The Roles of Hyaluronan/RHAMM/CD44 and Their Respective Interactions along the Insidious Pathways of Fibrosarcoma Progression

Abstract

Fibrosarcomas are rare malignant mesenchymal tumors originating from fibroblasts. Importantly, fibrosarcoma cells were shown to have a high content and turnover of extracellular matrix (ECM) components including hyaluronan (HA), proteoglycans, collagens, fibronectin, and laminin. ECMs are complicated structures that surround and support cells within tissues. During cancer progression, significant changes can be observed in the structural and mechanical properties of the ECM components. Importantly, hyaluronan deposition is usually higher in malignant tumors as compared to benign tissues, predicting tumor progression in some tumor types. Furthermore, activated stromal cells are able to produce tissue structure rich in hyaluronan in order to promote tumor growth. Key biological roles of HA result from its interactions with its specific CD44 and RHAMM (receptor for HA-mediated motility) cell-surface receptors. HA-receptor downstream signaling pathways regulate in turn cellular processes implicated in tumorigenesis. Growth factors, including PDGF-BB, TGFβ2, and FGF-2, enhanced hyaluronan deposition to ECM and modulated HA-receptor expression in fibrosarcoma cells. Indeed, FGF-2 through upregulation of specific HAS isoforms and hyaluronan synthesis regulated secretion and net hyaluronan deposition to the fibrosarcoma pericellular matrix modulating these cells' migration capability. In this paper we discuss the involvement of hyaluronan/RHAMM/CD44 mediated signaling in the insidious pathways of fibrosarcoma progression.

High and Low Molecular Weight Hyaluronic Acid Differentially Influence Macrophage Activation

“…88 Complete understanding of hyaluronan binding to RHAMM and subsequent signaling in other cell types has been complicated by the fact that RHAMM does not have a typical trans-membrane domain and is found both intracellularly as well as on the cell surface. 89-91 Several HA receptors exist as splice-variants, 92 directly interact with one-another, 93-94 and bind HA by different mechanisms, 92 further obscuring true mechanistic understanding of HA signaling.…”

Hyaluronan based hydrogels provide an improved model to study megakaryocyte–matrix interactions

“…Among the receptors involved in HA signaling, the CD44 is present in almost all human cells and activates signaling cascades that includes PI3K/PDK1/AKT pathway as well as Ras phosphorylation cascade involving RAF1, MEK and ERK1/2 (50, 51, 52). RHAMM receptor was described in tumor cell line (53) and in several cell types, including endothelial cells (54), and reported to trigger several cellular signaling including Ras, focal adhesion kinase (FAK), ERK1/2, protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) (55-56). …”

Receptor for hyaluronic acid-mediated motility (RHAMM, CD168) expression is prognostically important in both nodal negative and nodal positive large cell lung cancer

“…The observed negative prognostic effect of RHAMM might be related to its known functions to promote cell motility and thus enable early subclinical metastatic spread already observed in other carcinomas 8 18–21. On the other hand, overexpression of intracellular RHAMM interferes with centrosome–mitotic spindle interactions and can thus promote chromosomal segregation defects, which may perpetuate spontaneous subclonal tumour evolution to more aggressive clones, which can equally contribute to the pathogenesis of especially LCC 22 23. Finally, as already shown in leukaemia and lymphoma patients and also recently in lung cancer patients, RHAMM may be a potential therapeutic target since vaccination against RHAMM might be an additional treatment option for such high-risk patients with RHAMM-positive LCC 24 25…”