The role of anti-apoptotic Bcl-2 proteins for colorectal cancer development and progression

B细胞淋巴瘤(B细胞淋巴瘤)-2蛋白家族主要是由于其在线粒体死亡途径调节中的关键作用而为人所知。抗凋亡的Bcl2蛋白，如Bcl2、Bclxl和Mcl-1，除了抑制线粒体的激活外，还调节细胞的周期和增殖。在结直肠癌(CRC)中，抗细胞凋亡的Bcl2蛋白表达水平的变化已经被描述。例如，在结直肠癌组织中，Bclxl的表达增加与肿瘤的低分化和疾病的晚期相关。然而，到目前为止，对于抗凋亡的Bcl2蛋白在结直肠癌进展中的病理生理作用知之甚少。本课题组的重点是分析Bcl2、Bclxl和Mcl-1在结直肠癌发生、发展和转移中的作用。首先，我们计划在异种移植小鼠模型中研究Mcl-1、Bclxl和Bcl2的表达后，人结直肠癌细胞系在体内外的侵袭、生长和转移。此外，我们的目标是分析肠道特异的Mcl-1、Bclxl和Bcl2基因敲除小鼠模型中自发和致癌物诱导的结直肠癌的发生和发展。此外，我们还打算研究Mcl-1、Bcl一xl和Bcl一2在包括循环和播散性肿瘤细胞在内的人类结直肠癌标本中的表达模式及其预后价值。原发肿瘤以及相应的淋巴结和肝转移瘤将通过高分辨率自动显微镜进行分析，以绘制肿瘤样本中Bcl2蛋白的表达图。最后，结直肠癌患者血清和组织样本中的miRNA图谱应该有助于识别与调控Bcl2、Bclxl和Mcl-1相关的miRNAs。综上所述，我们的项目旨在明确抗凋亡的Bcl-2蛋白在结直肠癌发生发展中的作用。这可能有助于在不久的将来确定单独的治疗方法，因为抑制抗凋亡的Bcl-2蛋白的策略已经进入后期临床试验。

The Bcl (B-cell lymphoma)-2 protein family is mainly known due to its pivotal role in the regulation of the mitochondrial death pathway. Besides their inhibitory effects on mitochondrial activation, anti-apoptotic Bcl-2 proteins, such as Bcl-2, Bcl-xL and Mcl-1, also regulate cell cycle and proliferation. In colorectal cancer (CRC), changes in the expression levels of anti-apoptotic Bcl-2 proteins have been described. For example, increased expression of Bcl-xL in CRC tissue correlates with lower tumor differentiation and advanced disease stage. However, so far only little is known about the pathophysiological role of antiapoptotic Bcl-2 proteins in CRC progression. The focus of the subproject is to analyze the role of Bcl-2, Bcl-xL and Mcl-1 for the development, progression and metastases of CRC. First, we plan to investigate invasion, growth and metastases of human CRC cell lines in vitro and in vivo in a xenograft mouse model after manipulation of Mcl-1, Bcl-xL and Bcl-2 expression. Furthermore, we aim to analyze spontaneous as well as carcinogen-induced CRC development and progression in intestinal-specific Mcl-1, Bcl-xL and Bcl-2 knockout mouse models. In addition, we intend to investigate expression patterns of Mcl-1, Bcl-xL and Bcl-2 and their prognostic value in human CRC samples including circulating and disseminated tumor cells. Primary tumors as well as corresponding lymph node and liver metastases will be analysed by high-resolution automated microscopy to map Bcl-2 protein expression in tumor samples. Finally, miRNA profiling in sera and tissue samples of CRC patients should help to identify miRNAs relevant for the regulation of Bcl-2, Bcl-xL and Mcl-1. In conclusion, our project intends to specify the role of anti-apoptotic Bcl-2 proteins in the development and progression of CRC. This may help to identify individual treatment approaches in the near future, since strategies for inhibition of anti-apoptotic Bcl-2 proteins have already entered late-phase clinical trials.