Paracrine and autocrine regulation of gene expression by Wnt-inhibitor Dickkopf in wild-type and mutant hepatocytes.

摘要: Cells are able to communicate and coordinate their function within tissues via secreted factors. Aberrant secretion by cancer cells can modulate this intercellular communication, in particular highly organised such as the liver. Hepatocytes, major cell type of liver, secrete Dickkopf (Dkk), which inhibits Wnt/ β-catenin signalling an autocrine paracrine manner. Consequently, Dkk modulates expression target genes. We present a mathematical model that describes regulation hepatic gene under wild-type conditions well presence mutant cells. Our spatial competition Wnt at receptor level, intra-cellular signalling, for 21 individual hepatocytes. Autocrine is mediated through feedback mechanism diffusion along porto-central axis. Along axis APC concentration gradient modelled experimentally detected Simulations demonstrate already single increases overall concentration. The influence on surrounding hepatocytes limited magnitude restricted close proximity. To explore underlying molecular mechanisms, we perform comprehensive analysis parameters coefficient, mutation strength strength. simulations show elevated cell. However, impact these levels confined space magnitude. combination inter- intracellular processes, feedback, signal transduction, allow largely maintain expression.