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.
Highlights
The tumor microenvironment is a complex network of immune and non-immune host cells that communicate with each other and with the invading cancer cells through soluble mediators and cell-cell contact to regulate tumor cell growth
To begin to elucidate the effect of a long-term reduction in circulating IGF-I levels on the immune microenvironment of metastatic cells in the liver, we first measured the expression of a range of inflammatory/immune response indicators such as chemokines, cytokines and vascular cell adhesion molecules in the livers of iLID mice injected with GFP-tagged MC-38 cells, 1–6 days earlier
While in control, vehicle-treated and iLID2D mice an increase in VEGF mRNA relative to normal levels was evident by 6 days post tumor injection (Figure 1D), these levels did not change in iLID3W mice and were ~3-fold lower than in their respective, vehicle-treated controls (Figure 1C). mRNA expression levels for other inflammatory indicators including IL-1β, IL-18, CXCL-2, E-selectin, P-selectin, VCAM-1 and intercellular adhesion molecule-1 (ICAM-1) did not significantly differ in iLID3W, iLID2D and the respective control mice (Supplementary Figure 2)
Summary
The tumor microenvironment is a complex network of immune and non-immune host cells that communicate with each other and with the invading cancer cells through soluble mediators and cell-cell contact to regulate tumor cell growth. Cells of the innate immune system can promote or inhibit tumor growth, depending on their phenotype. Macrophages and neutrophilic granulocytes (neutrophils) in particular, have an inherent plasticity and their phenotypes can change within a spectrum of activation states in response to chemokines and cytokines in the tumor microenvironment [1, 2]. The type 1 insulin-like growth factor (IGF-I) axis has been implicated in several aspects of cancer progression (reviewed in [9]). The IGF axis has been implicated in paracrine as well as autocrine regulation of innate and acquired immunity [13]. IGF-IR silencing by a small interfering RNA was shown to induce the production of the pro-inflammatory cytokines TNF-α and INF-γ and alter host immunity in a mouse model of breast cancer [21]. IGF-I appears to play an active role in the regulation of immune cell function
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