Break the loop, escape the cycle?

Increasing evidence suggests that in many cancer types only a minor proportion of cells, the so-called ‘cancer stem cells’, is responsible for fostering continuous tumour growth. Similar to the non-malignant stem cells that maintain tissue homeostasis, cancer stem cells are seemingly able to self-renew indefinitely. A recent study from the lab of Walter Birchmeier, in cooperation with Ulrike Ziebold, published in The EMBO Journal (Wend et al, 2013) suggests that cancer stem cells hijack selfrenewal mechanisms similar to those observed in (induced) pluripotent stem cells. Interestingly, their data indicate that breaking this self-enforcing, proliferative loop might be sufficient to promote cancer stem cell differentiation and exhaust tumour growth. Upon analysing a series of salivary and head and neck squamous cell carcinomas the authors observed that these tumours often expressed high levels of nuclear b-catenin while lacking nuclear phospho-Smad staining, signifying augmented and reduced signalling through the WNT and BMP pathways, respectively. This prompted the authors to assess the role of these two signalling pathways in tumour formation by generating a conditional mouse model that allows the concomitant activation of Wnt/b-catenin (using a dominant-active Ctnnb1allele) and inactivation of BMP signalling (homozygous Bmpr1a) in keratin K14 (K14)expressing epithelial cells. This resulted in the efficient formation of murine salivary tumours that closely resembled high-grade human salivary gland cancers. A powerful method to identify cancer stem cells is to show their ‘tumour initiating’ or ‘tumor propagating’ capacity in transplantation experiments (Al-Hajj et al, 2003). The authors were indeed able to isolate such cells from the murine Bmpr1a;Ctnnb1 salivary gland tumours. Cells with a CD24 ;CD29 marker profile appeared far more efficient in forming tumours upon (serial) transplantation into immunodeficient recipient mice than unsorted tumour cells. Moreover, upon transplantation these CD24 ;CD29 tumour-propagating cells restored the CD24;CD29 profile of the original tumour, with B10% of the tumour cells being CD24 ;CD29 . This highlights a second important hallmark of cancer stem cells: they re-establish the cellular hierarchy of the tumours from which they were isolated, including the self-renewing cancer stem cell compartment. So then what drives this process? Part of the answer came from transcriptional profiling and gene-set enrichment analyses. Compared to non-transformed CD24 ;CD29 cells, the cancerous CD24 ;CD29 population showed enhanced expression of several pluripotency genes. In addition, these cells also displayed increased H3K4me3 (a mark for transcriptionally active promoters) and reduced H3K27me3 (associated with silent promoters) levels. Taken together, these analyses suggested that the