F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner
Kanae Yumimoto, … , Koshi Mimori, Keiichi I. Nakayama
Kanae Yumimoto, … , Koshi Mimori, Keiichi I. Nakayama
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(2):621-635. https://doi.org/10.1172/JCI78782.
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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 3

Ly6C+ Mo-MDSCs and F4/80+ monocytes/macrophages accumulate in the microenvironment of metastatic tumors in the lungs of mice reconstituted with FBXW7-deficient BM cells.

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Ly6C+ Mo-MDSCs and F4/80+ monocytes/macrophages accumulate in the microe...
Representative immunohistofluorescence staining (white) for TCRβ (A), B220 (B), Ly6G (C), Ly6C (D), F4/80 (E), and FSP (F) for lung sections from WT mice reconstituted with CAG-EGFP Fbxw7fl/fl (n = 10 [A, B, D, and E]; 9 [C]; 11 [F]) or CAG-EGFP Mx1-Cre Fbxw7Δ/Δ (n = 10 [A, C, and E]; 12 [B]; 14 [D]; 11 [F]) BM cells and subjected to orthotopic transplantation with tdTomato-labeled E0771 cells (20 days before analysis) as in Figure 2H. Intrinsic fluorescence of EGFP (green), tdTomato (red), and Hoechst 33258 (blue) was also imaged. Higher-magnification images (×2) are shown in the insets. Scale bars: 100 μm. The percentage of EGFP+ BMDCs positive for each marker in tumor-surrounding and nonsurrounding regions was quantified; horizontal bars indicate means. *P < 0.05, ***P < 0.001, 1-way ANOVA and Bonferroni test.