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Gremlins Sabotage the Mechanisms of Cancer Stem Cell Differentiation

2014; Cell Press; Volume: 25; Issue: 6 Linguagem: Inglês

10.1016/j.ccr.2014.06.002

1878-3686

Joan Seoane,

Tissue Engineering and Regenerative Medicine

BMP is highly expressed in glioblastoma and promotes differentiation of cancer stem cells (CSCs). Recently, Yan and colleagues found the explanation to this apparent paradox by showing that the antagonist of BMP, Gremlin1, is secreted by CSCs to protect them against the BMP-induced differentiation. BMP is highly expressed in glioblastoma and promotes differentiation of cancer stem cells (CSCs). Recently, Yan and colleagues found the explanation to this apparent paradox by showing that the antagonist of BMP, Gremlin1, is secreted by CSCs to protect them against the BMP-induced differentiation. Tumors often consist of a diverse mosaic of cells exhibiting different genomic alterations and epigenomic status and receiving multiple and pleiotropic extracellular signals. This implies that tumors contain functionally heterogeneous cancer cells with different sensitivities to pharmacological compounds. Within the concept of intratumoral heterogeneity, there is now evidence (through transplantation and lineage tracing experiments) of a population of cells that are more tumorigenic than the rest, are more resistant to DNA damage, and possess a higher capacity to reinitiate tumors. This cell population, called cancer stem cells (CSCs) or cancer-initiating cells, is thought to be in part responsible for tumor relapse and metastasis, making CSCs a crucial therapeutic target. CSCs are considered to have stem cell characteristics including the ability to self-renew or differentiate (Visvader and Lindeman, 2012Visvader J.E. Lindeman G.J. Cell Stem Cell. 2012; 10: 717-728Abstract Full Text Full Text PDF PubMed Scopus (983) Google Scholar). The balance between CSC self-renewal and differentiation is crucial for tumor development, and it is regulated by external cues including transforming growth factor β (TGF-β), Notch, Hedgehog, and Wnt. Work over the past years has shed light onto the role of the TGF-β superfamily of cytokines, including BMPs and TGF-βs, in the control of CSC biology. Interestingly, BMP and TGF-β, being members of the same family, exhibit opposed functions in the context of CSCs. Although BMP has been shown to induce CSC differentiation (Lee et al., 2008Lee J. Son M.J. Woolard K. Donin N.M. Li A. Cheng C.H. Kotliarova S. Kotliarov Y. Walling J. Ahn S. et al.Cancer Cell. 2008; 13: 69-80Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar, Piccirillo et al., 2006Piccirillo S.G. Reynolds B.A. Zanetti N. Lamorte G. Binda E. Broggi G. Brem H. Olivi A. Dimeco F. Vescovi A.L. Nature. 2006; 444: 761-765Crossref PubMed Scopus (979) Google Scholar), TGF-β has been described to induce CSC self-renewal (Ikushima et al., 2009Ikushima H. Todo T. Ino Y. Takahashi M. Miyazawa K. Miyazono K. Cell Stem Cell. 2009; 5: 504-514Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar, Peñuelas et al., 2009Peñuelas S. Anido J. Prieto-Sánchez R.M. Folch G. Barba I. Cuartas I. García-Dorado D. Poca M.A. Sahuquillo J. Baselga J. Seoane J. Cancer Cell. 2009; 15: 315-327Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). Yan et al., 2014Yan K. Wu Q. Yan D.H. Lee C.H. Rahim N. Tritschler I. DeVecchio J. Kalady M.F. Hjelmeland A.B. Rich J.N. Genes Dev. 2014; 28: 1085-1100Crossref PubMed Scopus (103) Google Scholar discerned the mechanism through which CSCs in glioblastoma (GBM) escape BMP-induced differentiation. Because BMP induces CSC differentiation, promoting the loss of CSCs within the tumor, one could predict that BMP is a tumor suppressor. However, BMP is highly expressed in several tumor types, including GBM. To understand this paradox, the authors studied the molecular mechanisms through which BMPs regulate CSC self-renewal. CSCs were isolated from patient samples based on the expression of CD133, and gene expression of CSCs versus non-CSCs was compared. They soon realized that CSCs isolated from GBM tumors exhibit decreased activity of the BMP pathway and, most importantly, they highly express Gremlin1. Being a morphogen with a critical function in embryonic development, BMP activity levels are exquisitely regulated at many different levels. One way to control the BMP cellular response is through the regulation of ligand access to the receptor. Several secreted BMP antagonists, including Gremlin1, act as decoys and sequester BMP ligand to prevent activation of the BMP pathway (Wakefield and Hill, 2013Wakefield L.M. Hill C.S. Nat. Rev. Cancer. 2013; 13: 328-341Crossref PubMed Scopus (287) Google Scholar). Yan et al., 2014Yan K. Wu Q. Yan D.H. Lee C.H. Rahim N. Tritschler I. DeVecchio J. Kalady M.F. Hjelmeland A.B. Rich J.N. Genes Dev. 2014; 28: 1085-1100Crossref PubMed Scopus (103) Google Scholar showed that, despite the high expression of BMP in GBM, CSCs escape the BMP differentiating effect by secreting Gremlin1 (Figure 1). Moreover, they went on to identify the main mediator of Gremlin1 effects on CSC differentiation. Gene expression analysis and further bioinformatic studies identified the CDK inhibitor p21 as the master regulator of a set of genes differentially expressed after knocking down Gremlin1. Interestingly, inhibition of p21 by Gremlin1 was independent of p53, and p21 was regulated at the posttranscriptional level. p21 is a critical regulator of cell proliferation inducing cell cycle arrest in the G1 phase, can regulate apoptosis, and can act as a transcription factor. Importantly, p21 has been reported to be involved in the control of stem cell self-renewal (Warfel and El-Deiry, 2013Warfel N.A. El-Deiry W.S. Curr. Opin. Oncol. 2013; 25: 52-58Crossref PubMed Scopus (230) Google Scholar). However, the effect of p21 on stem cell self-renewal is diverse and depends on the cellular context. On the one side, p21 has been shown to facilitate stem cell self-renewal, while, in other situations, p21 stops cell cycle arrest and promotes differentiation. Yan et al., 2014Yan K. Wu Q. Yan D.H. Lee C.H. Rahim N. Tritschler I. DeVecchio J. Kalady M.F. Hjelmeland A.B. Rich J.N. Genes Dev. 2014; 28: 1085-1100Crossref PubMed Scopus (103) Google Scholar consider that, in their system, p21 acts as an inducer of differentiation. Moreover, p21 is a well-known target of BMP, suggesting that the function of Gremlin1 could consist of preventing the induction of p21 by BMP and consequently inhibiting p21-induced differentiation. Yan and colleagues found the clue to solve the BMP pathway paradox in GBM when considering the mechanism of action of BMP in the context of embryonic development. Cancers often co-opt molecular mechanisms involved in normal embryonic development to their benefit. The exquisite regulation of the BMP pathway found to be crucial for the correct cellular patterning during development is used in cancer to shield CSCs against differentiation. Gremlin1, a critical factor for cell specification, through the control of the exact physiological activity of the morphogen BMP, is secreted by CSCs in GBM to promote CSC self-renewal and maintain a pool of CSCs in the tumor despite the presence of high BMP levels. As expected, this study opens an avenue of questions that warrant further research. For instance, how general is the phenomenon? Does this happen in all GBM tumors or in only some GBM subtypes (i.e., proneural and mesenchymal GBM)? The authors show that mutations in p53 do not impair the effect of Gremlin1 on CSCs, but are there other genomic alterations (i.e., mutations in NF1 or PDGFR) that affect this phenomenon? It has been described that the differentiating capacity of BMP depends on the methylation status of the BMPR1b gene (Lee et al., 2008Lee J. Son M.J. Woolard K. Donin N.M. Li A. Cheng C.H. Kotliarova S. Kotliarov Y. Walling J. Ahn S. et al.Cancer Cell. 2008; 13: 69-80Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar). Is that required for the effect of Gremlin1 on CSCs? The authors based their studies on CSCs that express the membrane marker CD133, but, because there are other CSC markers (i.e., CD44, CD15, the side population assay), is the described mechanism taking place in CSCs expressing other markers besides CD133? Or, is it possible that different GBM tumors present different CSC entities that could be regulated by alternative pathways? Importantly, all these questions have a crucial interest in the clinical context when considering Gremlin1 as a therapeutic target. It will be necessary to identify the tumors in which Gremlin1 acts as an oncogenic factor to select the patients who might benefit from Gremlin1 blockade. This work still leaves another paradox unexplained. BMP is an inducer of the transcription factor Id1 (López-Rovira et al., 2002López-Rovira T. Chalaux E. Massagué J. Rosa J.L. Ventura F. J. Biol. Chem. 2002; 277: 3176-3185Crossref PubMed Scopus (249) Google Scholar), which is highly expressed in CSCs. Moreover, TGF-β induces Id1 and promotes CSC self-renewal (Anido et al., 2010Anido J. Sáez-Borderías A. Gonzàlez-Juncà A. Rodón L. Folch G. Carmona M.A. Prieto-Sánchez R.M. Barba I. Martínez-Sáez E. Prudkin L. et al.Cancer Cell. 2010; 18: 655-668Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar). How can we reconcile the fact that BMP acts as a differentiation cytokine while inducing the expression of Id1? Further research is warranted to fully understand the role of BMP in CSC biology. The work from Yan et al., 2014Yan K. Wu Q. Yan D.H. Lee C.H. Rahim N. Tritschler I. DeVecchio J. Kalady M.F. Hjelmeland A.B. Rich J.N. Genes Dev. 2014; 28: 1085-1100Crossref PubMed Scopus (103) Google Scholar begins to explain the molecular mechanisms implicated in the finely regulated balance between CSC self-renewal and differentiation. This phenomenon is at the core of the intratumoral heterogeneity caused by cell differentiation and has critical therapeutic implications. The interplay between CSCs and non-CSCs is considered to regulate the ability of tumors to reinitiate. Therapies tackling the balance between CSC self-renewal and differentiation are needed to prevent CSC-dependent reinitiation of tumors in the same primary location (relapse) or in a distant location (metastasis). Moreover, the induction of CSC differentiation might sensitize tumors to chemo- and radiotherapy, because CSCs are more resistant to these types of DNA damage-inflicting treatments. In this context, Gremlin1 appears to be a very interesting therapeutic target in GBM, and further work is needed to assess whether the pharmacological blockade of Gremlin1 in isolation or in combination with BMP might provide hope against this dismal disease.