F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner.
F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner.
复制标题
DOI：
10.1172/jci78782
复制
发表时间：
2015-02
期刊：
影响因子：
--
通讯作者：
Kanae Yumimoto;S. Akiyoshi;H. Ueo;Y. Sagara;Ichiro Onoyama;H. Ueo;S. Ohno;M. Mori;K. Mimori
中科院分区：
文献类型：
--
作者：
Kanae Yumimoto;S. Akiyoshi;H. Ueo;Y. Sagara;Ichiro Onoyama;H. Ueo;S. Ohno;M. Mori;K. Mimori
编码F-box蛋白FBXW7的基因在许多人类癌症中经常发生突变。虽然以往的研究大多集中在FBXW7在肿瘤细胞本身的抑瘤能力上，但我们确定宿主微环境中的FBXW7也抑制肿瘤转移。在小鼠bm来源的基质细胞中，Fbxw7的缺失诱导NOTCH的积累和随后的Ccl2的转录激活。fbxw7缺陷小鼠血清中趋化因子CCL2水平升高，导致单核髓源性抑制细胞和巨噬细胞的募集，从而促进转移性肿瘤的生长。CCL2受体拮抗剂阻断了fbxw7缺陷小鼠转移的增强。此外，在人乳腺癌患者中，FBXW7在外周血中的表达与血清CCL2浓度和疾病预后相关。综上所述，这些结果表明FBXW7不仅以细胞自主的方式，也以非细胞自主的方式拮抗癌症的发展，并且FBXW7/NOTCH/CCL2轴的调节可能为抑制癌症转移提供了一种潜在的途径。
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.