Colorectal cancer (CRC) is the second most common malignant neoplasia in women and men worldwide. The B-cell lymphoma 2 (Bcl-2) protein family is mainly known for its pivotal role in the regulation of the mitochondrial death pathway. Anti-apoptotic Bcl-2 proteins may provide survival benefits and induce therapy resistance in cancer cells. Among anti-apoptotic Bcl-2 proteins, we found solely Bcl-xL strongly upregulated in human CRC specimens. In order to study protein function in the context of tumor initiation and progression in vivo, we generated a mouse model lacking Bcl-xL in intestinal epithelial cells (Bcl-xLIEC-KO). If challenged in an inflammation-driven tumor model, Bcl-xLIEC-KO mice showed a significantly reduced tumor burden with lower tumor numbers per animal and decreased tumor sizes. Analysis of cell death events by immunohistochemistry and immunoblotting revealed a striking increase of apoptosis in Bcl-xL-negative tumors. qRT-PCR and immunohistochemistry excluded changes in proliferative capacity and immune cell infiltration as reasons for the reduced tumor load and thereby identify apoptosis as key mechanism. Human CRC tissue was cultured ex vivo and treated with the small molecule compound ABT-737, which inhibits Bcl-xL and Bcl-2. Under ABT-737 treatment, the amount of apoptotic tumor cells significantly increased compared with controls, whereas proliferation levels remained unaltered. In summary, our findings identify Bcl-xL as a driver in colorectal tumorigenesis and cancer progression, making it a valuable target for clinical application.

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Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease, with a median survival time of less than 9 months and a 5-year survival rate of Ͻ1%. Current advances in surgical, (neo)adjuvant, and palliative treatments have failed to prevent recurrence and ultimate metastasis (1-3).In order to be effective, chemotherapy must reduce the tumor burden, promote anticancer immunity, and alleviate intratumoral immunosuppression (4-6). Forced tumor cell death in an immunogenic manner (i.e., immunogenic cell death [ICD]) has been proposed as the best way to trigger an adaptive immune response, boosting the therapeutic efficacy of a cytoreductive treatment (7,8). Preapoptotic surface exposure of calreticulin (CRT) (as a result of the endoplasmic reticulum stress response), as well as release of ATP (autophagy) and high-mobility group box B1 protein (HMGB1) (late apoptosis/necrosis), is considered the optimal ICD combination for dying tumor cells to enable paracrine activation of dendritic cells and the consequent priming of cytotoxic effectors. The surface exposure of CRT promotes uptake of dying tumor cells by dendritic cells, and the release of HMGB1 engages