<p>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 <i>Has</i> 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 <i>Has2</i> gene, whereas the <i>Has1</i> and <i>Has3</i> genes remained unaffected. The induction of <i>Has2</i> 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 <i>Has2 </i>gene. Thus, among the <i>Has</i> isoforms, <i>Has2</i> seems to be most markedly regulated in response to external stimuli.</p><p>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 <i>Has2</i> gene over-expression in colon carcinoma cells promoted cell growth <i>in vitro</i> and progression of transplantable tumors. In contrast, over-expression of <i>Hyal1 </i>lead to a considerable reduction of growth rates both <i>in vivo</i> and <i>in vitro</i>. 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-β inhibition on hyaluronan and collagen contents in tumor xenografts were investigated. We found that inhibition of TGF-β, 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.</p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-2004 |
| Date | January 2002 |
| Creators | Jacobson, Annica |
| Publisher | Uppsala University, Department of Medical Biochemistry and Microbiology, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
| Relation | Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 0282-7476 ; 1148 |
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