Research Papers:

Loss of neutrophil polarization in colon carcinoma liver metastases of mice with an inducible, liver-specific IGF-I deficiency

Roni F. Rayes, Simon Milette, Maria Celia Fernandez, Boram Ham, Ni Wang, France Bourdeau, Stephanie Perrino, Shoshana Yakar and Pnina Brodt _

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Oncotarget. 2018; 9:15691-15704. https://doi.org/10.18632/oncotarget.24593

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Roni F. Rayes1, Simon Milette1, Maria Celia Fernandez1, Boram Ham1, Ni Wang1, France Bourdeau1, Stephanie Perrino1, Shoshana Yakar2 and Pnina Brodt1,3,4

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

2Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA

3Department of Medicine, McGill University and the McGill University Health Centre, Montréal, QC, Canada

4Department of Oncology, McGill University and the McGill University Health Centre, Montréal, QC, Canada

Correspondence to:

Pnina Brodt, email: [email protected]

Keywords: IGF-I; colorectal carcinoma; liver metastasis; neutrophil polarization; tumor microenvironment

Received: August 03, 2017     Accepted: January 19, 2018     Epub: February 28, 2018     Published: March 20, 2018


The growth of cancer metastases in the liver depends on a permissive interaction with the hepatic microenvironment and neutrophils can contribute to this interaction, either positively or negatively, depending on their phenotype. Here we investigated the role of IGF-I in the control of the tumor microenvironment in the liver, using mice with a conditional, liver-specific, IGF-I deficiency (iLID) induced by a single tamoxifen injection. In mice that had a sustained (3 weeks) IGF-I deficiency prior to the intrasplenic/portal inoculation of colon carcinoma MC-38 cells, we observed an increase in neutrophil accumulation in the liver relative to controls. However, unlike controls, these neutrophils did not acquire the (anti-inflammatory) tumor-promoting phenotype, as evidenced by retention of high ICAM-1 expression and nitric oxide production and low CXCR4, CCL5, and VEGF expression and arginase production, all characteristic of the (pro-inflammatory) phenotype. This coincided with an increase in apoptotic tumor cells and reduced metastasis. Neutrophils isolated from these mice also had reduced IGF-IR expression levels. These changes were not observed in iLID mice with a short-term (2 days) IGF-I depletion, despite a 70% reduction in their circulating IGF-I levels, indicating that a sustained IGF-I deficiency was necessary to alter the neutrophil phenotype. Similar results were obtained with the highly metastatic Lewis lung carcinoma subline H-59 cells and in mice injected with an IGF-Trap that blocks IGF-IR signaling by reducing ligand bioavailability. Our results implicate the IGF axis in neutrophil polarization and the induction of a pro-metastatic microenvironment in the liver.

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