Brabletz Thomas, Spaderna Simone, Kolb Jochen, Hlubek Falk, Faller Gerhard, Bruns Christiane J, Jung Andreas, Nentwich Jens, Duluc Isabelle, Domon-Dell Claire, Kirchner Thomas, Freund Jean-Noel
Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany.
Cancer Res. 2004 Oct 1;64(19):6973-7. doi: 10.1158/0008-5472.CAN-04-1132.
The homeobox transcription factor Cdx2 specifies intestinal development and homeostasis and is considered a tumor suppressor in colorectal carcinogenesis. However, Cdx2 mutations are rarely found. Invasion of colorectal cancer is characterized by a transient loss of differentiation and nuclear accumulation of the oncoprotein beta-catenin in budding tumor cells. Strikingly, this is reversed in growing metastases, indicating that tumor progression is a dynamic process that is not only driven by genetic alterations but also regulated by the tumor environment. Here we describe a transient loss of Cdx2 in budding tumor cells at the tumor host interface, and reexpression of Cdx2 in metastases. Cell culture experiments show that collagen type I, through beta(1) integrin signaling, triggers a transient transcriptional down-regulation of Cdx2 and its intestine-specific target gene sucrase isomaltase, associated with a loss of differentiation. These data indicate an active role for the tumor environment in malignant tumor progression.
同源框转录因子Cdx2决定肠道发育和内环境稳定，在结直肠癌发生过程中被视为一种肿瘤抑制因子。然而，很少发现Cdx2突变。结直肠癌的侵袭特征是在出芽肿瘤细胞中分化暂时丧失且癌蛋白β-连环蛋白在细胞核内积聚。引人注目的是，在生长的转移灶中这种情况会逆转，这表明肿瘤进展是一个动态过程，不仅由基因改变驱动，还受肿瘤环境调节。在此我们描述了在肿瘤宿主界面的出芽肿瘤细胞中Cdx2的暂时丧失，以及在转移灶中Cdx2的重新表达。细胞培养实验表明，I型胶原通过β1整合素信号传导，触发Cdx2及其肠道特异性靶基因蔗糖异麦芽糖酶的短暂转录下调，这与分化丧失相关。这些数据表明肿瘤环境在恶性肿瘤进展中发挥积极作用。
