Endocrine Abstracts

Phaeochromocytomas are neuroendocrine tumours arising from adrenal medulla chromaffin cells. They are life threatening due to adrenaline and noradrenaline release and potential for metastatic spread. Understanding of phaeochromocytoma pathogenesis is incomplete with limited ability to predict malignant potential. Additionally, once metastatic, response to conventional therapies is disappointing.

Phaeochromocytomas are a common feature of the inherited cancer syndrome von Hippel-Lindau disease, which is caused by loss of function of the VHL protein. As well as its canonical function in degradation of the transcription factor hypoxia-inducible factor, VHL is implicated in formation and maintenance of primary cilia. These are microtubule-based organelles that protrude from the cells, functioning in transduction of extracellular signals. This is dependent on localisation of signalling components to cilia, including proteins linked to pathways that are dysregulated in tumorigenesis. Moreover, cilia are believed to act as a checkpoint for cell division, because they assemble from the basal body, which is a modified centriole and thus required for spindle pole formation at the end of interphase.

In this study we tested the hypothesis that primary cilia structure is disrupted in phaeochromocytomas, observing that incidence and length of primary cilia was reduced in sporadic and inherited phaeochromocytomas relative to normal adjacent tissue. This was also the case in primary cells cultured from phaeochromocytomas. Using the phaeochromocytoma derived PC12 cell line we showed that abrogation of cilia, through knockdown of the ciliary protein IFT88, correlated with an increased rate of cell division (quantified by Ki67 staining). We then investigated if features of the tumour microenvironment impact on ciliary function. These studies revealed that hypoxic conditions and succinate dehydrogenase inhibition result in disrupted cilia structure in the context of phaeochromocytoma.

Our data indicate primary cilia dysfunction is a feature of phaeochromocytomas, potentially contributing to pathogenesis and representing a target for therapeutic intervention.