The Identification and Clinical Significance of Pancreatic Cancer Stem Cells and Their Role for Chemotherapeutic Drug Resistance

Pancreatic ductal adenocarcinoma (PDAC) is rather difficult for early diagnosis and treatment, it is the 10th ~11th rank of cancer for male patients in Taiwan. The overall 5 years survival rate of pancreatic cancer is only 5 to 10%, and the 5 years survival rate of resectable pancreatic cancer is still only 15-20%. The genetic or molecular changes of pancreatic cancer have been studied for years, and they provide only partial information regarding the protein products of mutated or un-regulated genes. Cancer stem cells (CSCs) were found in 1997 and they were proposed not only a model of carcinogenesis, but also related to the mechanism of drug resistance and tumor recurrence in recent years. They have intrinsic detoxifying mechanisms for malignancy, which let them survival from conventional therapy due to multi-drugs resistance. Hence, cancer stem cells targeted therapy is armed for overcoming the drug resistance during chemotherapy and curing tumors. PDAC is usually resistant to chemotherapeutic agents, to overcome the drug resistance through CSCs is feasible way to investigate. The specific aims of this project are to obtain the identification of CSCs from PDAC cell lines or specimens, and investigate their roles in the prognosis of patients with PDAC. The objectives of this project are to set up the complete procedures for isolation and culture of pancreatic CSCs and found the mechanisms related to the resistance of chemotherapeutic agents for PDAC. We now propose a three years project to achieve the aims and objectives: The first year works will include (1). Isolate and culture pancreatic CSCs. (2). Test the characteristics of isolated pancreatic CSCs. (3). Perform different chemotherapeutic drugs sensitivity to pancreatic CSCs from different cell lines. (4). Investigate the role of transporter proteins. The second year works will include (1).Inoculate cultured pancreatic CSCs to the SCID mice. (2). Perform different chemotherapeutic drugs sensitivity to pancreatic CSCs from the growing tumors. (3). Investigate the activity of transporter proteins from pancreatic CSCs after inoculation. (4). Study the prognosis of PDCA patients with positive expression of CD24, CD44 or CD133. The third year works will include (1). Profile the expression of ABC transporters in pancreatic CSCs and silence the ABC transporters by siRNA. (2). Study the gene profiling of pancreatic CSCs by mRNA microarray analysis. (3). Investigate the effects of siRNA against CD44, CD24 or CD133 on pancreatic CSCs in vitro. (4). Evaluate the effects of siRNA therapy targeting CD44, CD24 or CD133 on pancreatic cancer in the mouse xenograft model.

Project ID:PC10007-1141
External Project ID:NSC100-2314-B182-013