Identifying therapeutic implications of cancer stem cells in human and canine insulinoma
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Date
30/06/2018Author
Capodanno, Ylenia
Metadata
Abstract
Pancreatic neuroendocrine tumours (PNETs) are the most common neuroendocrine
tumours diagnosed in humans and dogs. Due to the highly heterogeneous nature of
these tumours, definitive data are still lacking over the molecular mechanisms
involved in their cancerous behaviour.
This study focused on insulinoma (INS), as it is the most commonly diagnosed
PNET in human and veterinary oncology. INS is an insulin-producing tumour that
causes a hypoglycaemic syndrome related to the excessive insulin production. In
humans, it is often a small benign neoplasm readily curable by surgical resection
whereas, in dogs, INS is often malignant. Despite current treatment modalities,
malignant canine and human INS have a poor prognosis as patients tend to develop
metastases in liver and lymph nodes that do not respond to current therapies. From a
comparative oncology perspective, the close resemblance
of canine and human malignant INS makes canine INS an interesting study model
for human INS.
Cancer stem cells (CSCs) are critical for the engraftment and chemoresistance of
many tumours. Although CSCs have been isolated from a range of solid tumours, a
comprehensive characterisation of INS CSCs has not yet been reported. In this study,
it was confirmed that INS CSCs can be enriched and are potential targets for novel
INS therapies. Highly invasive and tumourigenic human and canine INS CSCs were
successfully isolated and exhibited greater resistance to chemotherapy, which may
play a significant role in the poor prognosis of this disease. To date, the mechanisms
by which tumours spread and the clinical causes of chemoresistance remain only
partially understood. Here, RNA-sequencing analysis was performed over a small set
of canine INS tumour samples in order to identify mechanisms involved in INS
carcinogenesis through different stages of the disease. Preliminary data showed that
distinct gene profiles characterised early and late stage of canine INS. Interestingly,
differential gene expression and gene pathways analysis, highlighted that sets of
genes involved in pancreatic embryogenesis and insulin secretion were
overexpressed in canine primary INS lesions compared with normal pancreas. The
Notch pathway is fundamental in pancreatic embryogenesis and it has been
previously associated with carcinogenesis of neuroendocrine tumours and with the
CSC phenotype. Protein analysis showed that the Notch pathway is activated in both
human and canine INS CSCs, particularly when treated with chemotherapy,
indicating that the Notch pathway may be involved in chemoresistance. Additionally,
it was demonstrated that inhibition of the Notch pathway decreased INS CSCs'
survival and chemoresistance, both in vitro and in vivo. These findings provide
preclinical evidence that anti-Notch therapy may improve outcomes for patients with
malignant INS.