Tumor necrosis factor alpha induces the expression of transforming growth factor alpha and the epidermal growth factor receptor in human pancreatic cancer cells.

Abstract

Recombinant human tumor necrosis factor (TNF)-a increased the expression of epidermal growth factor receptor (EGFR) mRNA and protein in all of six human pancreatic carcinoma cell lines tested. In addition, TNF-a increased the expression of an EGFR ligand, tnorming growth factor (TGF)-a, at the mRNA and protein level in all cell lines. Increased expression ofEGFR protein was assodated with elevated steady-state EGFR mRNA levels. Nuclear run-on analysis showed that increase in EGFR mRNA was due to an increased rate of transcription. Induction of EGFR mRNA expression by TNF-a was abrogated by cycloheximide but occurred independently of TNF-a-induced production of TGF-a protein. Protein kinase A or Gi-type nudeotide-binding proteins were not involved in this process as assessed by using appropriate stimulators and inhibitors of these signal transduction pathways. By contrast, staurosporine, an inhibitor of protein kinase C, partially inhibited, and 4-bromophenacyl bromide, a phospholipase inhibitor, completely inhibited TNF-a-dependent EGFR mRNA expression.The phospholipase C-specific inhibitor tricyclodecan-9-yl xanthogenate did not alter TNF-a-dependent EGFR mRNA expression, suggesting that phospholipase A2 is involved in the modulation of EGFR expression by TNF-a. The simultaneous induction of a ligand/receptor system by TNF-a suggests that this cytokine modulates autocrine growth-regulatory pathways in pancreatic cancer cells.

Aberrant Expression of a Disintegrin and Metalloproteinase 17/Tumor Necrosis Factor-α Converting Enzyme Increases the Malignant Potential in Human Pancreatic Ductal Adenocarcinoma

“…ADAM17/ TACE is considered to be a major supplier of EGFR ligands, including TGF-a, HB-EGF, and amphiregulin in vivo (17,34). Given the involvement of molecules, such as TGF-a, TNF receptors, IL-6R, erbB4, and L-selectin in the development of pancreatic cancer (35)(36)(37), it seems reasonable to postulate that aberrantly expressed ADAM17/TACE acts as the functional sheddase of these molecules (10)(11)(12)38) in PDAC. ADAM17/TACE is also involved in the expression of MUC1 glycoprotein, which is expressed in most PDACs and characterizes an aggressive phenotype (39).…”

Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis

“…The upregulation of TGF-␣ expression that occurs in this model may result both from the effect of cytokines produced by inflammatory cells and from the local regenerative response to cell loss in the cirrhotic liver. 29 TGF-␣, which is produced mainly by hepatocytes, 10 acts both as a paracrine and autocrine factor, induces its own expression, 30 stimulates hepatocyte proliferation, and may cause the onset of liver tumors at least partly through activation of the ERK signaling pathway. In keeping with these data, we observed a decrease in the phosphorylation levels of both EGFR and ERKs in liver tissues with cirrhosis from animals under gefitinib.…”

Targeted chemotherapy by intratumour injection of encapsulated cells engineered to produce CYP2B1, an ifosfamide activating cytochrome P450

“…This cell line has been extensively characterized by us and others. 17,[32][33][34] The cell line carries mutations in codon 12 of the ras oncogene and mutations in exon 5/6 of the p53 tumour suppressor gene while RB1 is wild-type. PaCa-44 cells were grown in RPMI with 10% FCS supplemented with penicillin and streptomycin (Gibco).…”