Canine and Human Insulinoma: prognostic factors, druggable genes and cancer stem cells

Abstract

Insulinoma (INS), which causes clinical signs associated with hypoglycaemia, is the most common pancreatic neuroendocrine tumour (pNET) of dogs and humans. Ten tot fifteen percent of human INS metastasise to regional lymph nodes and the liver, and these are referred to as ‘malignant INS’. Surgical excision of malignant INS is rarely complete and malignant INS generally respond poorly to traditional chemotherapeutic agent regimens. Therefore, recurrence is likely, leading to decreased survival times in affected individuals. In the dog, the biological course of INS resembles that of malignant INS in humans, since >95% of these canine tumours metastasise. In the dog, as in humans, surgery along with optional post-operative medical therapy, remains the recommended approach when possible. However, the prognosis for canine INS is still poor, because primary INS is frequently inoperable and/or micrometastases are missed during surgery. Therefore, novel approaches are needed to improve diagnosis, therapy and prognosis for both canine and human INS. Comparative oncology aims to utilise spontaneous tumours in pet animals as sophisticated models for the study of human cancer biology and therapy. Since the release of the canine genome in 2005, cancer in dogs has been repeatedly emphasised as an excellent model for humans. Naturally-occurring cancer in dogs and humans share similarities in histology, tumour biology, and response to conventional therapies. Regarding the close resemblance to human malignant INS, canine INS forms an interesting study model for human INS. Novel targets for human and canine INS therapy may be identified by uncovering the pathways underlying tumourigenesis of canine INS. The aims of this study were to: 1.Develop a novel surgical technique for resection of canine insulinomas and abdominal lymph node metastases; 2.Establish reliable prognostic biomarkers for canine insulinomas that facilitate optimal patient management; 3.Identify novel druggable targets in canine and human insulinomas. It was demonstrated that partial pancreatectomy using a bipolar vessel-sealing device (BVSD) was a safe and viable alternative to conventional methods of pancreatectomy for canine INS. BVSD pancreatectomy in dogs with INS significantly decreased operative and hospitalisation times and was not associated with more clinical complications than conventional pancreatectomy. Tumour size, TNM stage, stromal fibrosis and the Ki67 index proved to be useful parameters to predict clinical behaviour of canine INS. Novel druggable genes in canine and human INS were identified, using quantitative real-time PCR, and microarray analysis. Using flow cytometric analysis, athymic mice and zebrafish embryo xenografts assays, CD90 was identified as insulinoma cancer stem cell marker with the potential to serve as a druggable target.