F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner
Kanae Yumimoto, Sayuri Akiyoshi, Hiroki Ueo, Yasuaki Sagara, Ichiro Onoyama, Hiroaki Ueo, Shinji Ohno, Masaki Mori, Koshi Mimori, Keiichi I. Nakayama
Kanae Yumimoto, Sayuri Akiyoshi, Hiroki Ueo, Yasuaki Sagara, Ichiro Onoyama, Hiroaki Ueo, Shinji Ohno, Masaki Mori, Koshi Mimori, Keiichi I. Nakayama
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Research Article Oncology

F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner

Abstract

The gene encoding F-box protein FBXW7 is frequently mutated in many human cancers. Although most previous studies have focused on the tumor-suppressive capacity of FBXW7 in tumor cells themselves, we determined that FBXW7 in the host microenvironment also suppresses cancer metastasis. Deletion of Fbxw7 in murine BM-derived stromal cells induced accumulation of NOTCH and consequent transcriptional activation of Ccl2. FBXW7-deficient mice exhibited increased serum levels of the chemokine CCL2, which resulted in the recruitment of both monocytic myeloid-derived suppressor cells and macrophages, thereby promoting metastatic tumor growth. Administration of a CCL2 receptor antagonist blocked the enhancement of metastasis in FBXW7-deficient mice. Furthermore, in human breast cancer patients, FBXW7 expression in peripheral blood was associated with serum CCL2 concentration and disease prognosis. Together, these results suggest that FBXW7 antagonizes cancer development in not only a cell-autonomous manner, but also a non-cell-autonomous manner, and that modulation of the FBXW7/NOTCH/CCL2 axis may provide a potential approach to suppression of cancer metastasis.

Authors

Kanae Yumimoto, Sayuri Akiyoshi, Hiroki Ueo, Yasuaki Sagara, Ichiro Onoyama, Hiroaki Ueo, Shinji Ohno, Masaki Mori, Koshi Mimori, Keiichi I. Nakayama

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Figure 5

Increased Ccl2 gene expression in FBXW7-deficient BMSCs promotes cancer metastasis.

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Increased Ccl2 gene expression in FBXW7-deficient BMSCs promotes cancer ...
(A) Representative immunohistofluorescence staining of Ly6C and FSP in lung sections from WT mice reconstituted with indicated BM cells and subjected to orthotopic transplantation with tdTomato-labeled E0771 cells (20 days before analysis). (B) Genomic PCR analysis of BMSCs from the indicated mice incubated in the absence or presence of 10 μM tamoxifen. The positions of amplified fragments corresponding to floxed and exon 5–deleted (ΔE5) Fbxw7 alleles are indicated. (C) Relative abundance of Ccl2 mRNA in BMSCs from the indicated mice. (D) Concentration of CCL2 released into culture supernatants from the indicated BMSCs. (E) Relative abundance of Ccl2 mRNA in CAG-Cre-ERT2 Fbxw7Δ/Δ BMSCs infected with retroviruses encoding WT or ΔF mutant forms of FBXW7α or with the empty virus (Mock). (F) Relative abundance of Ccl2 mRNA in BMSCs from Fbxw7fl/fl or CAG-Cre-ERT2 Fbxw7fl/fl mice treated with tamoxifen and subjected to RNAi with shRNA vectors targeting EGFP (control) or CCL2. (G and H) Gross appearance of the lungs (G) and their occupancy by visible B16F10 colonies (H) for WT mice 2 weeks after injection both with B16F10 cells and with BMSCs isolated from the indicated mice and treated as in F (n = 10 per group). Scale bars: 10 μm (A), 10 mm (G). Data are mean ± SD (C–F); horizontal bars in H indicate means. *P < 0.05, ***P < 0.001, 1-way ANOVA and Bonferroni test (C, E, F, and H) or 2-tailed Student’s t test (D).