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

// Roni F. Rayes 1 , Simon Milette 1 , Maria Celia Fernandez 1 , Boram Ham 1 , Ni Wang 1 , France Bourdeau 1 , Stephanie Perrino 1 , Shoshana Yakar 2 and Pnina Brodt 1, 3, 4 1 Departments of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada 2 Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA 3 Department of Medicine, McGill University and the McGill University Health Centre, Montréal, QC, Canada 4 Department of Oncology, McGill University and the McGill University Health Centre, Montréal, QC, Canada Correspondence to: Pnina Brodt, email: pnina.brodt@mcgill.ca 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 ABSTRACT 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.