Journal
ONCOTARGET
Volume 8, Issue 32, Pages 52281-52293Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12595
Keywords
liver metastasis; tumor microenvironment; tumor stroma; hepatic stellate cells; colorectal carcinoma
Categories
Funding
- Canadian Institute for Health Research [MOP-80201]
- Quebec Ministere de l'Economie de l'Innovation et des Exportations [PSR-SIIRI-843]
- McGill Integrated Cancer Research Training Program fellowships
- MITACS internships
- Cedars Cancer Foundation fellowships
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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-alpha 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.
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