g., alcoholic liver disease without steatohepatitis). In our model, proinflammatory cytokines such as IL6, likely derived from Kupffer cells,
VX-809 clinical trial as well as regulators of mitosis such as Survivin may play a major role for hepatocarcinogenesis. Indeed, increased levels of Survivin and IL6 have also been described in human HCC tissues and sera of patients at increased risk for HCC development, respectively.35, 36 Hepatocellular proliferation in livers of Mcl-1Δhep mice preceded HCC development detected in 8-month-old and 12-month-old Mcl-1Δhep animals. These regenerative responses may represent a risk factor for HCC formation by triggering genomic aberrations. In line with this hypothesis, we found genetic aberrations in tumor nodules of Mcl-1Δhep mice by aCGH. Various genomic alterations, including amplifications
and deletions, were observed. We detected liver tumors of varying size from the age of 8 months in Mcl-1Δhep mice. Some liver tumors were small in size and did not (yet) meet the histological criteria of HCC. However, morphology on a macroscopic and histological level of larger tumors, combined with the expression of glutamine synthetase and overt chromosomal aberrations, confirmed them as HCC. In summary, HCC were heterogenous as corroborated by different patterns of morphology, immunohistochemistry (glutamine synthetase, A6) as well as chromosomal aberrations. This argues
against one particular MCE molecular pathway involved in HCC formation in Mcl-1Δhep mice. In contrast it favors Bortezomib cell line the notion that compensatory mechanisms underlie HCC formation in Mcl-1Δhep mice. We show that HCC of Mcl-1Δhep mice revealed no significant expression of Mcl-1, emphasizing that hepatocarcinogenesis in Mcl-1Δhep mice occurs in the absence of the prosurvival protein Mcl-1. Remarkably, Mcl-1 was also found to be highly expressed in human malignancies, including HCC, and is discussed in terms of contributing to apoptosis resistance of HCC cells.12, 13 Thus, depending on the context, Mcl-1 plays seemingly contrary roles in hepatocarcinogenesis. On the one hand, as observed in livers of Mcl-1Δhep mice, Mcl-1 deficiency can result in a hyperapoptotic environment, which provokes compensatory up-regulation of antiapoptotic pathways (e.g., Survivin) and compensatory hyperproliferation, finally resulting in the outgrowth of a malignant cell population. On the other hand, in tumors with Mcl-1–independent initiation, Mcl-1 overexpression can be acquired during tumor progression as an antiapoptotic factor of cancer cells. Whether Mcl-1 up-regulation in human malignancies is causally linked to carcinogenesis or a correlative finding still has to be examined.