Epigenetic silencing of bone morphogenetic protein (BMP) receptor 1B blocks differentiation in a subset of glioblastoma tumor-initiating cells and contributes to their tumorigenicity.
Tumour-initiating cells (TICs) share functional properties, such as clonogenicity and capability for multilineage differentiation, with normal stem cells. However, Howard Fine and colleagues hypothesized that there might be differences in their differentiation potential and found that epigenetic silencing of bone morphogenetic protein (BMP) receptor 1B (BMPR1B) blocks differentiation in a subset of glioblastoma TICs and contributes to their tumorigenicity.
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Neural stem cells (NSCs) are known to differentiate in response to BMP, which activates downstream SMADs, and ciliary neurotrophic factor (CNTF), which activates the janus kinase (JAK)–STAT (signal transducer and activator of transcription) pathway. The authors found that most TIC lines established from patients with glioblastoma had normal responses to BMP and CNTF. However, one TIC line, 0308-TIC, was non-responsive to CNTF and behaved more like early developmental-stage NSCs isolated from mice. Indeed, CNTF did not activate STAT3 or genes downstream in the JAK–STAT pathway. In addition, rather than inducing a differentiation signal, BMP acted as a mitogen for 0308-TICs as it does for early-stage NSCs. Expression of BMPR1B is required to induce the activation of STAT3 by tyrosine phosphorylation (PY-STAT3) and, although present in later developmental stage NSCs and most TIC lines, BMPR1B is absent from early-stage NSCs and the 0308-TIC line. To confirm the relevance of this lack of BMPR1B, Fine and colleagues overexpressed a constitutively active BMPR1B protein in 0308-TICs — this abolished BMP-induced proliferation, made them responsive to CNTF and led to astroglial differentiation. This potential to differentiate was mediated by STAT3 activity, as inhibition of STAT3 in BMPR1B-overexpressing cells prevented astroglial differentiation. In addition, while intracerebral injection of 0308-TICs into mice led to glioma formation and death, BMPR1B-overexpressing 0308-TICs did not form tumours.
So, what causes the lack of BMPR1B expression in 0308-TICs? No mutations were detected, so Fine and colleagues investigated epigenetic mechanisms. They found that the CpG islands of the BMPR1B gene were heavily methylated in 0308-TICs, and if the BMPR1B promoter was demethylated by treatment with 5-aza-2'-deoxycytidine, expression of BMPR1B mRNA increased and CNTF-mediated PY-STAT3 phosphorylation was restored. When the authors evaluated 54 primary human glioblastomas they found 20% had hypermethylation of the promoter region and reduced BMPR1B mRNA. Consistent with the in vitro data, these glioblastomas did not show significant astroglial differentiation.
It will be interesting to find out to what extent the BMPR1B-associated developmental block contributes to tumorigenesis.
Ezzie Hutchinson
References
Lee, J. et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell13, 69–80 (2008) | Article | PubMed |
20% had hypermethylation of the promoter region and reduced BMPR1B mRNA. Consistent with the in vitro data, these glioblastomas did not show significant astroglial differentiation.