Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal hyaluronan

Cancers are supported by a distinct type of connective tissue stroma, crucial for tumor survival and advancement. Hyaluronan is a major matrix molecule in the stroma of many common tumors, and involved in their growth and spreading. Here we focus in recent data on stromal hyaluronan in human tumors, and that on the surface of the malignant cells. Hyaluronan accumulation is most conspicuous in malignancies that develop in cells and tissues normally devoid of hyaluronan, such as single layered epithelia and their hyaluronan-poor connective tissue stroma. The magnitude of the hyaluronan accumulation in the malignant epithelium itself (e.g. colon and gastric cancers) or tumor stroma (breast, ovarian, prostate cancers) strongly correlates with an unfavorable prognosis of the patient, i.e. advancement of the malignancy. A completely different pattern arises from stratified epithelia that normally produce hyaluronan and are surrounded by a hyaluronan-rich stroma. The cell surface of the latter group of tumors (e.g. squamous cell carcinomas of skin, mouth, larynx and esophagus, and skin melanoma) show abundant hyaluronan which tends to get reduced and patchy in the most advanced stages of the tumors, suggesting enhanced turnover. While the assays of human tumors represent snapshots of currently unknown processes and kinetics of hyaluronan metabolism, it is obvious that hyaluronan accumulation at some stage is an inherent feature in most of the common epithelial malignant tumors. The possible contributions of inflammatory cells, stem cells, mutated stromal cells, or otherwise deranged growth factor exchange between stromal and cancer cells are discussed as possible explanations to hyaluronan abundance in the tumors. The importance of hyaluronan in human tumor progression will be further clarified when drugs become available to modify hyaluronan metabolism.