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 4

Increased production of CCL2 promotes metastasis in FBXW7-deficient mice.

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Increased production of CCL2 promotes metastasis in FBXW7-deficient mice...
(A) Serum cytokine levels in Fbxw7fl/fl and Mx1-Cre Fbxw7Δ/Δ mice after orthotopic transplantation of tdTomato-labeled E0771 cells or in nontransplant controls. Optical densities for cytokines are indicated according to the color scale. See also Supplemental Figure 5. (B) Serum concentration of CCL2, determined by ELISA, in the indicated mice transplanted with tdTomato-labeled E0771 cells. Data are mean ± SD (n = 4 per group). (C and D) Gross appearance of the lungs (C) and their occupancy by visible B16F10 tumor colonies (D) for Fbxw7fl/fl (n = 5 [not treated]; 8 [treated]) and Mx1-Cre Fbxw7Δ/Δ (n = 8 [not treated]; 6 [treated]) mice injected with B16F10 cells and treated or not with the CCR2 antagonist propagermanium. (E–H) WT mice were reconstituted with CAG-EGFP Mx1-Cre Fbxw7Δ/Δ BM cells, subjected to orthotopic transplantation with tdTomato-labeled E0771 cells, and treated or not with propagermanium (n = 7). At 20 days after tumor cell transplantation, lungs were subjected to fluorescence microscopy (E), and number of tumor nodules (F) and average tumor area (G) were determined. (H) The percentage of EGFP+ BMDCs positive for Ly6C in the tumor-bearing lungs of mice as in E–G was determined by immunohistofluorescence analysis. Scale bars: 10 mm (C); 100 μm (E). Horizontal bars in D, F, and H indicate means; box and whisker plots in G depict the smallest value, lower quartile, median, upper quartile, and largest value. *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA and Bonferroni test (B and D) or 2-tailed Student’s t test (F–H).