New discovery could prevent the development of brain tumours in children.

Scientists at the Institut de Recherches Cliniques de Montréal (IRCM) discovered a mechanism that promotes the progression of medulloblastoma, the most common brain tumour found in children. The team found that a protein known as Sonic Hedgehog induces DNA damage, which causes the cancer to develop. This important breakthrough is published in the journal Developmental Cell.

Sonic Hedgehog belongs to a family of proteins that gives cells the information needed for the embryo to develop properly. It also plays a significant role in tumorigenesis, the process that transforms normal cells into cancer cells.

The team studied a protein called Boc, which is a receptor located on the cell surface that detects Sonic Hedgehog. The researchers had previously shown that Boc is important for the development of the cerebellum, the part of the brain where medulloblastoma arises, so they decided to further investigate its role.

With the current study the group found that the presence of Boc is required for Sonic Hedgehog to induce DNA damage. In fact, Boc causes DNA mutations in tumour cells, which promotes the progression of precancerous lesions into advanced medulloblastoma.  The study shows that when Boc is inactivated, the number of tumours is reduced by 66 per cent.  The inactivation of Boc therefore reduces the development of early medulloblastoma into advanced tumours.

Medulloblastoma ranks among the leading causes of cancer-related mortality in children. Current treatments include surgery, as well as radiation therapy and chemotherapy. Although the majority of children survive the treatment, radiation therapy damages normal brain cells in infants and toddlers and causes long-term harm.

As a result, many children who undergo these treatments suffer serious side effects including cognitive impairment and disorders.  The results indicate that Boc could potentially be targeted to develop a new therapeutic approach that would stop the growth and progression of medulloblastoma and could reduce the adverse side effects of current treatments.

Source:  Institut de Recherches Cliniques de Montréal (IRCM)

 

Boc Promotes MB Progression from a Preneoplastic to an Advanced Stage  (A) In presence of Boc. Boc upregulation increases Shh signaling pathway activity in early MB, and Boc expression is also positively regulated by the Shh signaling pathway. Thus Boc participates in a positive feedback loop increasing Shh signaling. This positive feedback loop promotes the expression of Gli target genes known to stimulate proliferation. In addition, Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1.  Elevated DNA damage increases the incidence of Ptch1 LOH.  (B) After Ptch1 LOH has occurred, the absence of Smo repression due to loss of Ptch1 induces constitutive and ligand-independent expression of Gli target genes, leading to tumor progression to an advanced stage. These advanced tumors are Boc-independent.  (C) In absence of Boc, the positive feedback loop is disrupted. This results in lower proliferation and DNA damage compared to when Boc is present. Consequently, the frequency of Ptch1 LOH is reduced. Mice escaping Ptch1 LOH will not develop advanced MB.  The Shh Receptor Boc Promotes Progression of Early Medulloblastoma to Advanced Tumors.  Charron et al 2014.

Boc Promotes MB Progression from a Preneoplastic to an Advanced Stage (A) In presence of Boc. Boc upregulation increases Shh signaling pathway activity in early MB, and Boc expression is also positively regulated by the Shh signaling pathway. Thus Boc participates in a positive feedback loop increasing Shh signaling.
This positive feedback loop promotes the expression of Gli target genes known to stimulate proliferation. In addition, Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1. Elevated DNA damage increases the incidence of Ptch1 LOH. (B) After Ptch1 LOH has occurred, the absence of Smo repression due to loss of Ptch1 induces constitutive and ligand-independent expression of Gli target genes, leading to tumor progression to an advanced stage. These advanced tumors are Boc-independent. (C) In absence of Boc, the positive feedback loop is disrupted. This results in lower proliferation and DNA damage compared to when Boc is present. Consequently, the frequency of Ptch1 LOH is reduced. Mice escaping Ptch1 LOH will not
develop advanced MB. The Shh Receptor Boc Promotes Progression of Early Medulloblastoma to Advanced Tumors. Charron et al 2014.

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