Research Papers:

The type I insulin-like growth factor regulates the liver stromal response to metastatic colon carcinoma cells

Maria Celia Fernandez, Roni Rayes, Boram Ham, Ni Wang, France Bourdeau, Simon Milette, Martin lllemann, Nigel Bird, Ali Majeed, Jun Xu, Tatiana Kisselova and Pnina Brodt _

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Oncotarget. 2017; 8:52281-52293. https://doi.org/10.18632/oncotarget.12595

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Maria Celia Fernandez1, Roni Rayes1, Boram Ham1, Ni Wang1, France Bourdeau1, Simon Milette7, Martin lllemann2,3, Nigel Bird4, Ali Majeed5, Jun Xu6, Tatiana Kisselova6 and Pnina Brodt1,7,8

1Departments of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada

2The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark

3Biotech Research and Innovation Centre (BRIC), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

4Liver Research Group, Clinical Sciences, University of Sheffield, Yorkshire, UK

5Department of Oncology, School of Medicine, Sheffield Teaching Hospitals, Yorkshire, UK

6Department of Surgery, University of California, San Diego, La Jolla, CA, USA

7Medicine, McGill University and the McGill University Health Centre, Montréal, QC, Canada

8Oncology, McGill University and the McGill University Health Centre, Montréal, QC, Canada

Correspondence to:

Pnina Brodt, email: pnina.brodt@mcgill.ca

Keywords: liver metastasis, tumor microenvironment, tumor stroma, hepatic stellate cells, colorectal carcinoma

Received: August 05, 2016     Accepted: September 20, 2016     Published: October 12, 2016


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-α 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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