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.
View: Text | PDF
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

×

Figure 2

Fbxw7 deletion in BM promotes cancer metastasis in an orthotopic breast cancer transplantation model.

Options: View larger image (or click on image) Download as PowerPoint
Fbxw7 deletion in BM promotes cancer metastasis in an orthotopic breast ...
(A and B) E0771 cells were transplanted into the mammary fat pad of Fbxw7fl/fl (n = 11) and Mx1-Cre Fbxw7Δ/Δ (n = 13) mice. Primary tumor gross appearance after 32 days (A) and volume at the indicated times (B) are shown. (C–G) E0771 cells were transplanted into the mammary fat pad of Fbxw7fl/fl (n = 12) and Mx1-Cre Fbxw7Δ/Δ (n = 16) mice. After 32 days, lungs were subjected to H&E staining (C), and their gross weight was determined (D). Tumor total area (E), number of tumor nodules (F), and average tumor area (G) were calculated from the stained lung sections. (H–J) WT mice were reconstituted with BM cells of the indicated mice and subjected to orthotopic transplantation with tdTomato-labeled E0771 cells. Lungs were subjected to fluorescence microscopy for detection of BMDCs (green), tumor cells (red), and cell nuclei (Hoechst 33238) (H), and the number of tumor nodules (I) and average tumor area (J) were determined 16 (n = 8 per group) or 20 (n = 9 per group) days after tumor cell transplantation. Scale bars: 2 mm (C); 100 μm (H). Data in B are mean ± SEM; horizontal bars in D–G and I indicate means; box and whisker plots in J depict the smallest value, lower quartile, median, upper quartile, and largest value. **P < 0.01, ***P < 0.001, 2-tailed Student’s t test (B, D–G, I, and J).