transforming-growth-factor-alpha and Pancreatitis--Chronic

The purpose of this project was to investigate the expression and clinical significance of epidermal growth factor (EGF) and the transforming growth factor-α (TGF-α) in the occurrence and development of chronic pancreatitis and pancreatic cancer.. We recruited 31 patients with chronic pancreatitis, 42 with pancreatic cancer, and 20 with normal pancreas in our hospital. Chronic pancreatitis, pancreatic cancer, and normal pancreas expressed EGF and TGF-α mRNAs as well as EGF and TGF-α proteins.. Immunofluorescence showed that EGF and TGF-α were expressed in chronic pancreatitis and pancreatic cancer, but the expression levels for both proteins were higher in pancreatic cancer. Variance analysis indicated that the differences in the expression levels of EGF and TGF-α in chronic pancreatitis, pancreatic cancer, and normal pancreas were statistically significant. The abnormally elevated expression of EGF and TGF-α are closely associated with the occurrence and development of chronic pancreatitis and pancreatic cancer.. EGF and TGF-α have important research value as indicators to assess the progression of these conditions and provide a new basis for the clinical diagnosis.

Topics: Adult; Aged; Biomarkers; Biomarkers, Tumor; Disease Progression; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Pancreatitis, Chronic; Transforming Growth Factor alpha

The role that transforming growth factor-α (TGF-α) has in chronic pancreatitis and pancreatic cancer has not been fully elucidated. We evaluated the effects of TGF-α on the human pancreatic stellate cell (PSC) line RLT-PSC and primary human PSCs, and the expression levels of TGF-α and metalloproteinase-1 (MMP-1) in human chronic pancreatitis and pancreatic cancer tissues. TGF-α stimulated the proliferation and migration of PSCs. Although the mRNA expression levels of tissue inhibitor of metalloproteinase-1 and α1(I) collagen were unchanged, the mRNA expression levels of MMP-1 increased concomitant with increases in MMP-1 protein levels and collagenase activity. TGF-α-stimulated migration of RLT-PSC cells was partially blocked by tissue inhibitor of metalloproteinase-1 protein and MMP-1 small interfering RNA. MMP-1 was also observed to stimulate the migration of PSCs. TGF-α-induced MMP-1 expression was completely blocked by gefitinib in PSCs. The Ras-ERK and PI3/Akt pathways appear to be involved in the activation of MMP-1 in PSCs. Immunohistochemical analyses showed that MMP-1 expression was significantly increased in the pancreatic interstitial tissues in case of chronic pancreatitis or pancreatic cancer compared with those in case of normal pancreas. In conclusion, TGF-α increased proliferation and migration of PSCs. TGF-α-induced migration of cells may be partly due to upregulation of MMP-1. TGF-α and MMP-1 upregulation may contribute to the pathogenesis of chronic pancreatitis and pancreatic cancer.

Topics: Actins; Adult; Aged; Aged, 80 and over; Cell Line; Cell Proliferation; Cell Survival; ErbB Receptors; Female; Glial Fibrillary Acidic Protein; Humans; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 1; Middle Aged; Pancreatic Neoplasms; Pancreatic Stellate Cells; Pancreatitis, Chronic; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; ras Proteins; RNA, Messenger; Transforming Growth Factor alpha; Transforming Growth Factor beta1

Although chronic pancreatitis is a risk factor for pancreatic ductal adenocarcinoma (PDA), the relationship between chronic pancreatitis and PDA remains obscure. A critical obstacle to understanding the role of chronic pancreatitis is the lack of animal models. To develop one such model, mice were fed long-term with a choline deficient ethionine-supplemented (CDE) diet. Histological evaluation revealed that chronic pancreatitis, characterized by acinar atrophy, fibrosis and well-developed tubular complexes (TCs), was observed after 24 weeks of CDE diet treatment. Furthermore, expression of epidermal growth factor receptor (EGFR) and its ligands; serine protease inhibitor Kazal type 3 (Spink3) and transforming growth factor alpha (TGF alpha) and activation of K-Ras (GTP-Ras formation), which are frequently observed in human PDA, were indeed observed in parallel with TCs formation. Neoplastic lesions were not found after 54 weeks of treatment, suggesting that a continuation of CDE diet or another insult is required for the development of PDA.

Topics: Amylases; Animal Feed; Animals; Biomarkers; Blotting, Western; Choline Deficiency; Disease Models, Animal; ErbB Receptors; Ethionine; Female; Glycoproteins; Mice; Mice, Inbred C57BL; Pancreas; Pancreatitis, Chronic; Prostatic Secretory Proteins; ras Proteins; Transforming Growth Factor alpha; Trypsin Inhibitor, Kazal Pancreatic