The role and regulation of tumour-associated hyaluronan

Abstract

Significantly increased levels of the glycosaminoglycan hyaluronan are often associated with human and animal tumours. In the rabbit V2 carcinoma elevated levels of tumour-associated hyaluronan are also closely correlated with invasiveness. We have therefore initiated studies to better define the role and regulation of hyaluronan synthesis in tumour tissues. In cell culture many tumour cell types have reduced capacities to synthesize hyaluronan even when derived from tumours enriched in hyaluronan. We showed that several of these same cells can nevertheless stimulate hyaluronan synthesis by normal fibroblasts. In the LX-1 human lung carcinoma cell line this stimulatory potential resides in a membrane-bound, heat-sensitive, lipophilic, cell surface glycoprotein. These data suggest that production of tumour-associated hyaluronan occurs via tumour-stromal cell interactions. We recently demonstrated that some human tumour cells also possess unoccupied, high affinity, cell surface binding sites for hyaluronan which may allow tumour cells to interact directly with hyaluronan-enriched extracellular matrices. This interaction may in turn allow tumour cells to use hyaluronan as a support for adhesion and locomotion. The spatial organization of hyaluronan could then function to guide tumour cells into surrounding stroma. We attempted to visualize this spatial deposition of hyaluronan in situ within frozen sections of human tumour tissue using a morphological probe that specifically recognizes hyaluronan. Hyaluronan appears most prominently in the partially degraded connective tissue.