Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion.

Solid cancers like pancreatic ductal adenocarcinoma (PDAC), a type of pancreatic cancer, frequently exploit nerves for rapid dissemination. This neural invasion (NI) is an independent prognostic factor in PDAC, but insufficiently modeled in genetically engineered mouse models (GEMM) of PDAC. Here, we systematically screened for human-like NI in Europe's largest repository of GEMM of PDAC, comprising 295 different genotypes. This phenotype screen uncovered 2 GEMMs of PDAC with human-like NI, which are both characterized by pancreas-specific overexpression of transforming growth factor α (TGF-α) and conditional depletion of p53. Mechanistically, cancer-cell-derived TGF-α upregulated CCL2 secretion from sensory neurons, which induced hyperphosphorylation of the cytoskeletal protein paxillin via CCR4 on cancer cells. This activated the cancer migration machinery and filopodia formation toward neurons. Disrupting CCR4 or paxillin activity limited NI and dampened tumor size and tumor innervation. In human PDAC, phospho-paxillin and TGF-α-expression constituted strong prognostic factors. Therefore, we believe that the TGF-α-CCL2-CCR4-p-paxillin axis is a clinically actionable target for constraining NI and tumor progression in PDAC.

Ferulic acid attenuates pancreaticobiliary duct occlusion-induced inflammation in both pancreas and liver.

INTRODUCTION: Acute pancreatitis is a systemic inflammatory disorder characterized by the hyperactivation of digestion enzymes and the release of proinflammatory cytokines. Ferulic acid (FA) is a hydroxycinnamic acid derivative that has recently been shown to have antioxidant and anti-inflammatory properties. AIM: The anti-inflammatory effects of FA were investigated in the pancreaticobiliary duct ligation (PBDL)-induced pancreatitis model. METHODS: Wistar albino rats (250-300 g; female = male) were divided into sham operation and PBDL groups. Some PBDL-performed animals were given intragastric saline or 250 mg/kg FA or 500 mg/kg FA 30 min before the PBDL and for 3 consecutive days. Moreover, the control group received saline. Blood samples are collected at the 24th, 48th, and 72nd hours to measure serum tumor necrosis factor (TNF)-α, liver, and pancreatic enzymes. At the 72nd hour, rats were euthanized; pancreas, lung, and liver samples were collected, scored microscopically, and analyzed for myeloperoxidase activity, malondialdehyde, and glutathione levels. One-way ANOVA with Tukey-Kramer tests were used for statistical analysis. RESULTS: FA treatment reduced myeloperoxidase activity and prevented the depletion of glutathione in all three tissues. With FA treatments, high malondialdehyde levels in the pancreas and liver were reduced, as were serum TNF- α, amylase, lipase, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels. Additionally, FA ameliorated microscopic damage in the pancreas and liver significantly. CONCLUSION: According to the findings, FA protects endogenous antioxidant content, prevents neutrophil infiltration, and decreases lipid peroxidation in PBDL-induced pancreatitis. Furthermore, FA improves tissue damage induced by pancreatitis with its anti-inflammatory effects.

Caffeic acid attenuates gastric mucosal damage induced by ethanol in rats via nitric oxide modulation.

Anti-oxidant and anti-inflammatory properties of caffeic acid (CA) have been reported recently. In this study, the therapeutic effects of CA on ethanol-induced ulcer and the roles of nitric oxide and cholinergic pathways in these effects were investigated. Ulcer was induced by ethanol via oral gavage. Ulcer induced rats were treated with either vehicle (ulcer group) or CA (100, 250 or 500 mg/kg, per oral gavage). Macroscopic evaluation showed that 250 mg/kg CA was the effective dose. To elucidate the action mechanism of CA, 10 mg/kg l-NAME or 1 mg/kg atropine sulfate was administered to 250 mg/kg CA treated groups. All rats were decapitated 1 h after ulcer induction and gastric samples were scored macroscopically and microscopically, and analyzed for myeloperoxidase (MPO), malondialdehyde (MDA), and glutathione (GSH) levels. ANOVA test was used for statistical analyses. Macroscopic and microscopic damage scores, MDA levels and MPO activity were increased while GSH levels were decreased in ulcer group. Treatment with 250 mg/kg and 500 mg/kg CA reduced macroscopic and microscopic damage scores, decreased MPO activity and MDA levels, and preserved the depleted glutathione significantly. l-NAME administration before CA treatment elevated MDA levels, MPO activity and depleted glutathione. However, atropine sulfate had no effect on biochemical parameters. We conclude that CA ameliorates ethanol-induced gastric mucosal damage, and NO pathway contributes to this effect. On the other hand, there is a lack of evidence for the contribution of the muscarinic cholinergic system.