Transforming growth factor β receptor type II inactivation induces the malignant transformation of intestinal neoplasms initiated by Apc mutation
Transforming growth factor β receptor type II inactivation induces the malignant transformation of intestinal neoplasms initiated by Apc mutation
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DOI：
10.1158/0008-5472.can-06-0890
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发表时间：
2006-10-15
期刊：
影响因子：
11.2
通讯作者：
Grady, William M.
中科院分区：
文献类型：
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作者：
Munoz, Nina M.;Upton, Melissa;Grady, William M.
转化生长因子-β（TGF-β）信号通路是一种肿瘤抑制通路，通常在结肠癌中失活。TGF-β是一种分泌型配体，通过跨膜异聚受体复合物介导其作用，该复合物由I型（TGFBR 1）和II型亚基（TGFBR 2）组成。大约30%的结肠癌携带TGFBR 2突变，这表明它是这种癌症中突变失活的常见靶点。为了评估TGFBR 2失活在结肠癌多步进展序列中的功能作用，我们通过将Apc（1638 N/wt）小鼠与肠上皮中Tgfbr 2无效的小鼠Villin-Cre; Tgfbr 2（E2 flx/E2 flx）小鼠交配，产生了一种小鼠模型，该模型重现了在人类结肠癌中观察到的两种常见遗传事件。在该模型中，我们观察到与具有完整Tgfbr 2（Apc（1638 N/wt）; Tgfbr 2（E2 flx/E2 flx））的那些小鼠相比，Apc（1638 N/wt）; Villin-Cre; Tgfbr 2（E2 flx/E2 flx）小鼠（称为Apc（1638 N/wt）; Tgfbr 2（IEKO））中肠腺癌的数量急剧增加。此外，来自Apc（1638 N/wt）; Tgfbr 2（IEKO）小鼠的上皮肿瘤细胞的体外分析显示基质金属蛋白酶MMP-2和NIMP-9的表达和活性增强，以及条件培养基中TGF-β 1分泌增加。类似地，与Apc（1638 N/wt）; Tgfbr（E2 flx/E2 flx）衍生的肿瘤相比，来自Apc（1638 N/wt）; Tgfbr 2（IEKO）小鼠的原发性肿瘤组织也显示出升高的TGF-β 1量以及更高的MMP-2活性。因此，肠上皮细胞中TGFBR 2的缺失促进了由Apc突变引发的肿瘤的侵袭和恶性转化，提供了Wnt信号失调和TGF-β信号失活协同分别驱动体内肠癌的起始和进展的证据。
The transforming growth factor-beta (TGF-beta) signaling pathway is a tumor-suppressor pathway that is commonly inactivated in colon cancer. TGF-beta is a secreted ligand that mediates its effects through a transmembrane heteromeric receptor complex, which consists of type I (TGFBR1) and type II subunits (TGFBR2). Approximately 30% of colon cancers carry TGFBR2 mutations, demonstrating that it is a common target for mutational inactivation in this cancer. To assess the functional role of TGFBR2 inactivation in the multistep progression sequence of colon cancer, we generated a mouse model that recapitulates two common genetic events observed in human colon cancer by mating Apc(1638N/wt) mice with mice that are null for Tgfbr2 in the intestinal epithelium, Villin-Cre;Tgfbr2(E2flx/E2flx) mice. In this model, we observed a dramatic increase in the number of intestinal adenocarcinomas in the Apc(1638N/wt); Villin-Cre;Tgfbr2(E2flx/E2flx) mice (called Apc(1638N/wt); Tgfbr2(IEKO)) compared with those mice with intact Tgfbr2 (Apc(1638N/wt);Tgfbr2(E2flx/E2flx)). Additionally, in vitro analyses of epithelial tumor cells derived from the Apc(1638N/wt); Tgfbr2(IEKO) mice showed enhanced expression and activity of matrix metalloproteinase MMP-2 and NIMP-9, as well as increased TGF-beta 1 secretion in the conditioned medium. Similarly, primary tumor tissues from the Apc(1638N/wt); Tgfbr2(IEKO) mice also showed elevated amounts of TGF-beta 1 as well as higher MMP-2 activity in comparison with Apc(1638N/wt); Tgfbr(E2flx/E2flx)-derived tumors. Thus, loss of TGFBR2 in intestinal epithelial cells promotes the invasion and malignant transformation of tumors initiated by Apc mutation, providing evidence that Wnt signaling deregulation and TGF-beta signaling inactivation cooperate to drive the initiation and progression, respectively, of intestinal cancers in vivo.