Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3.
Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3.
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DOI：
10.1038/onc.2009.247
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发表时间：
2009-11-05
期刊：
影响因子：
8
通讯作者：
Klampfer, L.
中科院分区：
文献类型：
--
作者：
Kaler, P.;Augenlicht, L.;Klampfer, L.
肿瘤相关巨噬细胞介导炎症和癌症进展之间的联系。在这里，我们发现巨噬细胞衍生的可溶性因子诱导结肠癌细胞中的经典Wnt信号传导并促进其生长。肿瘤细胞诱导巨噬细胞释放IL-1β，从而诱导肿瘤细胞中GSK 3 β磷酸化，稳定β-catenin，增强TCF依赖的基因激活，并诱导Wnt靶基因的表达。使用抗IL-1β特异性抗体的中和实验或THP 1巨噬细胞中IL-1β的沉默显示，IL-1β是巨噬细胞诱导Wnt信号传导和支持肿瘤细胞生长所必需的。THP 1巨噬细胞中STAT 1的组成性激活对于IL-1β的诱导以及因此对于肿瘤细胞中β-catenin信号传导的激活是必需的。维生素D3是一种有效的化学预防剂，通过阻断巨噬细胞中STAT 1的组成性激活和IL-1β的产生来中断这种串扰，因此-以维生素D受体依赖性方式-抑制巨噬细胞激活结肠癌细胞中Wnt信号传导的能力。因此，我们的数据确定，维生素D3通过中断肿瘤上皮细胞和肿瘤微环境之间的串扰来发挥其化学预防活性。
Tumor associated macrophages mediate the link between inflammation and cancer progression. Here we showed that macrophage-derived soluble factors induce canonical Wnt signaling in colon cancer cells and promote their growth. Tumor cells induced the release of IL-1β from macrophages, which induced phosphorylation of GSK3β, stabilized β-catenin, enhanced TCF-dependent gene activation, and induced the expression of Wnt target genes in tumor cells. Neutralization experiments using anti IL-1β specific antibodies, or silencing of IL-1β in THP1 macrophages, revealed that IL-1β was required for macrophages to induce Wnt signaling and to support the growth of tumor cells. Constitutive activation of STAT1 in THP1 macrophages was essential for the induction of IL-1β and thus for the activation of β–catenin signaling in tumor cells. Vitamin D3, an effective chemopreventive agent, interrupted this crosstalk by blocking the constitutive activation of STAT1 and the production of IL-1β in macrophages, and therefore- in a vitamin D receptor dependent manner- inhibited the ability of macrophages to activate Wnt signaling in colon carcinoma cells. Our data therefore established that vitamin D3 exerts its chemopreventive activity by interrupting a cross-talk between tumor epithelial cells and the tumor microenvironment.
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影响因子：
2.8
作者：
Brabletz, T;Jung, A;Kirchner, T
通讯作者：
Kirchner, T
影响因子：
20.3
作者：
Biswas, SK;Gangi, L;Sica, A
通讯作者：
Sica, A
DOI：
10.1093/jnci/95.12.896
发表时间：
2003-06-18
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Kumagai, T;O'Kelly, J;Koeffler, HP
通讯作者：
Koeffler, HP
影响因子：
11.2
作者：
Klampfer, Lidija;Huang, Jie;Augenlicht, Leonard
通讯作者：
Augenlicht, Leonard
影响因子：
11.4
作者：
Oguma, Keisuke;Oshima, Hiroko;Aoki, Masahiro;Uchio, Ryusei;Naka, Kazuhito;Nakamura, Satoshi;Hirao, Atsushi;Saya, Hideyuki;Taketo, Makoto Mark;Oshima, Masanobu
通讯作者：
Oshima, Masanobu