In several of these cases, activation of HH-GLI signaling is mediated by overproduction of HH ligands (e.g., prostate cancer), loss-of-function mutations in <i>PTCH1</i> or gain-of-function mutations in <i>SMO</i>, which occur in the majority of basal cell carcinoma (BCC), SHH-subtype medulloblastoma and rhabdomyosarcoma.
In conjunction with CD15, proliferating CD24+/CD15+ granule cell precursors (GCPs) were identified as a TIC population in Ptch1 deleted medulloblastoma.
Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma.
Shh-associated MBs originate postnatally, from dysregulated hyperproliferation of GCPs in developing cerebellum's external granular layer (EGL), as shown in heterozygous Ptch1<sup>+/-</sup> knock-out mouse strains that model human MB occurrence and progression.
We firstly isolated CSCs from Sonic Hedgehog (SHH) MB derived from Ptch1 heterozygous mice and compared their expression level of EMT-related transcripts and microRNAs with cerebellar NSCs.
Nevoid basal cell carcinoma syndrome (NBCCS), caused by a PTCH1 mutation in the hedgehog signaling pathway, occasionally exhibits macrocephaly and medulloblastoma.
Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (<i>PTCH1)</i> and Suppressor of fused (<i>SUFU)</i><i>SUFU</i> mutation carriers appear to have an especially high risk of early-onset medulloblastoma.
Mice heterozygous for patched homolog 1 mutations, like heterozygous patched 1 humans, have a higher incidence of Shh subgroup medulloblastoma (MB) and other tumors.
These findings demonstrate an indispensable role for astrocytes in MB tumorigenesis and reveal a novel Ptch1-independent Shh pathway involved in MB progression.<i></i>.
Patched1 heterozygous (Ptch1 <sup>+/-</sup>) mice, carrying a germ-line heterozygous inactivating mutation in the Ptch1 gene, the Shh receptor and negative regulator of the pathway, are uniquely susceptible to MB development after radiation damage in neonatal cerebellum.
Surprisingly, GADD34 homozygous mutation strongly enhanced the ISR, but significantly decreased the incidence of medulloblastoma in adult Ptch1+/- mice.
Using Ptch1(+/-) mice to study medulloblastoma progression, we found that Ptch1 loss of heterozygosity (LOH) is an early event that is associated with high levels of cell senescence in preneoplasia.
Conversely, patients with PTCH1 germline mutations experience Shh overstimulation resulting in Gorlin (Nevoid Basal Cell Carcinoma) syndrome and an increased incidence of malignant transformation of CGNPs leading to medulloblastoma formation.
Eight genetic variants annotating three genes in the sonic hedgehog signaling pathway; CCND2, PTCH1, and GLI2, were found to be associated with the risk of medulloblastoma (P(combined) < 0.05).
Treatment of Med in Ptch1(+/-) Trp53(-/-) mice with the antiestrogen chemotherapeutic drug Faslodex significantly increased symptom-free survival, which was associated with increased apoptosis and decreased BCL2 and IGF1R expression and signaling.
Each SUFU-positive family included a single case of medulloblastoma, whereas only two (1.7%) of 115 individuals with Gorlin syndrome and a PTCH1 mutation developed medulloblastoma.
Together, our results indicate that DNA damage promoted by Boc leads to the demise of its own coreceptor, Ptch1, and consequently medulloblastoma progression.
By combining SB mutagenesis with Patched1 heterozygous mice (Ptch1(lacZ/+)), we observed an increased frequency of MB and decreased tumor-free survival compared with Ptch1(lacZ/+) controls.
Abnormal activation of components of the Hedgehog pathway--specifically, resulting from mutations in the Patched 1 gene--is associated with the development of basal cell carcinoma, as well as several other cancers, including medulloblastoma.