Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation
Laetitia A. Mauti, … , Paolo Provero, Ivan Stamenkovic
Laetitia A. Mauti, … , Paolo Provero, Ivan Stamenkovic
Published June 6, 2011
Citation Information: J Clin Invest. 2011;121(7):2794-2807. https://doi.org/10.1172/JCI41936.
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Research Article Oncology

Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation

Abstract

Metastasis depends on the ability of tumor cells to establish a relationship with the newly seeded tissue that is conducive to their survival and proliferation. However, the factors that render tissues permissive for metastatic tumor growth have yet to be fully elucidated. Breast tumors arising during pregnancy display early metastatic proclivity, raising the possibility that pregnancy may constitute a physiological condition of permissiveness for tumor dissemination. Here we have shown that during murine gestation, metastasis is enhanced regardless of tumor type, and that decreased NK cell activity is responsible for the observed increase in experimental metastasis. Gene expression changes in pregnant mouse lung and liver were shown to be similar to those detected in premetastatic sites and indicative of myeloid cell infiltration. Indeed, myeloid-derived suppressor cells (MDSCs) accumulated in pregnant mice and exerted an inhibitory effect on NK cell activity, providing a candidate mechanism for the enhanced metastatic tumor growth observed in gestant mice. Although the functions of MDSCs are not yet understood in the context of pregnancy, our observations suggest that they may represent a shared mechanism of immune suppression occurring during gestation and tumor growth.

Authors

Laetitia A. Mauti, Marie-Aude Le Bitoux, Karine Baumer, Jean-Christophe Stehle, Dela Golshayan, Paolo Provero, Ivan Stamenkovic

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Figure 8

Gene expression profiling of pregnant versus virgin mouse lung and comparative dataset analysis reveal similarities with a premetastatic lung signature characterized by accumulation of myelomonocytic cells.

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Gene expression profiling of pregnant versus virgin mouse lung and compa...
RNA from 2 mice each (16-day pregnant and virgin NOD/SCID) were pooled for 1 Affymetrix mouse 430 chip, and 3 chips were used per condition. Differentially expressed genes in the lungs and livers were determined by the rank product method by setting the false detection rate (FDR) to 5%. (A) Comparative analysis of upregulated genes in pregnant mouse lung with upregulated genes in premetastatic lung (mice harboring aggressive versus benign primary tumors; data derived from the heatmap of Supplemental Figure 1D in ref. 10). Overlap P = 4.1 × 10–20. (B) Quantitative RT-PCR for Lox in lung RNA of 16-day pregnant (P-) and virgin (V-) NOD/SCID mice. (C) Comparative analysis of upregulated genes in pregnant mouse liver with upregulated genes (>2 fold change) in premetastatic (untreated) liver (data derived from ref. 28). Overlap P = 1.3 × 10–6. (D) Commonly upregulated genes in pregnant mouse lung and liver. Overlap P = 1.1 × 10–11. (E) Unsupervised hierarchical clustering of lung cancer patients (from ref. 29) using orthologs of downregulated genes in pregnant mouse lung followed by Kaplan-Meier analysis of the 2 main patient groups (red, poor prognosis; blue, good prognosis). P = 0.0423. See also Supplemental Table 2.