Hyaluronan and RHAMM in wound repair and the "cancerization" of stromal tissues

Abstract

Tumors and wounds share many similarities including loss of tissue architecture, cell polarity and cell differentiation, aberrant extracellular matrix (ECM) remodeling (Ballard et al., 2006) increased inflammation, angiogenesis, and elevated cell migration and proliferation. Whereas these changes are transient in repairing wounds, tumors do not regain tissue architecture but rather their continued progression is fueled in part by loss of normal tissue structure. As a result tumors are often described as wounds that do not heal. The ECM component hyaluronan (HA) and its receptor RHAMM have both been implicated in wound repair and tumor progression. This review highlights the similarities and differences in their roles during these processes and proposes that RHAMM-regulated wound repair functions may contribute to "cancerization" of the tumor microenvironment.

Figure 1

Schematic summarizing wound and tumor microenvironment remodeling in skin. The normal tissue architecture of skin is well-organized in both the epidermis, which consists of differentiated cohesive keratinocytes, and the dermis, which is composed of fibroblasts, blood vessels, and well-organized collagen fibrils amongst other ECM components. Tissue injury results in temporary changes in tissue architecture as keratinocytes dedifferentiate and migrate across wound gaps, proinflammatory macrophages migrate into the dermis, angiogenesis is promoted, and subpopulations of fibroblasts differentiate into myofibroblasts that organize collagen fibrils, which contribute to scar tissue. Tumor initiation also results in dedifferentiation, proliferation and migration/invasion of keratinocytes, influx of macrophages, differentiation of fibroblasts into myofibroblasts that increase deposition and scar like organization of collagen fibrils, and formation of new immature blood vessels. However, this disorganized tissue architecture is not transient as it is in wound repair but increases with tumor progression.

Figure 2

HA functions are molecular weight dependent. HA occurs as a large native polymer in homeostatic tissues but is degraded following tissue injury by free radicals and hyaluronidases. The resulting fragments have different bioactivity than the native polymer depending upon their size. For example, intermediate fragments can stimulate cell proliferation while smaller fragments have been reported to only promote cell migration.

Figure 3

RHAMM isoforms, protein secondary structure, and posttranslational modification (a) RHAMM exon structure is shown as black boxes. Lines underneath this diagram show the known isoform structures. The full-length protein (85 kDa in human) is largely associated with interphase microtubules and the mitotic spindle during the cell cycle. Three isoforms are generated by alternative splicing of exon 4, 5, or 13. Loss of exon 4 sequence disrupts stable association with interphase microtubules and results in the appearance of RHAMM in the interphase cell nucleus. N-terminal truncations that may be generated by posttranslational mechanism or alternative start codon usage are very transiently expressed during early tissue injury but are constitutively present in some aggressive breast cancer cell lines and tumors. These accumulate in the nucleus and on the cell surface. (b) RHAMM protein is predicted to be largely a-helical, with unstructured sequences at the extreme N and C-termini. The orange P at the carboxyl terminus indicates an AURKA and ERK1,2 phosphoacceptor site. RHAMM also contains approximately 30 putative protein kinase C phosphoacceptor sites (not shown). This posttranslational modification is associated with the nuclear accumulation of RHAMM. Although RHAMM is phosphorylated by protein kinase C, the acceptor sites have not yet been reported. Protein kinase C modification of RHAMM is linked to interphase centrosomal placement. (c) The secondary structure predictions shown in (b) indicate that RHAMM proteins can self-associate to form random coiled coils.

Figure 4

Model of RHAMM signaling. Model summarizes the known signaling functions of cell surface and intracellular RHAMM. Cell surface RHAMM interacts with CD44, HA, and growth factors to activate protein tyrosine kinase signaling cascades that activate the ERK1,2 MAP kinase cascade. This signaling can increase random motility in the absence of intracellular RHAMM. Intracellular RHAMM also binds to a number of protein partners that mediate its functions as a regulator of microtubule dynamics, centrosome structure/function, and gene expression. For example, during interphase, cytoplasmic RHAMM:protein partner interactions (MEK1/ERK1,2 shown) contribute to the dynamic properties of interphase microtubules and the number, placement, and structure of centrosomes, which affect cell polarity and direct cell migration. Nuclear RHAMM:MEK1:ERK1,2 complexes also control expression of genes involved in cell motility such as PAI-1 and MMP-9. During the cell cycle, RHAMM:TPX2 complexes contribute to mitotic spindle integrity and cell cycle progression through G2M while RHAMM:supervillin complexes promote cytokinesis.