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• W2332592059 abstract "Medulloblastoma driven by Wnt/β-catenin and Sonic hedgehog pathway mutations show favorable and poor patient survival upon treatment, respectively. In this Cancer Cell issue, Phoenix et al., 2016Phoenix T.N. Patmore D.M. Boop S. Boulos N. Jacus M.O. Patel Y.T. Roussel M.F. Finkelstein D. Goumnerova L. Perreault S. et al.Cancer Cell. 2016; 29 (this issue): 508-522Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar report disruption of the blood-brain barrier by Wif1 specifically in Wnt-driven medulloblastoma, resulting in increased treatment response and survival in mouse models. Medulloblastoma driven by Wnt/β-catenin and Sonic hedgehog pathway mutations show favorable and poor patient survival upon treatment, respectively. In this Cancer Cell issue, Phoenix et al., 2016Phoenix T.N. Patmore D.M. Boop S. Boulos N. Jacus M.O. Patel Y.T. Roussel M.F. Finkelstein D. Goumnerova L. Perreault S. et al.Cancer Cell. 2016; 29 (this issue): 508-522Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar report disruption of the blood-brain barrier by Wif1 specifically in Wnt-driven medulloblastoma, resulting in increased treatment response and survival in mouse models. Medulloblastoma (MB) is the most frequent primary malignant brain tumor in infants and adolescents. The traditional treatment regime of children >3 years of age encompasses surgery, radiation to the entire cranio-spinal axis, and chemotherapy with cisplatin, carboplatin, cyclophosphamide, or vincristine. The highly efficacious, cranio-spinal radiotherapy is often accompanied with severe side effects such as emotional disorders, pain, seizures, and an increased risk for developing secondary malignancies (Turner et al., 2009Turner C.D. Rey-Casserly C. Liptak C.C. Chordas C. J. Child Neurol. 2009; 24: 1455-1463Crossref PubMed Scopus (149) Google Scholar). Consequently, alternative treatment options are urgently needed to maximize not only progression-free survival but also quality of life. Only recently, distinct molecular subgroups of medulloblastoma were defined, differing in genetic, as well as in transcriptional and clinical, aspects (Taylor et al., 2012Taylor M.D. Northcott P.A. Korshunov A. Remke M. Cho Y.-J. Clifford S.C. Eberhart C.G. Parsons D.W. Rutkowski S. Gajjar A. et al.Acta Neuropathol. 2012; 123: 465-472Crossref PubMed Scopus (1245) Google Scholar). Genome-wide DNA and mRNA expression profiling of primary MB identified four subgroups named after WNT and Sonic hedgehog (SHH) pathway activation, as well as group 3 and group 4, in which no mutated pathways were identified but correlation with MYC/MYCN amplification was seen. This classification provides new opportunities for personalized therapy, depending on mutation-related diagnosis. Interestingly, while SHH-driven MBs and group 3 have intermediate to poor prognosis, depending on the different mutations, WNT-driven MBs have by far the best prognosis among the four subgroups (Ramaswamy et al., 2016Ramaswamy V. Remke M. Adamski J. Bartels U. Tabori U. Wang X. Huang A. Hawkins C. Mabbott D. Laperriere N. et al.Neuro Oncol. 2016; 18: 291-297Crossref PubMed Scopus (97) Google Scholar). Hence, the trend leads toward a reduced therapy for the Wnt-driven sub-group with less-aggressive radiation and chemotherapy (Ramaswamy et al., 2016Ramaswamy V. Remke M. Adamski J. Bartels U. Tabori U. Wang X. Huang A. Hawkins C. Mabbott D. Laperriere N. et al.Neuro Oncol. 2016; 18: 291-297Crossref PubMed Scopus (97) Google Scholar). However, the answer to the crucial question regarding the biological reason for the better responsiveness of WNT-type MBs and, consequently, for their better prognosis and patient survival was essentially unclear. This is particularly relevant, as aberrant Wnt/β-catenin activation strongly correlates with neoplastic transformation in colorectal carcinoma (CRC), breast cancer, and some forms of melanoma. Therefore, the favorable prognosis of Wnt-type MB appears to create a paradox. Although all forms of MB are not described to be highly angiogenic tumors, Phoenix and colleagues picked up the emerging concept in the field that the tumor stroma, including blood vessels, pericytes/smooth muscle, and inflammatory cells, plays a crucial role in tumor progression, therapy response, and resistance (Hanahan and Coussens, 2012Hanahan D. Coussens L.M. Cancer Cell. 2012; 21: 309-322Abstract Full Text Full Text PDF PubMed Scopus (2895) Google Scholar, Phoenix et al., 2016Phoenix T.N. Patmore D.M. Boop S. Boulos N. Jacus M.O. Patel Y.T. Roussel M.F. Finkelstein D. Goumnerova L. Perreault S. et al.Cancer Cell. 2016; 29 (this issue): 508-522Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). Specifically, the authors described that in human biopsies and in tumors from mouse models of WNT-, SHH-, and MYC-type MB, soluble Wnt pathway inhibitors such as Dickkopf 1 (Dkk1) and Wnt inhibitor factor 1 (Wif1) are highly upregulated in the Wnt-type MB, whereas they showed low-level expression in the Shh- and the MYC-type MB. Along with the expression of Wnt/β-catenin targets in tumor cells, the authors observed a considerable reduction of blood-brain barrier (BBB) characteristics and pronounced fenestrations in tumoral blood vessels that were not apparent in the three other MB sup-groups. Given the well-characterized role of the Wnt/β-catenin pathway in BBB formation and maintenance (Engelhardt and Liebner, 2014Engelhardt B. Liebner S. Cell Tissue Res. 2014; 355: 687-699Crossref PubMed Scopus (203) Google Scholar), Phoenix et al. could show that the overexpression of Wif1 leads to diminished Wnt/β-catenin signaling in endothelial cells, resulting in reduced BBB properties of tumor vessels. Moreover, the authors demonstrated that WNT-type MBs specifically responded to the chemotherapeutic drug vincristine in vivo, which exhibits poor BBB penetration in the normal brain, as well as in SHH- and MYC-type MBs (Phoenix et al., 2016Phoenix T.N. Patmore D.M. Boop S. Boulos N. Jacus M.O. Patel Y.T. Roussel M.F. Finkelstein D. Goumnerova L. Perreault S. et al.Cancer Cell. 2016; 29 (this issue): 508-522Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). Consequently, sealing blood vessels in WNT-type MB and BBB opening in SHH-type MB resulted in vincristine-resistant WNT-type and vincristine-responsive SHH-type MBs, respectively. Previously, it has been shown that WNT and SHH pathway activation is mutually exclusive in MB. Therefore, it has been proposed that activation of the WNT pathway in SHH-driven MB might be able to convert the tumor phenotype of the SHH type into the more-favorable phenotype of the WNT type (Pöschl et al., 2014Pöschl J. Bartels M. Ohli J. Bianchi E. Kuteykin-Teplyakov K. Grammel D. Ahlfeld J. Schüller U. Acta Neuropathol. 2014; 127: 605-607Crossref PubMed Scopus (26) Google Scholar, Zhukova et al., 2014Zhukova N. Ramaswamy V. Remke M. Martin D.C. Castelo-Branco P. Zhang C.H. Fraser M. Tse K. Poon R. Shih D.J.H. et al.Acta Neuropathol. Commun. 2014; 2: 174Crossref PubMed Scopus (32) Google Scholar, Zinke et al., 2015Zinke J. Schneider F.T. Harter P.N. Thom S. Ziegler N. Toftgård R. Plate K.H. Liebner S. Mol. Cancer. 2015; 14: 17Crossref PubMed Scopus (42) Google Scholar). In light of the publication by Phoenix et al., it is not surprising that systemic Wnt/β-catenin pathway activation by LiCl treatment in mice, bearing SHH-driven MB, did not show significant reduction of tumor growth. Logically, LiCl will activate Wnt/β-catenin in endothelial as well as in tumor cells, which does not diminish endothelial barrier characteristics. Moreover, these studies did not include a parallel treatment with vincristine or other chemotherapeutic agents. Although the work by Phoenix et al. opens a new therapeutic avenue for the treatment of MB of the Shh group, as well as for groups 3 and 4, some open questions remain. How would cellular specificity of anti-Wnt therapy be achieved in SHH-type MBs, because Wif1 and Dkk1 suppress Wnt-mediated signals not only in blood vessels, but also in tumor cells in which high Wnt activity might be favorable? Mechanistically, Wif1 sequesters Wnt growth factors, consequently reducing the availability for binding to frizzled receptors, whereas Dkk1 interacts with the frizzled co-receptors LRP-5/-6, leading to their internalization. Regarding formation and maintenance of the BBB, the cerebellum appears to have slightly different properties than other regions of the CNS (central nervous system), as activation of endothelial Wnt/β-catenin signaling is mainly mediated by the non-Wnt-related frizzled-4 ligand norrin (Zhou et al., 2014Zhou Y. Wang Y. Tischfield M. Williams J. Smallwood P.M. Rattner A. Taketo M.M. Nathans J. J. Clin. Invest. 2014; 124: 3825-3846Crossref PubMed Scopus (200) Google Scholar). These characteristics raise the question of how Wif1 leads to Wnt/β-catenin pathway inhibition, because Wif1 is not described to bind norrin. Dkk1 instead can interfere with LRP-5 function, which is also required for norrin signaling in the cerebellum. Along this line, merely the lack of Wnt/β-catenin signaling in endothelial cells is not known to lead to the formation of fenestrations, which were frequently observed in the vessel of Wnt-type MB by Phoenix et al. The vascular endothelial growth factor (VEGF)—also known as vascular permeability factor (VPF)—is a described target of Wnt/β-catenin in CRC. Therefore, VEGF is a likely candidate for inducing fenestrations in WNT-type MB vessels. Hence, it will be important to determine which additional consequences result from the over-activation of the Wnt/β-catenin pathway in WNT-type MBs. It should be noted that clinical trials are carried out to test the efficiency of anti-Shh therapy by vismodegib (Erivedge, Roche/Genentech) for SHH-type MB, together with classical chemotherapeutic agents like temozolomide (clinical trial #NCT01601184). According to the present work by Phoenix et al., it could be interesting to combine vismodegib with Wnt/β-catenin inhibitors to render MB blood vessels leaky, and then also apply vincristine or temozolomide. In conclusion, this crucial finding by Phoenix et al. is highly relevant for future therapeutic strategies for MB, particularly for the SHH and MYC/MYCN types. Moreover, this study nicely shows that all cellular compartments and regulated pathways have to be considered, which remains a challenge for targeted therapy but also a chance for the understanding of tumor formation, progression, and therapy resistance. Medulloblastoma Genotype Dictates Blood Brain Barrier PhenotypePhoenix et al.Cancer CellMarch 31, 2016In BriefPhoenix et al. show that medulloblastoma genotype dictates tumor vessel phenotype, partially explaining disparate prognoses among subtypes. WNT-medulloblastoma paracrine signals block endothelial WNT signaling, and manipulation of the paracrine axis can alter chemotherapy permeability and response in vivo. Full-Text PDF Open Archive" @default.
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• W2332592059 title "Blood-Brain Barrier Breakdown Determines Differential Therapeutic Outcome in Genetically Diverse Forms of Medulloblastoma" @default.
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