SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion
SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion
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DOI：
10.1038/ng1997
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发表时间：
2007-04-01
期刊：
影响因子：
30.8
通讯作者：
Taketo, Makoto M.
中科院分区：
文献类型：
--
作者：
Kitamura, Takanori;Kometani, Kohei;Taketo, Makoto M.
TGF-β家族信号转导的失活与结直肠肿瘤进展有关。使用cis-Apc（+/Delta 716）Smad 4（+/-）突变小鼠（称为cis-Apc/Smad 4），一种TGF-β家族信号传导被阻断的侵袭性结直肠癌模型，我们在这里展示了一种新类型的未成熟髓样细胞（iMC）从骨髓募集到肿瘤侵袭前沿。这些CD 34（+）iMC表达基质金属蛋白酶MMP 9和MMP 2以及CC-趋化因子受体1（CCR 1），并向CCR 1配体CCL 9迁移。在腺癌中，肿瘤上皮中CCL 9的表达增加。通过在cis-Apc/Smad 4突变体的背景中删除Ccr 1，我们进一步表明CCR 1的缺乏阻止了CD 34（+）iMCs在侵袭前沿的积累，并抑制了肿瘤侵袭。这些结果表明，肿瘤上皮中转化生长因子-β家族信号传导的丧失导致促进肿瘤侵袭的iMC的积累。
Inactivation of TGF-beta family signaling is implicated in colorectal tumor progression. Using cis-Apc(+/Delta 716) Smad4(+/-) mutant mice (referred to as cis-Apc/Smad4), a model of invasive colorectal cancer in which TGF-b family signaling is blocked, we show here that a new type of immature myeloid cell (iMC) is recruited from the bone marrow to the tumor invasion front. These CD34(+) iMCs express the matrix metalloproteinases MMP9 and MMP2 and the CC-chemokine receptor 1 (CCR1) and migrate toward the CCR1 ligand CCL9. In adenocarcinomas, expression of CCL9 is increased in the tumor epithelium. By deleting Ccr1 in the background of the cis-Apc/Smad4 mutant, we further show that lack of CCR1 prevents accumulation of CD34(+) iMCs at the invasion front and suppresses tumor invasion. These results indicate that loss of transforming growth factor-beta family signaling in tumor epithelium causes accumulation of iMCs that promote tumor invasion.