Hyaluronan: from extracellular glue to pericellular cue

Key Points

  • Hyaluronan is a large, negatively charged polysaccharide that participates in defining the properties of pericellular matrices and in transducing signals in proliferating and migrating cells.

  • Hyaluronan and hyaluronidase are overproduced in many types of human tumour.

  • Experimentally increased hyaluronan production stimulates tumour growth and metastasis in xenograft models, whereas antagonists of hyaluronan synthesis or of the interactions between hyaluranon and its receptors suppress these phenomena.

  • Interactions between hyaluronan and tumour cell-surface receptors influence many intracellular signalling pathways, notably ERBB2 activity and anti-apoptotic pathways.

  • Increased production of hyaluronan induces drug resistance, whereas hyaluronan antagonists suppress multidrug resistance.

  • Hyaluronan promotes cell invasiveness and epithelial–mesenchymal transition.

  • Breakdown products of hyaluronan stimulate angiogenesis.

Abstract

Hyaluronan is an extracellular and cell-surface-associated polysaccharide that is traditionally regarded as a biological 'goo' that participates in lubricating joints or holding together gel-like connective tissues. Although these are common physiological roles of hyaluronan in adult organisms, hyaluronan also functions as a microenvironmental cue that co-regulates cell behaviour during embryonic development, healing processes, inflammation and tumour development. Recent work highlights a key role for interactions between hyaluronan and tumour cells in several aspects of malignancy and indicates the possibility of new therapeutic strategies.

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Figure 1: Hyaluronan interactions with the cell surface.
Figure 2: Perturbation of hyaluronan function.
Figure 3: Cooperative signalling by hyaluronan receptors and ERBB2.
Figure 4: Hyaluronan and drug resistance.

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Acknowledgements

The author thanks the many colleagues, especially S. Misra and S. Ghatak, who contributed to the work described in this review and provided a critique of the manuscript and many helpful suggestions. He also apologizes to the authors of many interesting studies that were omitted due to limited space.

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DATABASES

Cancer.gov

bladder cancer

brain cancer

breast cancer

colorectal cancer

gastric cancer

head and neck cancer

kidney cancer

lung cancer

melanoma

non-small-cell lung cancer

ovarian cancer

prostate cancer

Entrez Gene

AKT

CD44

EMMPRIN

ERBB1

ERBB2

ERBB3

ERBB4

ezrin

FAK

HAS1

HAS2

HAS3

HYAL1

MMP2

MMP9

PI3K

RHAMM

FURTHER INFORMATION

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Glossary

PROTEOGLYCANS

Specialized glycoproteins with polysaccharide side chains known as glycosaminoglycans. Glycosaminoglycans — such as chondroitin sulphate, heparin and hyaluronan — are composed of repeating disaccharides, which are highly negatively charged as they contain carboxyl and/or sulphate groups. Proteoglycans are characteristic components of extracellular matrices and the cell surface.

STROMA

Most organs are composed of two associated compartments — the parenchyma and stroma. In adult organisms, the stroma is composed of connective tissue and contains fibroblasts, cells derived from the circulation, blood vessels, nerves and associated extracellular matrices. Carcinomas usually contain an extensive stromal compartment.

PARENCHYMA

The parenchyma is regarded as the 'business' part of an organ. It is composed of epithelial or epithelial-like cells that produce the characteristic structures of the differentiated organ.

ASCITES

When tumour cells accumulate in the peritoneal cavity, a voluminous fluid exudate forms — known as ascites —in which the cancer cells are suspended. This phenomenon is common in ovarian carcinomas and mesotheliomas.

EPITHELIAL–MESENCHYMAL TRANSITION

Conversion from an epithelial to a mesenchymal phenotype, which is a normal process of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

MUCINS

Large extracellular and cell-surface glycoproteins with numerous oligosaccharide side-groups. Mucins have several physiological functions, including signal transduction. Their expression and glycosylation are altered in cancer cells.

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Toole, B. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 4, 528–539 (2004). https://doi.org/10.1038/nrc1391

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