Epithelial-to-mesenchymal transdifferentiation (EMT) mediated by transforming growth factor-b (TGF-b) signaling leads to aggressive cancer progression. In this study, we identified zinc-a2-glycoprotein (AZGP1, ZAG) as a tumor suppressor in pancreatic ductal adenocarcinoma whose expression is lost due to histone deacetylation. In vitro, ZAG silencing strikingly increased invasiveness of pancreatic cancer cells accompanied by the induction of a mesenchymal phenotype. Expression analysis of a set of EMT markers showed an increase in the expression of mesenchymal markers (vimentin (VIM) and integrin-a5) and a concomitant reduction in the expression of epithelial markers (cadherin 1 (CDH1), desmoplakin and keratin-19). Blockade of endogenous TGF-b signaling inhibited these morphological changes and the downregulation of CDH1, as elicited by ZAG silencing. In a ZAG-negative cell line, human recombinant ZAG (rZAG) specifically inhibited exogenous TGF-b-mediated tumor cell invasion and VIM expression. Furthermore, rZAG blocked TGF-b-mediated ERK2 phosphorylation. PCR array analysis revealed that ZAG-induced epithelial transdifferentiation was accompanied by a series of concerted cellular events including a shift in the energy metabolism and prosurvival signals. Thus, epigenetically regulated ZAG is a novel tumor suppressor essential for maintaining an epithelial phenotype.
Insulin-like growth factor-1 (IGF-1) leads via its receptor IGF-1R to the activation of the PI3K/Akt pathway, providing antiapoptotic signals to pre-malignant and malignant cells. In pancreatic cancer, IGF-1 and its receptor are constitutively overexpressed. Mammalian target of rapamycin (mTOR) is the main mediator of mitogenic stimuli transduced by PI3K/Akt. Interestingly, inhibition of mTOR activates PI3K/Akt by up-regulating IGF-1R signaling. Several targeted agents have been developed to inhibit the activity of IGF-1 or to block IGF-1R. These pharmaceuticals may offer additional ways of stimulating apoptosis in neoplastic cells. Yet, there are difficulties in targeting this pathway: The ideal anti-cancer drug target is expressed only in cancer cells; however, IGF-1 and its receptor IGF-1R are ubiquitously expressed throughout the body. Moreover, when using antibodies against IGF-1R, the structurally similar insulin receptor might also be blocked, leading to hyperglycemia as a severe side effect. There are currently several phase I/II trials investigating IGF-1 and its receptor as a drug target in various kinds of cancer. Specifically, therapeutic effects on pancreatic cancer by combining a humanized monoclonal antibody against IGF-1R with other chemotherapeutics are being investigated. To improve the clinical outcome of mTOR inhibitors such as everolimus, it has been suggested to use combination therapies of mTOR inhibitors and IGF-1/IGF-1R inhibitors. In theory, this would counterbalance the feedback effects of mTOR inhibition on IGF-1 signaling. In conclusion, IGF-1 and its receptor are promising new drug targets in cancer therapy. Combination therapies of IGF-1/IGF-1R inhibitors and mTOR inhibitors could improve the clinical outcome.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with an overall 5-year survival rate of less than 5%. This dismal prognosis is largely due to the advanced stage of the disease at presentation, i.e., the late diagnosis. Therefore, early detection would have the potential to significantly improve the overall prognosis of PDAC patients. Diabetes mellitus (DM) has a high prevalence in PDAC patients and is frequently of new onset. The aim of this study was to analyze whether DM can be utilized as an early disease marker in PDAC. Quantitative RT-PCR analysis and immunohistochemistry for insulin and glucagon was performed in 22 PDAC and 16 normal pancreas tissues. Blood samples of 66 patients suffering from PDAC, 35 DM type 2 patients, and 29 healthy donors were analyzed for insulin, glucagon, C-peptide and glucose levels. Quantitative RT-PCR showed a two-fold increase of the glucagon/insulin ratio in pancreatic cancer tissues in comparison to the normal pancreas. By immunohistochemistry a shift in the expression pattern of glucagon and insulin, i.e., a higher glucagon/insulin ratio was found in PDAC associated islets compared to islets in the normal pancreas. Fasting insulin levels in PDAC patients were lower compared to DM patients. The calculated serum glucagon/ insulin ratio was significantly different between PDAC and DM patients. At a cut-off of 7.4 ng/mU glucagon/insulin, pancreatic cancer induced new-onset DM could be discriminated from type 2 DM with 77% sensitivity and 69% specificity. In conclusion, the suggested serum glucagon/insulin ratio showed significant differences in patients with PDAC related DM and type 2 DM. Therefore, this analysis might help to identify PDAC in patients with new-onset DM in the age group at risk. Larger clinical trials have to confirm these findings.
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