Telomerase limits chromosomal instability and promotes tumor progression at the ‘crisis’ stage of in vivo carcinogenesis

Introduction: During early cancer formation most human epithelial cancers transit through a ‘crisis’ stage characterized by profound chromosomal instability associated with telomere dysfunction and loss of p53 checkpoint function.

Methods: To analyze the role of telomerase reactivation during carcinogenesis at the crisis stage in vivo we generated a mouse model in which hepatocellular cancer (HCC) was induced by chronic liver damage (HBs), telomere dysfunction, targeted p53 deletion, and chromosomal instability thus closely resembling several molecular hallmarks of ‘crisis’ and human HCC.

Results: The formation of HCCs was strongly suppressed in mice lacking telomerase (TERC-) compared to siblings that were genetically rescued for telomerase gene expression (TERC+). Although the level of telomere dysfunction was similar in HCCs of both cohorts, the extent of chromosomal instability was significantly lower in telomerase-positive compared to telomerase-negative tumors. Increased chromosomal instability in telomerase-negative tumors was associated with suppression of tumor cell proliferation and induction of tumor cell apoptosis.

Conclusion: These data indicate that in the context of telomere- and p53-dysfunction telomerase limits chromosomal instability and promotes tumor progression, whereas excessive chromosomal instability evolves in telomerase-negative tumors coinciding with p53-independent tumor suppression.