MRC National Institute for Medical Research, London
Science for Health
A cause of pituitary tumours
15 June 2011
Activation of the Wnt/β-catenin pathway in the developing pituitary gland of mice leads to tumours which resemble rare but potentially devastating tumours in children, scientists at UCL Institute of Child Health and NIMR have found. The research is published in Proceedings of the National Academy of Sciences, USA.
During normal development the Wnt/β-catenin signalling pathway is a critical regulator of stem cells, and has been associated with cancer in many tissues. This pathway controls the maintenance of embryonic and adult progenitor/stem cells, influencing not only their cell numbers but also the balance between self-renewal and differentiation in many tissues and organs. Upsetting this biological process leads to disease, including cancer. Mutations in components of the Wnt pathway have been identified as the molecular mechanism underlying a number of human tumours, including colorectal, epidermal, liver, intestinal, brain, and prostate cancer. In several cases where aberrant Wnt signaling is involved the cellular mechanism underlying tumorigenesis is mediated via progenitor/stem cells.
The anterior pituitary is a major endocrine organ controlling basic physiological functions in vertebrates including growth, metabolism, stress response, and reproduction. It has been shown that the adult anterior pituitary contains cells derived from both embryonic and adult pituitary progenitor/stem cells. Evidence for a possible role of pituitary progenitor/stem cells in the genesis of mouse tumours has been shown recently but the involvement of β-catenin in the genesis of pituitary tumours is not clear.
Paul Le Tissier (pictured), from NIMR’s Division of Molecular Neuroendocrinology, working with Juan Pedro Martinez-Barbera's group at the UCL Institute of Child Health, has investigated these questions by using a genetic approach to stimulate the Wnt pathway in specific pituitary cell types. Their study has shown that continuous activation of the Wnt pathway in progenitor but not differentiated cells of the murine pituitary leads to the development of pituitary tumours that resemble the paediatric form of human craniopharyngioma, ACP.
Using an in vitro culture approach, they demonstrated that Wnt signaling plays an essential role in the specification of the progenitor/stem cell pool in the pituitary gland and that its overactivation leads to an elevation in total numbers and proliferation rate of these cells. This research argues that aberrant expression of mutant β-catenin in pituitary progenitors is likely to play an essential role in the etiology of these tumours, rather than representing a second hit targeted during tumour progression.
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Double immunostaining with anti-ß-catenin (green) and anti-Ki67 (red) antibodies on histological sections of mouse (left) and human (right) adamantinomatous craniopharyngioma. Note that proliferating cells (Ki-67-positive) are detected around the ß-catenin accumulating cell clusters. Research in a newly generated mouse model has provided insights on the cellular and molecular aetiology of these devastating childhood tumours.
Our genetic data have shed light on the role of β-catenin during normal pituitary development and support the concept that human ACP arises from pituitary progenitors. This concept has clinical implications. ACP often behaves aggressively with invasion of the hypothalamus and visual pathways and/or intracranial metastases, making total resection of the tumour difficult. If a conservative surgical approach is taken, tumour recurrence is still high. The presence of tumorigenic progenitors in human ACP may explain why human ACP recurs, and emphasizes the need to identify novel therapies. A better understanding of the molecular and cellular mechanisms underlying ACP will lead to more refined, efficient, and safer treatments.
Paul Le Tissier
Original article
Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans (2011)
Carles Gaston-Massuet, Cynthia Lilian Andoniadou, Massimo Signore, Sujatha A. Jayakody, Nicoletta Charolidi, Roger Kyeyune, Bertrand Vernay, Thomas S. Jacques, Makoto Mark Taketo, Paul Le Tissier, Mehul T. Dattani, and Juan Pedro Martinez-Barbera.
Proceedings of the National Academy of Sciences, USA epub ahead of print. Full-text available
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