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

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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.