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 1

Fbxw7 deletion in BM promotes cancer metastasis in an intravenous tumor cell transplantation model.

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Fbxw7 deletion in BM promotes cancer metastasis in an intravenous tumor ...
(A and B) B16F10 cells were transplanted into Fbxw7+/fl (n = 7), Fbxw7fl/fl (n = 8), Mx1-Cre Fbxw7+/Δ (n = 11), and Mx1-Cre Fbxw7Δ/Δ (n = 12) mice. The gross appearance of the lungs (A) and their occupancy by tumor colonies (B) were examined. Horizontal bars in B indicate mean values. (C) Kaplan-Meier survival curves for Fbxw7fl/fl (n = 9) and Mx1-Cre Fbxw7Δ/Δ (n = 10) mice after injection of B16F10 cells. (D and E) LLC cells were transplanted into Fbxw7+/fl (n = 4), Fbxw7fl/fl (n = 5), Mx1-Cre Fbxw7+/Δ (n = 5), and Mx1-Cre Fbxw7Δ/Δ (n = 12) mice. (F and G) B16F1 cells were transplanted into Fbxw7+/fl (n = 9), Fbxw7fl/fl (n = 8), Mx1-Cre Fbxw7+/Δ (n = 8), and Mx1-Cre Fbxw7Δ/Δ (n = 8) mice. Lungs were subjected to H&E staining (D and F), and their gross weight was determined (E and G). (H–J) Metastasis assays performed in WT mice reconstituted with CAG-EGFP Fbxw7fl/fl (n = 8) or CAG-EGFP Mx1-Cre Fbxw7Δ/Δ (n = 7) donor BM. (K–M) Metastasis assays performed in Fbxw7fl/fl (n = 10) or Mx1-Cre Fbxw7Δ/Δ (n = 12) mice reconstituted with WT donor BM. Schematic representation (H and K), gross appearance of the lungs (I and L), and their occupancy by tumor colonies (J and M) are shown. Scale bars: 10 mm (A, I, and L); 2 mm (D and F). Horizontal bars in B, E, G, J, and M indicate means. ***P < 0.001, 1-way ANOVA and Bonferroni test (B, E, and G) or 2-tailed Student’s t test (J).