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2017 ; 8
(32
): 52281-52293
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The type I insulin-like growth factor regulates the liver stromal response to
metastatic colon carcinoma cells
#MMPMID28881729
Fernandez MC
; Rayes R
; Ham B
; Wang N
; Bourdeau F
; Milette S
; Lllemann M
; Bird N
; Majeed A
; Xu J
; Kisselova T
; Brodt P
Oncotarget
2017[Aug]; 8
(32
): 52281-52293
PMID28881729
show ga
Hepatic stellate cells (HSC) play a major role in initiating the liver fibrogenic
(wounding) response of the liver and can also orchestrate a pro-metastatic
microenvironment in the liver in response to invading cancer cells. Here we
explored the role of the hepatic stellate cells in colon carcinoma liver
metastasis with emphasis on the contribution of the insulin-like growth factor
(IGF) axis to their activation and function. To this end, we used mice with a
Tamoxifen inducible liver IGF-I deficiency. We found that in mice with a
sustained IGF-I deficiency, recruitment and activation of HSC into
tumor-infiltrated areas of the liver were markedly diminished, resulting in
decreased collagen deposition and reduced tumor expansion. In addition, IGF-I
could rescue HSC from apoptosis induced by pro-inflammatory factors such as TNF-?
known to be upregulated in the early stages of liver metastasis. Moreover, in
surgical specimens, activated IGF-IR was observed on HSC-like stromal cells
surrounding colorectal carcinoma liver metastases. Finally, IGF-targeting in vivo
using an IGF-Trap caused a significant reduction in HSC activation in response to
metastatic colon cancer cells. Therefore, our data identify IGF as a survival
factor for HSC and thereby, a promoter of the pro-metastatic microenvironment in
the liver. IGF-targeting could therefore provide a strategy for curtailing the
pro-metastatic host response of the liver during the early stages of liver
metastasis.