CXCR4 Activation Defines a New Subgroup of Sonic Hedgehog-Driven Medulloblastoma

Department of Pediatrics, Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Cancer Research (Impact Factor: 9.33). 11/2011; 72(1):122-32. DOI: 10.1158/0008-5472.CAN-11-1701
Source: PubMed


Medulloblastoma prognosis tends to be poor, despite aggressive therapy, but defining molecular subgroups may identify patients who could benefit from targeted therapies. This study used human gene array and associated clinical data to identify a new molecular subgroup of medulloblastoma characterized by coactivation of the Sonic hedgehog (SHH) and CXCR4 pathways. SHH-CXCR4 tumors were more common in the youngest patients where they were associated with desmoplastic histology. In contrast to tumors activating SHH but not CXCR4, coactivated tumors exhibited greater expression of Math1 and cyclin D1. Treatment with the CXCR4 antagonist AMD3100 inhibited cyclin D1 expression and maximal tumor growth in vivo. Mechanistic investigations revealed that SHH activation stimulated CXCR4 cell surface localization and effector signaling activity, whereas SHH absence caused CXCR4 to assume an intracellular localization. Taken together, our findings define a new medulloblastoma subgroup characterized by a functional interaction between the SHH and CXCR4 pathways, and they provide a rationale to clinically evaluate combined inhibition of SHH and CXCR4 for medulloblastoma treatment.

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Available from: Kristen L Kroll, Aug 12, 2014
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    • "Sexdifferencesinbraintumortherapy FIGURE2|SexdifferencesinthecAMPpathway.(A)ActivationofGαi wasmeasuredbyWesternblotfortheGTPloadedandtotalGαiformsusing akitfromNeweastBiosciencesasdescribed(Senguptaetal.,2012).Male andfemaleNf1−/−astrocytespreparedasdescribed(Warringtonetal., 2015),serumstarvedfor48h,andtreatedwithvehicle(PBS)orCXCL12 (0.1ug/ml,5min).ShownisarepresentativeWesternblotandaplotofthe folddifferencesrelativetothebasalmalecondition,inthemeanandSEMof thefractionofGTPloaded(active)tototalGαi.N=4.*p<0.05,**p<0.005 asdeterminedbytwo-tailedt-test.AccompanyingWesternblotsofCXCR4 withactinloadingcontrolindicatethatdifferencesinGαiactivationarenot theresultofdifferencesinCXCR4expression.(B)CyclicAMPlevelswere "
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    ABSTRACT: A relationship between cyclic adenosine 3', 5'-monophosphate (cAMP) levels and brain tumor biology has been evident for nearly as long as cAMP and its synthetase, adenylate cyclase (ADCY) have been known. The importance of the pathway in brain tumorigenesis has been demonstrated in vitro and in multiple animal models. Recently, we provided human validation for a cooperating oncogenic role for cAMP in brain tumorigenesis when we found that SNPs in ADCY8 were correlated with glioma (brain tumor) risk in individuals with Neurofibromatosis type 1 (NF1). Together, these studies provide a strong rationale for targeting cAMP in brain tumor therapy. However, the cAMP pathway is well-known to be sexually dimorphic, and SNPs in ADCY8 affected glioma risk in a sex-specific fashion, elevating the risk for females while protecting males. The cAMP pathway can be targeted at multiple levels in the regulation of its synthesis and degradation. Sex differences in response to drugs that target cAMP regulators indicate that successful targeting of the cAMP pathway for brain tumor patients is likely to require matching specific mechanisms of drug action with patient sex.
    Frontiers in Pharmacology 08/2015; 6:153. DOI:10.3389/fphar.2015.00153 · 3.80 Impact Factor
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    • "Children diagnosed with sonic hedgehog-activated MB (SHH MB) displaying desmoplastic histology have a good prognosis, while those with non-desmoplastic histology have higher rates of metastasis and an intermediate prognosis, indicating that additional factors to SHH activation account for the clinical dichotomy observed [2-4,17]. Recent evidence shows that CXCR4 signaling, which is critical to the proliferation and migration of granule neuron precursors during development, is dependent on SHH for its activation in MB [13,18,30,31]. This finding, coupled to CXCR4’s reported role in tumor progression [14,16,32,33], point towards dysregulated CXCR4 signaling as a possible key determinant of SHH MB clinical behavior. "
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