title: 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.forename: Kanae
authors.initials: K
authors.lastname: Yumimoto
authors.forename: Sayuri
authors.initials: S
authors.lastname: Akiyoshi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ueo
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Sagara
authors.forename: Ichiro
authors.initials: I
authors.lastname: Onoyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ueo
authors.forename: Shinji
authors.initials: S
authors.lastname: Ohno
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D018801:CD2 Antigens / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D044783:F-Box Proteins / Q000096:biosynthesis* / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C111835:CCL2 protein, human; D018801:CD2 Antigens; C491768:Ccl2 protein, mouse; D018797:Cell Cycle Proteins; D018932:Chemokine CCL2; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse; D009363:Neoplasm Proteins; D051880:Receptors, Notch; D044767:Ubiquitin-Protein Ligases