Journal
CANCER RESEARCH
Volume 81, Issue 4, Pages 873-884Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-2818
Keywords
-
Categories
Funding
- 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]
- Foundation for Returned Oversea Chinese Scholars [48-12]
- Joint Foundation of Shanghai Anticancer Association and Fudan University Shanghai Cancer Center
Ask authors/readers for more resources
This study found that combinatorial counterbalances of the leptin and Igf1 signaling pathways in HCC models significantly relieve cachexia. Genetic replenishment of Igf1 in a lepr-mutant background effectively relieved the cachexia-like phenotype without affecting tumor growth, providing a practical strategy for treating certain HCC-associated cachexia. The results describe the synergistic impact of leptin and Igf1 normalization in rescuing anorexia, muscle wasting, and adipose wasting in HCC models.
The role and significance of liver-derived cytokines in cancer-associated cachexia syndrome 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 musde 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 nontumor tissues. Together, these results describe the synergistic impact of leptin and lgf1 normalization in treating certain HCC-associated cachexia as a practical strategy. Significance: Disruption of leptin signaling with normalized Igf1 expression significantly rescues anorexia, muscle wasting, and adipose wasting in Ras- and Myc-driven zebrafish models of HCC.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available