[The clinical relevance of experimental acute pancreatitis models]. / A kísérletes akut pancreatitismodellek klinikai relevanciája.

The clinical diagnostics and therapeutic standards applied in the routine management of human acute pancreatitis are based on the results of animal experiments and human studies performed in the past several decades. During this time period, a number of experimental acute pancreatitis models have been developed, which allowed us to study the etiopathogenesis of acute pancreatitis, analyzing the local and remote complications of the inflammatory processes and also the preclinical testing of potentially effective drugs and agents. Only animal models are suitable to examine the very early phase of the pathogenetic processes in acute pancreatitis. In recent years, the progress in molecular genetic methods allowed us to create genetically engineered animal models to clarify the role of different mediators in the pathogenetic process. There is no doubt that the results gained from experimental animal studies are of limited value concerning human pancreatitis. Nevertheless, experimental studies seem to be indispensable in the progress of management of human pancreatic disorders.

Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment.

The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here, we report that neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin that promote α5ß1 integrin-dependent fibronectin fibril assembly, matrix stiffness, and tumor growth. Tumor growth and fibronectin fibril assembly were reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo. Mechanistically, the increase in fibronectin fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl that augmented α5ß1 fibronectin fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of fibronectin fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment.