Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.tumor stroma | cancer therapy | Sonic hedgehog | hedgehog agonist | cerulein P ancreatic ductal adenocarcinoma (PDA) is the fourth most common cause of cancer-related death in the United States and is the most lethal of common human malignancies, with a 5-y survival rate of ∼7% (1, 2). The most effective chemotherapy regimens for metastatic or locally advanced inoperable disease are largely palliative and are capable of extending overall survival by only several months (3, 4). Even localized disease, treatable with surgery followed by adjuvant chemotherapy, has a dismal 5-y survival rate of 24% (1). Among gastrointestinal malignancies, PDA is unique in that it is predominantly driven by oncogenic Kras activity. In addition, PDA pathogenesis is marked by a striking desmoplastic reaction to invading tumor cells. This desmoplasia includes a dense extracellular matrix with abundant stromal fibroblasts and influences the cellular biology of the tumor as well as its response to chemotherapeutic agents.Hedgehog (Hh) signaling has been thought to play a role in PDA desmoplasia and tumor progression but is notable during embryonic development of the pancreas for its absence in the region of embryonic endoderm from which the pancreas forms (5-7). This absence of activity is required for normal specification of early pancreatic progenitor fate, and pharmacologic or antibody treatments that inhibit Hh ...

Our results demonstrated that reference gene choice for qPCR data analysis has a great effect on the study outcome, and that it is necessary to choose a suitable reference for reliable expression data. We recommend miR-16 and miR-93 as suitable reference genes for serum miRNA analysis for gastric cancer patients and healthy controls.

Root colonization of plants with certain rhizobacteria, such as Pseudomonas chlororaphis O6, induces tolerance to biotic and abiotic stresses. Tolerance to drought was correlated with reduced water loss in P. chlororaphis O6-colonized plants and with stomatal closure, indicated by size of stomatal aperture and percentage of closed stomata. Stomatal closure and drought resistance were mediated by production of 2R,3R-butanediol, a volatile metabolite of P. chlororaphis O6. Root colonization with bacteria deficient in 2R,3R-butanediol production showed no induction of drought tolerance. Studies with Arabidopsis mutant lines indicated that induced drought tolerance required the salicylic acid (SA)-, ethylene-, and jasmonic acid-signaling pathways. Both induced drought tolerance and stomatal closure were dependent on Aba-1 and OST-1 kinase. Increases in free SA after drought stress of P. chlororaphis O6-colonized plants and after 2R,3R-butanediol treatment suggested a primary role for SA signaling in induced drought tolerance. We conclude that the bacterial volatile 2R,3R-butanediol was a major determinant in inducing resistance to drought in Arabidopsis through an SA-dependent mechanism.