Post on 20-Dec-2015
description
Pancreatic cancer therapy using engineered mesenchymal stem
cells
Pancreas
• Two functions - Exocrine and endocrine• Exocrine: The acinar cells generate digestive enzymes. Ductal cells secrete bicarbonate and mucous. Tumour originates from Ductal tissue(95%).
• Endocrine: Islets- β-cells - insulin, α-cells - glucagon, δ-cells – somatostatin, PP cells - pancreatic polypeptide, ε cells - ghrelin. Tumour originates from islet cells (2-4%).
Pancreatic Cancer
• According to 2012 cancer statistics, pancreatic cancer is ranked 10th in terms of new cancer cases and 4th in cancer deaths.
• Pancreatic cancer presents in up to 50% at a locally advanced stage dramatically reducing the chance of curative resection
Pathways - AKT
WNT pathway
Therapies
• Current: – Chemotherapy– Palliative surgery – to relieve pain
• New therapeutic strategies can be categorized as:– RNA interference/ antisense oligonucleotides that inhibits the activated oncogenes.
– restore function of the tumor suppressor genes
• Gene therapy using engineered MSCs with anticancer genes in order to target pancreatic cancer cell lines.
Mesenchymal stem cells
• Group of adult stem cells, sourced from bone marrow.
• Capable of differentiating into tissue of muscle, vascular system, and connective tissue.
• Use of MSCs in therapeutics : easy and fast acquisition ex vivo and ease of transfection.
• Due to tumour migration and incorporation capacity, engineered MSCs together with anticancer genes can be used as a delivery vector to treat pancreatic cancer cells.
Anticancer activity of MSCs
MSCs engineered with anticancer genes are capable of specifically attacking tumour cells through multiple mechanisms :
• tumour-directed migration and incorporation• anticancer agent delivery
Tumour-directed migration
• Advancing tumours continuously produce cytokines, chemokines, and other inflammatory mediators.
• Such signals are capable of attracting respondent cell types such as MSCs.
• IL-8, neurotrophin-3, TGF-, IL-1, TNF-a, platelet-derived growth factor, and EGF have also been shown to enhance MSCs tumour tropism capabilities.
Anticancer agent delivery
• Wnt pathway-induced apoptosis– Inhibitor of Wnt - Sostdc1(Sclerostin domain-containing protein 1)
• Supression of AKT pathway– Inhibitor of PI3K(tumour suppressor PTEN)
• Suicide genes- TK gene and GCV gene
Expected personalized treatment of pancreatic cancer with engineered mesenchymal stem cells