophy and AtrophyPublished by Springer Science and Business Media LLC ,2010
- Expression of leptin receptor gene in developing and adult zebrafishGeneral and Comparative Endocrinology, 2010
- IGF-1 is downregulated in experimental cancer cachexiaAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2006
- Potential role of leptin expression in hepatocellular carcinomaJournal of Clinical Pathology, 2006
- Divergence of Melanocortin Pathways in the Control of Food Intake and Energy ExpenditureCell, 2005
- Absence of growth-hormone receptor in hepatocellular carcinoma and cirrhotic liverHepatology, 1990