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2017 ; 36
(43
): 6020-6029
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Wnt/?-catenin activation and macrophage induction during liver cancer development
following steatosis
#MMPMID28671671
Debebe A
; Medina V
; Chen CY
; Mahajan IM
; Jia C
; Fu D
; He L
; Zeng N
; Stiles BW
; Chen CL
; Wang M
; Aggarwal KR
; Peng Z
; Huang J
; Chen J
; Li M
; Dong T
; Atkins S
; Borok Z
; Yuan W
; Machida K
; Ju C
; Kahn M
; Johnson D
; Stiles BL
Oncogene
2017[Oct]; 36
(43
): 6020-6029
PMID28671671
show ga
Obesity confers an independent risk for carcinogenesis. In the liver, steatosis
often proceeds cancer formation; however, the mechanisms by which steatosis
promotes carcinogenesis is unknown. We hypothesize that steatosis alters the
microenvironment to promote proliferation of tumor initiating cells (TICs) and
carcinogenesis. We used several liver cancer models to address the mechanisms
underlying the role of obesity in cancer and verified these findings in patient
populations. Using bioinformatics analysis and verified by biochemical assays, we
identified that hepatosteatosis resulting from either Pten deletion or transgenic
expression of HCV core/NS5A proteins, promotes the activation of Wnt/?-catenin.
We verified that high fat diet lipid accumulation is also capable of inducing
Wnt/?-catenin. Caloric restriction inhibits hepatosteatosis, reduces
Wnt/?-catenin activation and blocks the expansion of TICs leading to complete
inhibition of tumorigenesis without affecting the phosphatase and tensin
homologue deleted on chromosome 10 (PTEN) loss regulated protein kinase B (AKT)
activation. Pharmacological inhibition or loss of the Wnt/?-catenin signal
represses TIC growth in vitro, and decreases the accumulation of TICs in vivo. In
human liver cancers, ontology analysis of gene set enrichment analysis
(GSEA)-defined Wnt signature genes indicates that Wnt signaling is significantly
induced in tumor samples compared with healthy livers. Indeed, Wnt signature
genes predict 90% of tumors in a cohort of 558 patient samples. Selective
depletion of macrophages leads to reduction of Wnt and suppresses tumor
development, suggesting infiltrating macrophages as a key source for
steatosis-induced Wnt expression. These data established Wnt/?-catenin as a novel
signal produced by infiltrating macrophages induced by steatosis that promotes
growth of tumor progenitor cells, underlying the increased risk of liver tumor
development in obese individuals.
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