Suppression of Medulloblastoma Lesions by Forced Migration of Preneoplastic Precursor Cells with Intracerebellar Administration of the Chemokine Cxcl3

Ceccarelli, Manuela; Micheli, Laura; Tirone, Felice

doi:10.3389/fphar.2016.00484

Cited by 9 publications

(6 citation statements)

References 28 publications

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“…Then, we hypothesized that, in the Ptch1 +/− /Tis21 KO mouse model, the Cxcl3 down-regulation, by forcing GCPs to remain longer in the EGL under the proliferative influence of Shh instead of migrating internally and differentiating, induces the GCPs to become neoplastic cells. We confirmed our hypothesis by showing that in Ptch1 +/− /Tis21 KO mice the chronic intracerebellar administration of the chemokine Cxcl3 inhibits MB growth (31).…”

Section: Introductionsupporting

confidence: 86%

“…We hypothesized that the defect of migration of the GCPs from the EGL, forcing the GCPs to remain exposed longer to the effect of Shh, may favor mutations, followed by transformation from a preneoplastic to a neoplastic state with proliferative activation. This hypothesis is supported by experimental data showing that the rescue of the defect of migration in Ptch1 +/− /Tis21 KO cerebella by exogenous administration of Cxcl3 significantly reduces MB frequency (31). Additionally, we propose here that the neoplastic transformation in the high frequency Shh-MB model Ptch1 +/− / Tis21 KO could be the result of a synergy between the Tis21 KOdependent down-regulation of Cxcl3, which forces the GCPs to remain in the EGL, and the activation of the PI3K/AKT/mTOR pathway, that fully displays its pro-proliferative effects when the transition from preneoplastic to neoplastic GCPs takes place.…”

Section: Dual Effect Of Tis21 Deletion On Ptch1-dependent Medulloblastoma Development Through Cxcl3-dependent Control Of Migration and Pimentioning

confidence: 59%

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Tumor Growth in the High Frequency Medulloblastoma Mouse Model Ptch1+/−/Tis21KO Has a Specific Activation Signature of the PI3K/AKT/mTOR Pathway and Is Counteracted by the PI3K Inhibitor MEN1611

et al. 2021

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We have previously generated a mouse model (Ptch1+/−/Tis21KO), which displays high frequency spontaneous medulloblastoma, a pediatric tumor of the cerebellum. Early postnatal cerebellar granule cell precursors (GCPs) of this model show, in consequence of the deletion of Tis21, a defect of the Cxcl3-dependent migration. We asked whether this migration defect, which forces GCPs to remain in the proliferative area at the cerebellar surface, would be the only inducer of their high frequency transformation. In this report we show, by further bioinformatic analysis of our microarray data of Ptch1+/−/Tis21KO GCPs, that, in addition to the migration defect, they show activation of the PI3K/AKT/mTOR pathway, as the mRNA levels of several activators of this pathway (e.g., Lars, Rraga, Dgkq, Pdgfd) are up-regulated, while some inhibitors (e.g. Smg1) are down-regulated. No such change is observed in the Ptch1+/− or Tis21KO background alone, indicating a peculiar synergy between these two genotypes. Thus we investigated, by mRNA and protein analysis, the role of PI3K/AKT/mTOR signaling in MBs and in nodules from primary Ptch1+/−/Tis21KO MB allografted in the flanks of immunosuppressed mice. Activation of the PI3K/AKT/mTOR pathway is seen in full-blown Ptch1+/−/Tis21KO MBs, relative to Ptch1+/−/Tis21WT MBs. In Ptch1+/−/Tis21KO MBs we observe that the proliferation of neoplastic GCPs increases while apoptosis decreases, in parallel with hyper-phosphorylation of the mTOR target S6, and, to a lower extent, of AKT. In nodules derived from primary Ptch1+/−/Tis21KO MBs, treatment with MEN1611, a novel PI3K inhibitor, causes a dramatic reduction of tumor growth, inhibiting proliferation and, conversely, increasing apoptosis, also of tumor CD15+ stem cells, responsible for long-term relapses. Additionally, the phosphorylation of AKT, S6 and 4EBP1 was significantly inhibited, indicating inactivation of the PI3K/AKT/mTOR pathway. Thus, PI3K/AKT/mTOR pathway activation contributes to Ptch1+/−/Tis21KO MB development and to high frequency tumorigenesis, observed when the Tis21 gene is down-regulated. MEN1611 could provide a promising therapy for MB, especially for patient with down-regulation of Btg2 (human ortholog of the murine Tis21 gene), which is frequently deregulated in Shh-type MBs.

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Section: Introductionsupporting

confidence: 86%

Section: Dual Effect Of Tis21 Deletion On Ptch1-dependent Medulloblastoma Development Through Cxcl3-dependent Control Of Migration and Pimentioning

confidence: 59%

Tumor Growth in the High Frequency Medulloblastoma Mouse Model Ptch1+/−/Tis21KO Has a Specific Activation Signature of the PI3K/AKT/mTOR Pathway and Is Counteracted by the PI3K Inhibitor MEN1611

et al. 2021

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“…In this regard, we have already identified two molecules that act as tumor suppressors of MB, PC3 TIS21/BTG2 (40,41) and Cxcl3 (74). Then, in this report, we investigated the role in the MB pathogenesis of the PC3 TIS21/BTG2 -related gene Btg1, which we have previously shown to be required for the development and function of the cerebellum by operating basically as a negative regulator of the proliferation of cerebellar cell precursors (GCPs) through inhibition of cyclin D1 (12).…”

Section: Discussionmentioning

confidence: 99%

Deletion of Btg1 Induces Prmt1-Dependent Apoptosis and Increased Stemness in Shh-Type Medulloblastoma Cells Without Affecting Tumor Frequency

et al. 2020

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About 30% of medulloblastomas (MBs), a tumor of the cerebellum, arise from cerebellar granule cell precursors (GCPs) undergoing transformation following activation of the Sonic hedgehog (Shh) pathway. To study this process, we generated a new MB model by crossing Patched1 heterozygous (Ptch1 +/− ) mice, which develop spontaneous Shh-type MBs, with mice lacking B-cell translocation gene 1 (Btg1), a regulator of cerebellar development. In MBs developing in Ptch1 +/− mice, deletion of Btg1 does not alter tumor and lesion frequencies, nor affect the proliferation of neoplastic precursor cells. However, in both tumors and lesions arising in Ptch1 +/− mice, ablation of Btg1 increases by about 25% the apoptotic neoplastic precursor cells, as judged by positivity to activated caspase-3. Moreover, although Btg1 ablation in early postnatal GCPs, developing in the external granule cell layer, leads to a significant increase of proliferation, and decrease of differentiation, relative to wild-type, no synergy occurs with the Ptch1 +/− mutation. However, Btg1 deletion greatly increases apoptosis in postnatal GCPs, with strong synergy between Btg1-null and Ptch1 +/− mutations. That pronounced increase of apoptosis observed in Ptch1 +/− /Btg1 knockout young or neoplastic GCPs may be responsible for the lack of effect of Btg1 ablation on tumorigenesis. This increased apoptosis may be a consequence of increased expression of protein arginine methyltransferase 1 (Prmt1) protein that we observe in Btg1 knockout/Ptch1 +/− MBs. In fact, apoptotic genes, such as BAD, are targets of Prmt1. Moreover, in Btg1-null MBs, we observed a two-fold increase of cells positive to CD15, which labels tumor stem cells, raising the possibility of activation of quiescent tumor cells, known for their role in long-term resistance to treatment and relapses. Thus, Btg1 appears to play a role in cerebellar tumorigenesis by regulating the balance between apoptosis and proliferation during MB development, also influencing the number of tumor stem cells.

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“…The detection of the BrdU incorporation was performed as previously described [ 38 , 43 ]. Briefly, the tumors of mice i.p.…”

Section: Methodsmentioning

confidence: 99%

“…As we revealed by genome-wide analysis, Tis21 affects the migration of GCPs through the direct transcriptional control of the Cxcl3 chemokine [ 38 , 42 ]. The treatment in vivo with Cxcl3 significantly reduces the development of preneoplastic lesions [ 38 , 43 ]. Surprisingly, the Tis21 deletion did not result in changes in the proliferation rate of GCPs in the EGL, likely for the action of the highly homologous family-related gene Btg1 [ 44 ].…”

Section: Introductionmentioning

confidence: 99%

Tis21-gene therapy inhibits medulloblastoma growth in a murine allograft model

et al. 2018

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Medulloblastoma (MB), the tumor of the cerebellum, is the most frequent brain cancer in childhood and a major cause of pediatric mortality. Based on gene profiling, four MB subgroups have been identified, i.e., Wnt or Sonic Hedgehog (Shh) types, and subgroup 3 or 4. The Shh-type MB has been shown to arise from the cerebellar precursors of granule neurons (GCPs), where a hyperactivation of the Shh pathway leads to their neoplastic transformation. We have previously shown that the gene Tis21 (PC3/Btg2) inhibits the proliferation and promotes the differentiation and migration of GCPs. Moreover, the overexpression or the deletion of Tis21 in Patched1 heterozygous mice, a model of spontaneous Shh-type MB, highly reduces or increases, respectively, the frequency of MB. Here we tested whether Tis21 can inhibit MB allografts. Athymic nude mice were subcutaneously grafted with MB cells explanted from Patched1 heterozygous mice. MB allografts were then injected with adeno-associated viruses either carrying Tis21 (AAV-Tis21) or empty (AAV-CBA). We observed that the treatment with AAV-Tis21 significantly inhibited the growth of tumor nodules, as judged by their volume, and reduced the number of proliferating tumor cells (labeled with Ki67 or BrdU), relative to AAV-CBA-treated control mice. In parallel, AAV-Tis21 increased significantly tumor cells labeled with early and late neural differentiation markers. Overall the results suggest that Tis21-gene therapy slows down MB tumor growth through inhibition of proliferation and enhancement of neural differentiation. These results validate Tis21 as a relevant target for MB therapy.

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Suppression of Medulloblastoma Lesions by Forced Migration of Preneoplastic Precursor Cells with Intracerebellar Administration of the Chemokine Cxcl3

Cited by 9 publications

References 28 publications

Tumor Growth in the High Frequency Medulloblastoma Mouse Model Ptch1+/−/Tis21KO Has a Specific Activation Signature of the PI3K/AKT/mTOR Pathway and Is Counteracted by the PI3K Inhibitor MEN1611

Tumor Growth in the High Frequency Medulloblastoma Mouse Model Ptch1+/−/Tis21KO Has a Specific Activation Signature of the PI3K/AKT/mTOR Pathway and Is Counteracted by the PI3K Inhibitor MEN1611

Deletion of Btg1 Induces Prmt1-Dependent Apoptosis and Increased Stemness in Shh-Type Medulloblastoma Cells Without Affecting Tumor Frequency

Tis21-gene therapy inhibits medulloblastoma growth in a murine allograft model

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