Regulation of hyaluronan biosynthesis Expression in vitro and importance for tumor progression

Sammanfattning: Hyaluronan, a component of the extracellular matrix, is synthesized by either of three hyaluronan-synthesizing enzymes termed Has1, Has2 and Has3. The expression level of each Has gene varies between cell types of mesenchymal origin and is differentially regulated in response to external stimuli. For example, stimulation of mesothelial cells with PDGF-BB induced an up-regulation of the Has2 gene, whereas the Has1 and Has3 genes remained unaffected. The induction of Has2 gene expression correlated well with increased Has2 protein levels and accumulation of hyaluronan. Moreover, treatment of mesothelial cells with hydrocortisone suppressed hyaluronan synthesis in cell culture primarily through down-regulation of the Has2 gene. Thus, among the Has isoforms, Has2 seems to be most markedly regulated in response to external stimuli.In an attempt to investigate the importance of hyaluronan in tumor progression, the hyaluronan synthesizing enzyme Has2 and the hyaluronan degrading enzyme Hyal1 were over-expressed in a rat colon adenocarcinoma cell line, PROb. We found that Has2 gene over-expression in colon carcinoma cells promoted cell growth in vitro and progression of transplantable tumors. In contrast, over-expression of Hyal1 lead to a considerable reduction of growth rates both in vivo and in vitro. A linear correlation between tumor growth rate and hyaluronan amount in tumor tissue was observed. In another tumor model, experimental anaplastic thyroid carcinoma, the effects of TGF-? inhibition on hyaluronan and collagen contents in tumor xenografts were investigated. We found that inhibition of TGF-?, a stimulator of hyaluronan and collagen synthesis, lead to reduced collagen deposition whereas the hyaluronan levels in stromal tissue only marginally differed. Our results indicate that a high ratio of collagen to hyaluronan may be characteristic of a pathogenic mechanism that leads to elevated interstitual tumor pressure.