Dissecting the Dual Nature of Hyaluronan in the Tumor Microenvironment.

Muhan Liu,Eva Turley,Cornelia Tolg

doi:10.3389/fimmu.2019.00947

Muhan Liu, Eva Turley + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2019.00947

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Abstract

Hyaluronan (HA) is a glycosaminoglycan with a simple structure but diverse and often opposing functions. The biological activities of this polysaccharide depend on its molecular weight and the identity of interacting receptors. HA is initially synthesized as high molecular-weight (HMW) polymers, which maintain homeostasis and restrain cell proliferation and migration in normal tissues. These HMW-HA functions are mediated by constitutively expressed receptors including CD44, LYVE-1, and STABILIN2. During normal processes such as tissue remodeling and wound healing, HMW-HA is fragmented into low molecular weight polymers (LMW-HA) by hyaluronidases and free radicals, which promote inflammation, immune cell recruitment and the epithelial cell migration. These functions are mediated by RHAMM and TLR2,4, which coordinate signaling with CD44 and other HA receptors. Tumor cells hijack the normally tightly regulated HA production/fragmentation associated with wound repair/remodeling, and these HA functions participate in driving and maintaining malignant progression. However, elevated HMW-HA production in the absence of fragmentation is linked to cancer resistance. The controlled production of HA polymer sizes and their functions are predicted to be key to dissecting the role of microenvironment in permitting or restraining the oncogenic potential of tissues. This review focuses on the dual nature of HA in cancer initiation vs. resistance, and the therapeutic potential of HA for chemo-prevention and as a target for cancer management.

Highlights

Cancer is the second leading cause of mortality worldwide according to GLOBOCAN estimates, accounting for ∼9.6 million death in 2018 [1]
Increases in hyaluronidases, HAS and HA receptors are significantly linked to reduced survival in colorectal (e.g., HAS2, HMMR, CD44, HYAL1, p = 0.013) [62], and breast [e.g., HAS2, HMMR, HYAL2, p = 0.023, [63] and p = 5.24e-3(64)] cancers
Cell sorting of breast tumor cell lines that bind to high levels of HA identifies highly invasive, metastatic subpopulations [68]. Experimental evidence from these types of studies suggests that elevated high molecular-weight (HMW)-HA accumulation in either the peri-tumor stroma or tumor parenchyma performs several key functions that favor tumor growth in addition to protection from apoptosis

Summary

Dissecting the Dual Nature of Hyaluronan in the Tumor Microenvironment

Reviewed by: Vincent Charles Hascall, Cleveland Clinic Lerner College of Medicine, United States. HA is initially synthesized as high molecular-weight (HMW) polymers, which maintain homeostasis and restrain cell proliferation and migration in normal tissues These HMW-HA functions are mediated by constitutively expressed receptors including CD44, LYVE-1, and STABILIN2. During normal processes such as tissue remodeling and wound healing, HMW-HA is fragmented into low molecular weight polymers (LMW-HA) by hyaluronidases and free radicals, which promote inflammation, immune cell recruitment and the epithelial cell migration. These functions are mediated by RHAMM and TLR2,4, which coordinate signaling with CD44 and other HA receptors.

INTRODUCTION

THE HYALURONOME

Inhibiting HA Synthesis

Findings

CONCLUSIONS