S100A8/A9 activate key genes and pathways in colon tumor progression.
S100A8/A9 activate key genes and pathways in colon tumor progression.
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DOI：
10.1158/1541-7786.mcr-10-0394
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发表时间：
2011-02
期刊：
影响因子：
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通讯作者：
Srikrishna G
中科院分区：
文献类型：
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作者：
Ichikawa M;Williams R;Wang L;Vogl T;Srikrishna G
肿瘤微环境在调节肿瘤进展中起着重要作用。我们早些时候发现，肿瘤和转移部位存在的髓系抑制细胞(MDSC)分泌的S100A8/A9蛋白促进MDSC的自分泌途径积累。在结肠炎相关性结肠癌的小鼠模型中，我们还显示S100A8/A9阳性细胞聚集在异型增生和腺瘤的所有区域。在此，我们提出了S100A8/A9与结肠肿瘤细胞上的RAGE和羧化多糖相互作用并促进MAPK和NF-κB信号通路激活的证据。通过比较S100A8/A9激活的结肠肿瘤细胞和未激活的细胞的基因表达谱，我们发现了一小部分在激活的细胞中上调的基因，包括CXCL1、CCL5和Ccl7、SLc39a10、Lcn2、Zc3h12a、Enpp2和其他基因，它们的产物促进白细胞募集、血管生成、肿瘤迁移、伤口愈合和在远端转移器官形成转移前的壁龛。与此观察一致的是，在小鼠结肠癌模型中，我们发现趋化因子在肿瘤中上调，并在荷瘤野生型小鼠的血清中上调。缺乏S100A9的小鼠肿瘤发生率、生长和转移显著降低，趋化因子水平降低，CD11b+Gr1+细胞在肿瘤和转移前器官中的浸润减少。使用骨髓嵌合小鼠的研究表明，髓系细胞上S100A8/A9的表达对结肠肿瘤的发展是必不可少的。因此，我们的结果揭示了髓系来源的S100A8/A9在激活与肿瘤发生相关的特定下游基因以及促进肿瘤生长和转移方面的新作用。
The tumor microenvironment plays an important role in modulating tumor progression. We earlier showed that S100A8/A9 proteins secreted by myeloid-derived suppressor cells (MDSC) present within tumors and metastatic sites promote an autocrine pathway for accumulation of MDSC. In a mouse model of colitis-associated colon cancer, we also showed that S100A8/A9 positive cells accumulate in all regions of dysplasia and adenoma. Here we present evidence that S100A8/A9 interact with RAGE and carboxylated glycans on colon tumor cells and promote activation of MAPK and NF-κB signaling pathways. Comparison of gene expression profiles of S100A8/A9-activated colon tumor cells versus unactivated cells led us to identify a small cohort of genes upregulated in activated cells, including Cxcl1, Ccl5 and Ccl7, Slc39a10, Lcn2, Zc3h12a, Enpp2 and other genes, whose products promote leukocyte recruitment, angiogenesis, tumor migration, wound healing, and formation of premetastatic niches in distal metastatic organs. Consistent with this observation, in murine colon tumor models we found that chemokines were up-regulated in tumors, and elevated in sera of tumor-bearing wild-type mice. Mice lacking S100A9 showed significantly reduced tumor incidence, growth and metastasis, reduced chemokine levels, and reduced infiltration of CD11b+Gr1+ cells within tumors and premetastatic organs. Studies using bone marrow chimeric mice revealed that S100A8/A9 expression on myeloid cells is essential for development of colon tumors. Our results thus reveal a novel role for myeloid-derived S100A8/A9 in activating specific downstream genes associated with tumorigenesis and in promoting tumor growth and metastasis.