Profiling desmoid tumours and exploring new strategies to prevent and treat desmoid tumours in familial adenomatous polyposis using a novel mouse model
AffiliationSurgery (St Vincent's)
Access StatusOpen Access
© 2018 Dr. Timothy Chittleborough
Desmoid tumour is a benign growth that causes morbidity and mortality from local enlargement. Desmoids are thought to result from dysfunction in WNT signalling. Trauma, including that from surgical intervention, is implicated in the pathogenesis of desmoid tumour, with desmoids often occurring at surgical sites. Patients with familial adenomatous polyposis (FAP) possess a germline mutation in the APC gene on chromosome 5, resulting in numerous colorectal adenomas that inevitably develop into colorectal carcinoma. Patients with FAP undergo prophylactic colectomy to manage risk of future carcinoma. The germline mutation in APC, combined with surgical trauma from prophylactic colectomy, place patients with FAP at a significant risk of future desmoid tumour development. Desmoid tumour is the largest cause of mortality for patients with FAP following prophylactic colectomy. There is controversy regarding the utility of laparoscopic prophylactic colectomy in FAP, with some series suggesting that laparoscopic surgery results in a higher risk of future desmoid tumour. Desmoid tumours in FAP patients occur in the mesentery and abdominal wall. Management options are limited due to the precarious location, often in close relationship to the mesenteric vasculature. Desmoid tumours in this cohort pose significant clinical management challenges, with high recurrence rates after surgical excision, and no consensus on best medical management. Since desmoid tumours are rare tumours, a pre-clinical model would facilitate research in this area. This research thesis describes the development of a novel murine model for abdominal desmoid tumour that occurs in FAP. The Apcmin/+:p53-/- mouse develops numerous abdominal wall desmoid tumours. This model has been validated with histopathology and immunohistochemistry, and has facilitated the development of desmoid tumour cell lines, and xenograft studies in this area. The impact of surgical approach on future desmoid risk was investigated using the Apcmin/+:p53-/- mouse. Mice were subjected to laparotomy or laparoscopy and were then observed until they reached ethical endpoints, at which time an assessment of desmoid tumour burden was made. In the Apcmin/+:p53-/- mouse model, surgical approach had no impact on survival or the number of macroscopically identifiable desmoid tumours. Furthermore, the use of humidification/warming device for open and laparoscopic surgery was trialed and found to have no impact on survival or desmoid tumour burden. This research has also investigated the genomic landscape of human abdominal and abdominal wall desmoid tumours through RNA sequencing and immunohistochemistry. This study has identified that abdominal desmoid tumours share genomic similarity to wild-type gastrointestinal stromal tumours (negative for CD117 and PDGFRα). Sequencing identified a number of pathways (Such as VEGF, EGF and mTOR) involved in desmoid tumour formation that could be targets for therapy.
Keywordsdesmoid tumour; familial adenomatous polyposis
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