A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer
A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer
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DOI：
10.1053/j.gastro.2006.06.016
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发表时间：
2006-09-01
期刊：
影响因子：
29.4
通讯作者：
Brabletz, Thomas
中科院分区：
文献类型：
--
作者：
Spaderna, Simone;Schmalhofer, Otto;Brabletz, Thomas
背景与目的：基底膜（BM）的缺失被认为是肿瘤恶性化的重要一步。然而，BM仍然在大多数典型的结直肠腺癌中表达;然而，这些肿瘤可以侵袭并发生转移。本研究的目的是探讨BM周转在恶性结直肠癌（CRC）进展中的作用、机制和临床相关性。方法：在人CRCs和细胞系中研究BM组分的表达及其转录调控和临床意义。结果如下：我们的数据显示了CRC中BM更新的新方面，其对恶性肿瘤进展具有影响：（1）BM仍然在大多数结直肠腺癌的主要肿瘤块中表达，但在许多情况下在肿瘤的侵袭性区域选择性地丢失。(2)在侵袭性前沿选择性丢失BM与远处转移和生存具有高度的临床和肿瘤生物学相关性。(3)BM在转移瘤中重新表达，表明其损失是短暂的，并受环境因素的调节。(4)这种瞬时丢失不仅是由于蛋白水解分解，而且是由于下调的合成，并与肿瘤细胞中的上皮-间充质转化（EMT）有关，因此，锌指增强子蛋白1（ZEB 1）是CRC中BM组分的关键转录抑制因子。结论：在侵袭性前沿的短暂BM丢失与远处转移增加和患者生存率差相关，表明其作为预后标志物的肿瘤生物学相关性和有用性。靶向ZEB 1可能是预防转移的一种有希望的治疗选择。
Background & Aims: Loss of the basement membrane (BM) is considered an important step toward tumor malignancy. However, the BM is still expressed in most typical colorectal adenocarcinomas; nevertheless, these tumors can invade and develop metastases. The aim of this study was to investigate the role, mechanisms, and clinical relevance of BM turnover in malignant colorectal cancer (CRC) progression. Methods: Expression of BM components and their transcriptional regulation and clinical relevance were investigated in human CRCs and cell lines. Results: Our data show new aspects in BM turnover in CRCs with impact on malignant tumor progression: (1) The BM is still expressed in the main tumor mass of most colorectal adenocarcinomas, but selectively lost at invasive regions of the tumor in many cases. (2) Selective loss of the BM at the invasive front has high clinical and tumor biologic relevance for distant metastasis and survival. (3) The BM is reexpressed in metastases, indicating that its loss is transient and regulated by environmental factors. (4) This transient loss is not only due to proteolytic breakdown but to a down-regulated synthesis and linked to an epithelial-mesenchymal transition (EMT) in tumor cells, and, thereby, zinc-finger-enhancer protein 1 (ZEB1) is the crucial transcriptional repressor of BM components in CRCs. Conclusions: A transient BM loss at the invasive front is correlated with increased distant metastasis and poor patient survival, indicating its tumor biologic relevance and usefulness as a prognostic marker. Targeting ZEB1 might be a promising therapeutic option to prevent metastasis.