Speeding up Sonic Hedgehog slows cancer down
In order to grow, cancer cells shut down or over-activate genes that normally maintain a cell’s health. The Sonic Hedgehog gene – named after a Japanese cartoon character – is associated with the cancer of several tissues, including the bladder. In 2014, our team found that losing the Sonic Hedgehog gene (Shh) is necessary for bladder cancers to become aggressive: Shh signals prompt healthy cells near the tumor to inhibit the cancer cell growth, whilst aggressive bladder cancer cells turn off the Shh gene. SungEun Kim, a graduate student in our lab, now investigate how cancer cells switch off the Shh gene and what effect it has on bladder cancer cells and their surrounding tissue if we turn this gene back on.
DNA sequencing the bladder cancer cells of nearly 400 patients showed that there were no genetic deletions or mutations within the Shh gene. However, the Shh gene and nearby regions of DNA did contain methylations – a chemical modification that generally switches off genes. When mice with early stages of bladder cancer were treated with a drug that inhibits methylation, the Shh gene turned back on, the bladder cancers stopped growing and the tumors stayed at an early stage of development. When the same drug was used on mice with aggressive bladder cancer, this caused non-cancer cells in the surrounding tissue to respond to the Shh, sending tumor restraining signals back to the tumor, and eventually stopping cancer growth and converting the tumor into a less aggressive type of bladder cancer. This work was recently published in journal eLIFE.
Human patients with the worst prognosis tend to have the aggressive type of bladder cancer with low activity of the Shhgene, and drugs that decrease methylation and turn on the Shh gene could be a way of managing cancer in these patients. However, future studies will need to further understand what exactly happens within cancer cells during tumor conversion and to determine if this kind of intervention could have unintended consequences.