Transcriptional variations in the wider peritumoral tissue environment of pancreatic cancer.

Transcriptional profiling was performed on 452 RNA preparations isolated from various types of pancreatic tissue from tumour patients and healthy donors, with a particular focus on peritumoral samples. Pancreatic ductal adenocarcinomas (PDAC) and cystic tumours were most different in these non-tumorous tissues surrounding them, whereas the actual tumours exhibited rather similar transcript patterns. The environment of cystic tumours was transcriptionally nearly identical to normal pancreas tissue. In contrast, the tissue around PDAC behaved a lot like the tumour, indicating some kind of field defect, while showing far less molecular resemblance to both chronic pancreatitis and healthy tissue. This suggests that the major pathogenic difference between cystic and ductal tumours may be due to their cellular environment rather than the few variations between the tumours. Lack of correlation between DNA methylation and transcript levels makes it unlikely that the observed field defect in the peritumoral tissue of PDAC is controlled to a large extent by such epigenetic regulation. Functionally, a strikingly large number of autophagy-related transcripts was changed in both PDAC and its peritumoral tissue, but not in other pancreatic tumours. A transcription signature of 15 autophagy-related genes was established that permits a prognosis of survival with high accuracy and indicates the role of autophagy in tumour biology.

Diagnosis of pancreatic ductal adenocarcinoma and chronic pancreatitis by measurement of microRNA abundance in blood and tissue.

A solid process for diagnosis could have a substantial impact on the successful treatment of pancreatic cancer, for which currently mortality is nearly identical to incidence. Variations in the abundance of all microRNA molecules from peripheral blood cells and pancreas tissues were analyzed on microarrays and in part validated by real-time PCR assays. In total, 245 samples from two clinical centers were studied that were obtained from patients with pancreatic ductal adenocarcinoma or chronic pancreatitis and from healthy donors. Utilizing the minimally invasive blood test, receiver operating characteristic (ROC) curves and the corresponding area under the curve (AUC) analysis demonstrated very high sensitivity and specificity of a distinction between healthy people and patients with either cancer or chronic pancreatitis; respective AUC values of 0.973 and 0.950 were obtained. Confirmative and partly even more discriminative diagnosis could be performed on tissue samples with AUC values of 1.0 and 0.937, respectively. In addition, discrimination between cancer and chronic pancreatitis was achieved (AUC = 0.875). Also, several miRNAs were identified that exhibited abundance variations in both tissue and blood samples. The results could have an immediate diagnostic value for the evaluation of tumor reoccurrence in patients, who have undergone curative surgical resection, and for people with a familial risk of pancreatic cancer.

Identification of malignancy factors by analyzing cystic tumors of the pancreas.

AIM: The diversity in the aggressiveness of cystic tumors of the pancreas - ranging from the usually benign serous cystadenoma to lesions of variable degrees of malignancy - was utilized for the identification of molecular factors that are involved in the occurrence of malignancy. METHODS: We analyzed the transcript profiles of different cystic tumor types. The results were confirmed at the protein level by immunohistochemistry. Also, functional studies with siRNA silencing were performed. RESULTS: Expression variations at the RNA and protein level were identified that are closely correlated with the degree of malignancy. Besides, all tumors could be classified effectively by this means. Many of the identified factors had not previously been known to be associated with malignant cystic lesions. siRNA silencing of the gene with the most prominent variation - the anti-apoptotic factor FASTK (Fas-activated serine/threonine kinase) - revealed a regulative effect on several genes known to be relevant to the development of tumors. CONCLUSION: By a molecular analysis of rare types of pancreatic cancer, which are less frequent in terms of disease, variations could be identified that could be critical for the regulation of malignancy and thus relevant to the treatment of also the majority of pancreatic tumors.