PUBLICATION

Combinatorial normalization of liver-derived cytokine pathways alleviates hepatic tumor-associated cachexia in zebrafish

Authors
Fei, F., Sun, S., Li, Q., Pei, Z., Wang, L., Zhang, R., Luo, F., Yu, M., Wang, X.
ID
ZDB-PUB-201229-5
Date
2020
Source
Cancer research   81(4): 873-884 (Journal)
Registered Authors
Wang, Xu
Keywords
none
MeSH Terms
  • 3T3-L1 Cells
  • Adipose Tissue/drug effects
  • Adipose Tissue/metabolism
  • Adipose Tissue/pathology
  • Animals
  • Animals, Genetically Modified
  • Benzofurans/administration & dosage*
  • Benzofurans/pharmacology
  • Cachexia/genetics
  • Cachexia/metabolism
  • Cachexia/pathology
  • Cachexia/prevention & control*
  • Carcinoma, Hepatocellular/drug therapy*
  • Carcinoma, Hepatocellular/genetics
  • Carcinoma, Hepatocellular/metabolism
  • Carcinoma, Hepatocellular/pathology
  • Cells, Cultured
  • Cytokines/metabolism
  • Cytokines/physiology
  • Disease Models, Animal
  • Drug Synergism
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Insulin Resistance/genetics
  • Insulin-Like Growth Factor I/administration & dosage*
  • Insulin-Like Growth Factor I/genetics
  • Insulin-Like Growth Factor I/metabolism
  • Insulin-Like Growth Factor I/therapeutic use
  • Leptin/genetics
  • Leptin/metabolism
  • Liver/drug effects*
  • Liver/metabolism
  • Liver/physiology
  • Liver Neoplasms/drug therapy*
  • Liver Neoplasms/genetics
  • Liver Neoplasms/metabolism
  • Liver Neoplasms/pathology
  • Mice
  • Muscular Atrophy/pathology
  • Muscular Atrophy/prevention & control
  • Naphthoquinones/administration & dosage*
  • Naphthoquinones/pharmacology
  • Receptors, Leptin/genetics
  • Receptors, Leptin/metabolism
  • Signal Transduction/drug effects
  • Signal Transduction/physiology
  • Wasting Syndrome/genetics
  • Wasting Syndrome/metabolism
  • Wasting Syndrome/pathology
  • Wasting Syndrome/prevention & control
  • Xenograft Model Antitumor Assays
  • Zebrafish
PubMed
33355239 Full text @ Cancer Res.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes