Cancer senescence: licence to kill

In Nature, researchers headed by Clemens Schmitt from University Hospital Charité in Berlin report that chemotherapy-induced senescence may generate tumour cells that have an enhanced potential to drive tumour growth. In mouse and human cancer cell cultures, the researchers found that epigenetic modification of histone proteins, which supports the switch to cell senescence, also triggers cancer stemness.

Analysing gene-expression profiles in mice with lymphoma, the authors observed that cellular signalling pathways activated during chemotherapy-induced senescence are similar to those observed in stem cells, patterns that collectively define a cellular state called stemness, which drives cancer growth, as well as tumour-cell migration and dispersal to other locations in the body; briefly metastasis. 

To investigate whether these acquired stemness features affect growth when cancer cells escape from senescence, Schmitt and colleagues used a genetically engineered tumour in mice in which a state of cell-cycle arrest could be maintained by administration of the drug tamoxifen Surprisingly, the researchers observed that cells exiting senescence when tamoxifen was removed have a greater capacity to drive tumour growth than do control tumour cells that did not go through a senescent phase.

Thus, in cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. They concluse that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential.

Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. The data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells.