Endocrine Abstracts

While just a few years ago we rarely thought about genetics when looking after patients with pituitary tumours, now this aspect of endocrinology, similar to many others, is keeping the genetic labs increasingly busy. Understanding the molecular mechanisms involved in pituitary tumorigenesis and discovering the importance of the microenvironment of these tumours led to deeper understanding of pituitary tumorigenesis. Applying these new discoveries to predict tumour behaviour and to design novel therapies are the challenge what pituitary researchers are facing now. Our lab concentrated on the role of one of the genes that is associated with the development of adenomas/pituitary neuroendocrine tumours. Loss-of-function heterozygote germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene predispose to young-onset growth hormone- or prolactin-secreting tumours, which are often large and grow invasively. This is puzzling: why only young-onset; why only growth hormone- or prolactin-secreting tumours and why more aggressive than sporadic tumours? Using various in vitro and in vivo models, while enjoying working with skilful and talented collaborators, we attempted to answer these interesting questions. Acting as a co-chaperone, AIP interacts with the intracellular fragment of the RET receptor, activating a pathway involving PIT1 and leading to p53 accumulation and apoptosis. In one of our mouse models the pituitary-specific loss of AIP leads to abnormal pituitary development. We hypothesise that altered pituitary development may explain the strictly young-onset nature of the disease. As AIP mutation positive tumours are often large and invasive, we studied the tumour microenvironment in human and rodent samples and identified pathways leading to upregulation of pathways leading to cytokine activation and macrophage infiltration. These are just examples, how clinical observations lead to studies explaining the observed phenotype and potentially lead to better diagnostic, prognostic and therapeutic options.