Mutated stem cells trigger pituitary tumours in children

A type of pituitary tumour known as craniopharyngioma appears to form via a different mechanism to that thought to occur in more common tumours, according to a paper in the journal Cell Stem Cell.

The novel findings, generated by a team led by the UCL Institute of Child Health (ICH), will be further explored to better understand how cell signalling triggers the growth of such tumours – the third most common brain tumour in children - and whether new treatments could be devised to block these signals.

The ICH study, funded by the Wellcome Trust, used mouse models to investigate cells in the pituitary gland which are thought to act as stem cells, in that they give rise to all the different cell types in the gland.

Researchers used a genetic approach to follow these cells and the 'daughters' they produced, establishing that they did indeed generate new hormone-producing cells across all the different specialised types.

However, when the original cells acquired a genetic mutation often found in the childhood tumour adamantinomatous craniopharyngioma, instead of dividing uncontrollably to generate the tumour, they sent signals to induce changes in nearby cells, causing the latter to divide and give rise to the tumour. The team now needs to determine how widespread this alternative tumour-forming model is across the range of endocrine tumours and cancers.

The pituitary gland, a small endocrine (hormone-producing) organ, controls a multitude of functions in the body. Termed the 'Master Gland', it directs other organs and endocrine glands by producing hormones that regulate blood sugar, blood pressure, metabolism and growth in children, and also control the sex hormones and thereby reproduction and sexual function.

Pituitary tumours arise in around one in 1,000 people. Most of these tumours are adenomas, which usually respond well to surgery and / or radiotherapy.

Craniopharyngioma, though much rarer, is the third most common brain tumour in children. Craniopharyngioma can behave aggressively and tends to infiltrate nearby structures such as the brain and optic tracts, leading to severe and life-threatening side effects, including blindness, severe obesity, sleep disorders and type 2 diabetes mellitus, which can result in a poor quality of life for many patients.

The molecular mechanisms underlying most pituitary tumours have remained unknown up to now; these tumours rarely contain cells carrying mutations in the most commonly found oncogenes and tumour suppressor genes critical in other human tumours and cancers.

The ICH study reveals a new possible mechanism which could explain how pituitary tumours form.

Professor Mehul Dattani, paediatric endocrinologist at Great Ormond Street Hospital and co-author of the study, says, ''Craniopharyngiomas are currently treated by removing most of the tumour surgically, and then giving the patient radiotherapy. These tumours often recur and there is no specific treatment targeting the mutated stem cells.''

Dr Juan Pedro Martinez-Barbera, who led the research team at the UCL Institute of Child Health, adds, ''The next stage of our research will be to better understand the mechanisms that take place after the cells acquire the mutation which leads to them to produce the tumour-promoting signals. Understanding what signals these cells are releasing in the pituitary gland could help us to find new treatments that specifically block the signals and prevent or slow down the growth of the tumour.

''Advanced cancer can be very powerful, with cells having developed multiple ways to evade the patient's immune system and generate new cancer cells that are resistant to treatments. At the initial stages of tumour formation, tumour cells are easier to target and eliminate. Early diagnosis of cancer and new treatments targeting tumour cells would help to boost survival rates as well as reducing the damaging effects of both cancer and the intensive treatments required to eradicate it.''