Transdifferentiation and transformation of acinar cells in transforming growth factor alpha transgenic mice - a model for pancreatic cancer development

摘要

While in colon cancer a multistep model of carcinogenesis, based on a definitive progression from hyperplasia and dysplasia through benign tumours to malignant invasive carcinoma, is generally accepted, such a sequence is so far not established for pancreatic cancer. Changes in ductal epithelium, ranging from papillary hyperplasia and atypia to carcinoma in situ, are observed in cases of ductal adenocarci-noma, but our current understanding of pancreatic cancer does not allow us to define a clear relationship between the hyperplastic lesions and unequivocal carcinoma. The problem is that papillary hyperplasia without atypia can be seen frequently at autopsy in otherwise 'normal' pancreas, or in patients with chronic pancreatitis. These lesions were thus suspected to be reactive rather than prema-lignant changes. However, the characterization of genetic changes revealed the presence of K-ras mutations in ductal lesions in chronic pancreatitis, classifying them as potentially neoplastic. These observations point towards these lesions representing an initial event in the multistep process towards invasive pancreatic carcinoma. In support of this idea it is interesting that the risk of pancreatic cancer is significantly elevated in subjects with chronic pancreatitis.