Dissecting the Dual Nature of Hyaluronan in the Tumor Microenvironment

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.

Keywords: CD44; RHAMM; cancer resistance; hyaluronan; hyaluronan receptors; tumor initiation; tumor microenvironment.

Figure 1

Hyaluronan synthesis and fragmentation in normal and tumor microenvironments. (A) Homeostatic skin is characterized by an organized epidermis with the regulated symmetric and asymmetric division of basal keratinocytes. These are covered by layers of HMW-HA coats (blue outline). Dermal fibroblasts are quiescent and HMW-HA is organized into complexes with proteins and proteoglycans. Extracellular LMW-HA accumulation is restricted. (B) Tumor-initiating events result in disorganized growth of epidermal cells and changes to HA organization and processing. HA synthesis increases, hyaluronidases are expressed/released and reactive oxygen/nitrogen species (ROS/NOS) production is high, resulting in HA fragmentation and reduced organization of macromolecular complexes. HMW-HA coats around epidermal cells are reduced. LMW-HA activates fibroblasts (CAFs, cancer-associated or activated fibroblasts) and attracts immune cells [tumor-associated neutrophils (TANs) and tumor-associated macrophages (TAMs)] that produce ROS/NOS. The fragmented and disorganized tumor microenvironment supports tumor proliferation and evasion of immune surveillance. (C) In disease states such as tumors or chronically inflamed tissues, native or HMW-HA synthesis is increased by constitutively elevated HAS expression. LMW-HA accumulates due to increased expression and activity of extracellular hyaluronidase activity and reactive oxygen/nitrogen species (ROS/NOS) produced by stressed tissues. LMW-HA activates pro-migratory and proliferation pathways through CD44, RHAMM and TLR2,4, whose expression is also increased. In a disease such as cancer, HMW-HA contributes to a stem cell-like microenvironment that is immuno-suppressive and may protect tumor cells from DNA damage. (D) The continued accumulation of HMW HA polymers also provides a source for generating LMW-HA that accumulates in tumor microenvironments as shown in (A). These fragments can be targeted by peptide mimetics that bind and sequestering them, preventing their activation of pro-migration and proliferation signaling pathways.

Figure 2

HMW-HA functions in tumor prevention. (A) LMW-HA:CD44 interactions promote proliferation while HMW-HA:CD44 interactions suppress proliferation, which can be mediated by an association of CD44 with the tumor suppressor, Merlin (NF2). HMW-HA:CD44 signals result in cell cycle arrest and are one mechanism for reducing susceptibility to cancer. (B) Dorsal skin of UVB-exposed keratinocyte tumor-susceptible mice treated topically with HMW-hyaluronan-phosphatidylethanolamine (HA-enriched) do not form tumors, accumulate higher levels of HMW-HA (top panels) and CD44 (bottom panels), and lower levels of hyaluronidases than UVB-irradiated controls. Epidermal HA (brown) is detected via an HA-binding biotinylated protein on paraffin-embedded tissue counterstained with hematoxylin (blue). CD44 (red) and RHAMM (green) are detected using pan-antibodies in dorsal skin of mice counterstained with DAPI (blue).