Molecular characteristics of pancreatic carcinogenesis

Abstract

Ductal adenocarcinoma of the pancreas is a very aggressive disease with a high mortality rate. Pancreatic carcinoma is the fourth leading cause of cancer-related death in Western countries, despite the fact this cancer accounts for only about 3% of all malignant tumors. Most pancreatic cancers (approximately 80%) are diagnosed at a late, incurable stage. The poor prognosis and late presentation of pancreatic cancer patients underscore the importance of early detection, which is the sine qua non for the fight against pancreatic cancer. The possibility for early detection of pancreatic cancer may be realized by increasing our knowledge of the histology and molecular genetics of precursor lesions of pancreatic cancer in conjunction with the development of sensitive and specific screening tests (both invasive and non-invasive) to detect early pancreatic cancer. In this thesis we examined the potential use of MicroRNAs (miRNAs) as a biomarker for the early detection of pancreatic cancer and investigated several signaling pathways to explore their role in pancreatic tumorigenesis and the development of its precursor lesions. We found out that aberrant miRNA expression is an early event in the multistage progression of pancreatic cancer, and specifically miR-155 warrants further evaluation as a biomarker for pancreatic cancer in clinical samples. Furthermore, we looked at the Notch and Axl pathway in the setting of pancreatic cancer. Both pathways play a significant role in pancreatic carcinogenesis. Inhibition of the Notch or Axl pathway, in a panel of pancreatic cancer cell lines, resulted in significant reduction in cell viability, anchorage independent growth, as well as attenuation of migratory and invasive properties. These reports support and emphasize an important function of Notch and Axl in pancreatic cancer and both signaling pathways might be a promising therapeutic strategy in this carcinoma. Finally, we have characterized DNA Damage Response markers (DDR) in PanIN lesions to determine whether or not these are involved in early pancreatic neoplasia. Activation of the ATM-Chk2 checkpoint pathways was commonly observed in PanIN lesions, which suggest that ATM and Chk2 activation at early stage of pancreatic tumorigenesis suppresses tumor progression. Loss of p53 function appears to be a critical determinant for bypassing this checkpoint and the subsequent progression to invasive adenocarcinoma. In summary, the above studies in this thesis describe potential clinically useful biomarkers for pancreatic carcinogenesis. Moreover, our increased knowledge of the Notch and Axl signaling pathway in pancreatic tumorigenesis may provide the basis for developing more sensitive screening strategies and the identification of new drug targets enabling directed drug design. All this will enable us to develop better tools for primary and secondary prevention of pancreatic cancer, as well as improve existing tools for early diagnosis.