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, Pnina Brodt

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)15691-15704
Number of pages14
JournalOncotarget
Volume9
Issue number21
DOIs
StatePublished - Jan 1 2018

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Insulin-Like Growth Factor I
Colon
Neutrophils
Neoplasm Metastasis
Carcinoma
Liver
Phenotype
Lewis Lung Carcinoma
Arginase
Neoplasms
Tumor Microenvironment
Intercellular Adhesion Molecule-1
Tamoxifen
Vascular Endothelial Growth Factor A
Biological Availability
Nitric Oxide
Anti-Inflammatory Agents
Ligands
Injections
Growth

Keywords

  • Colorectal carcinoma
  • IGF-I
  • Liver metastasis
  • Neutrophil polarization
  • Tumor microenvironment

ASJC Scopus subject areas

  • Oncology

Cite this

Rayes, R. F., Milette, S., Fernandez, M. C., Ham, B., Wang, N., Bourdeau, F., ... Brodt, P. (2018). Loss of neutrophil polarization in colon carcinoma liver metastases of mice with an inducible, liver-specific IGF-I deficiency. Oncotarget, 9(21), 15691-15704. https://doi.org/10.18632/oncotarget.24593

Loss of neutrophil polarization in colon carcinoma liver metastases of mice with an inducible, liver-specific IGF-I deficiency. / Rayes, Roni F.; Milette, Simon; Fernandez, Maria Celia; Ham, Boram; Wang, Ni; Bourdeau, France; Perrino, Stephanie; Yakar, Shoshana; Brodt, Pnina.

In: Oncotarget, Vol. 9, No. 21, 01.01.2018, p. 15691-15704.

Research output: Contribution to journalArticle

Rayes, RF, Milette, S, Fernandez, MC, Ham, B, Wang, N, Bourdeau, F, Perrino, S, Yakar, S & Brodt, P 2018, 'Loss of neutrophil polarization in colon carcinoma liver metastases of mice with an inducible, liver-specific IGF-I deficiency', Oncotarget, vol. 9, no. 21, pp. 15691-15704. https://doi.org/10.18632/oncotarget.24593
Rayes, Roni F. ; Milette, Simon ; Fernandez, Maria Celia ; Ham, Boram ; Wang, Ni ; Bourdeau, France ; Perrino, Stephanie ; Yakar, Shoshana ; Brodt, Pnina. / Loss of neutrophil polarization in colon carcinoma liver metastases of mice with an inducible, liver-specific IGF-I deficiency. In: Oncotarget. 2018 ; Vol. 9, No. 21. pp. 15691-15704.
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AU - Wang, Ni

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AU - Yakar, Shoshana

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