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

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.

• Publication year

  2013

• Venue

  BioMed Research International

• Publication date

  2013-09-05

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1155/2013/929531PMID 24083250PMCID 3780471
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Extracellular Matrix

  2015cited by this paper
• Aberrant splicing, hyaluronan synthases and intracellular hyaluronan as drivers of oncogenesis and potential drug targets.

  2013cited by this paper
• The extracellular matrix: A dynamic niche in cancer progression

  2012cited by this paper
• Targeting the tumor proteasome as a mechanism to control the synthesis and bioactivity of matrix macromolecules.

  2012cited by this paper
• Immune Responses to RHAMM in Patients with Acute Myeloid Leukemia after Chemotherapy and Allogeneic Stem Cell Transplantation

  2012cited by this paper
• RHAMM and CD44 peptides-analytic tools and potential drugs.

  2012cited by this paper
• Overexpression of receptor for hyaluronan-mediated motility (RHAMM) in MC3T3-E1 cells induces proliferation and differentiation through phosphorylation of ERK1/2

  2012cited by this paper
• TCR-transgenic lymphocytes specific for HMMR/Rhamm limit tumor outgrowth in vivo.

  2012cited by this paper
• Insights into targeting colon cancer cell fate at the level of proteoglycans / glycosaminoglycans.

  2012cited by this paper
• Hyaluronan regulation of vascular integrity.

  2011cited by this paper
• RHAMM/ERK interaction induces proliferative activities of cementifying fibroma cells through a mechanism based on the CD44–EGFR

  2011cited by this paper
• Role of Receptor for Hyaluronic Acid-mediated Motility (RHAMM) in Low Molecular Weight Hyaluronan (LMWHA)-mediated Fibrosarcoma Cell Adhesion

  2011cited by this paper
• Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated hyaluronic acid in prostate cancer cells.

  2011cited by this paper
• Hyaluronan in human malignancies.

  2011cited by this paper
• Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting

  2011cited by this paper
• How does a protein with dual mitotic spindle and extracellular matrix receptor functions affect tumor susceptibility and progression?

  2011cited by this paper
• Extracellular matrix degradation and remodeling in development and disease.

  2011cited by this paper
• Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression

  2011cited by this paper
• Adult-type Fibrosarcoma: A Reevaluation of 163 Putative Cases Diagnosed at a Single Institution Over a 48-year Period

  2010cited by this paper
• RHAMM Promotes Interphase Microtubule Instability and Mitotic Spindle Integrity through MEK1/ERK1/2 Activity*

  2010cited by this paper
• Hyaluronan-CD44 Interaction Promotes c-Src-mediated Twist Signaling, MicroRNA-10b Expression, and RhoA/RhoC Up-regulation, Leading to Rho-kinase-associated Cytoskeleton Activation and Breast Tumor Cell Invasion*

  2010cited by this paper
• Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting

  2010cited by this paper
• Matrix metalloproteinases: regulators of the tumor microenvironment.

  2010cited by this paper
• Future treatment of soft tissue sarcomas will be driven by histological subtype and molecular aberrations.

  2010cited by this paper
• Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells.

  2010cited by this paper
• Increasing incidence rates of soft tissue sarcomas? A population-based epidemiologic study and literature review.

  2010cited by this paper
• Cancer esearch oenvironment and Immunology luronan Deficiency in Tumor Stroma Impairs Macrophage R fficking and Tumor Neovascularization

  2010cited by this paper
• Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth.

  2010cited by this paper
• bFGF induces changes in hyaluronan synthase and hyaluronidase isoform expression and modulates the migration capacity of fibrosarcoma cells.

  2009cited by this paper
• Matrix crosslinking forces tumor progression by enhancing integrin signaling.

  2009cited by this paper
• MT2-MMP-dependent release of collagen IV NC1 domains regulates submandibular gland branching morphogenesis.

  2009cited by this paper
• Decreased hyaluronan in airway smooth muscle cells from patients with asthma and COPD

  2009cited by this paper
• Proteoglycans: from structural compounds to signaling molecules

  2009cited by this paper
• Extracellular Matrix Molecules: Potential Targets in Pharmacotherapy

  2009cited by this paper
• Tissue architecture and function: dynamic reciprocity via extra- and intra-cellular matrices

  2009cited by this paper
• RHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53

  2008cited by this paper
• Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response

  2008cited by this paper
• Intralymphatic chemotherapy using a hyaluronan-cisplatin conjugate.

  2008cited by this paper
• Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions?

  2008cited by this paper
• Differential effects of hyaluronan and its fragments on fibroblasts: Relation to wound healing

  2008cited by this paper
• Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal hyaluronan.

  2008cited by this paper
• Hyaluronidase induces murine L929 fibrosarcoma cells resistant to tumor necrosis factor and fas cytotoxicity in the presence of actinomycin D

  2008cited by this paper
• Significance of tumor-associated stroma in promotion of intratumoral lymphangiogenesis: pivotal role of a hyaluronan-rich tumor microenvironment.

  2008cited by this paper
• Hyaluronidases in cancer biology.

  2008cited by this paper
• CD44 and hyaluronate in the differential diagnosis of dermatofibroma and dermatofibrosarcoma protuberans.

  2008cited by this paper
• Regulation of hyaluronan and versican deposition by growth factors in fibrosarcoma cell lines.

  2008cited by this paper
• Hyaluronan Synthases: A Decade-plus of Novel Glycosyltransferases*

  2007cited by this paper
• Hyaluronan-dependent pericellular matrix.

  2007cited by this paper
• The magic glue hyaluronan and its eraser hyaluronidase: a biological overview.

  2007cited by this paper
• Clinical uses of hyaluronan.

  2007cited by this paper
• Hyperproduction of hyaluronan in neu-induced mammary tumor accelerates angiogenesis through stromal cell recruitment: possible involvement of versican/PG-M.

  2007cited by this paper
• The Hyaluronan Receptors CD44 and Rhamm (CD168) Form Complexes with ERK1,2 That Sustain High Basal Motility in Breast Cancer Cells*

  2007cited by this paper
• Transforming Growth Factor‐β as a key molecule triggering the expression of versican isoforms v0 and v1, Hyaluronan Synthase‐2 and synthesis of Hyaluronan in Malignant Osteosarcoma cells

  2006cited by this paper
• Macrophages regulate the angiogenic switch in a mouse model of breast cancer.

  2006cited by this paper
• Collagen reorganization at the tumor-stromal interface facilitates local invasion

  2006cited by this paper
• Rhamm−/− fibroblasts are defective in CD44-mediated ERK1,2 motogenic signaling, leading to defective skin wound repair

  2006cited by this paper
• Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis.

  2006cited by this paper
• Skp2 Overexpression Is Highly Representative of Intrinsic Biological Aggressiveness and Independently Associated with Poor Prognosis in Primary Localized Myxofibrosarcomas

  2006cited by this paper
• γδ T cell–induced hyaluronan production by epithelial cells regulates inflammation

  2005cited by this paper
• Hyaluronan and hyaluronan synthases: potential therapeutic targets in cancer.

  2005cited by this paper
• Receptor for hyaluronan-mediated motility correlates with centrosome abnormalities in multiple myeloma and maintains mitotic integrity.

  2005cited by this paper
• Crosslinked hyaluronic acid hydrogels: a strategy to functionalize and pattern.

  2005cited by this paper
• Regulation of lung injury and repair by Toll-like receptors and hyaluronan

  2005cited by this paper
• Tumour regulation of fibroblast hyaluronan expression: a mechanism to facilitate tumour growth and invasion.

  2005cited by this paper
• HYAL1 hyaluronidase: a molecular determinant of bladder tumor growth and invasion.

  2005cited by this paper
• Critical regulation of genes for tumor cell migration by AP-1

  2004cited by this paper
• Structure of the regulatory hyaluronan binding domain in the inflammatory leukocyte homing receptor CD44.

  2004cited by this paper
• Hyaluronan: from extracellular glue to pericellular cue

  2004cited by this paper
• Stromal fibroblasts in cancer initiation and progression

  2004cited by this paper
• RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy

  2004cited by this paper
• Heparan sulfate proteoglycans and heparanase--partners in osteolytic tumor growth and metastasis.

  2004cited by this paper
• Intracellular Hyaluronan in Arterial Smooth Muscle Cells: Association with Microtubules, RHAMM, and the Mitotic Spindle

  2004cited by this paper
• Hyaluronan synthase expression in ovarian cancer.

  2004cited by this paper
• Altered endochondral bone development in matrix metalloproteinase 13-deficient mice

  2004cited by this paper
• Low‐grade fibromyxoid sarcoma versus low‐grade myxofibrosarcoma in the extremities and trunk. A comparison of clinicopathological and immunohistochemical features

  2004cited by this paper
• Elevated transcript level of hyaluronan synthase1 gene correlates with poor prognosis of human colon cancer

  2004cited by this paper
• Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis

  2003cited by this paper
• Altered expression of cell cycle regulators in myxofibrosarcoma, with special emphasis on their prognostic implications.

  2003cited by this paper
• Hyaluronan-mediated CD44 Interaction with RhoGEF and Rho Kinase Promotes Grb2-associated Binder-1 Phosphorylation and Phosphatidylinositol 3-Kinase Signaling Leading to Cytokine (Macrophage-Colony Stimulating Factor) Production and Breast Tumor Progression*

  2003cited by this paper
• Devising a pathway for hyaluronan catabolism: are we there yet?

  2003cited by this paper
• CD44 in Cancer Progression: Adhesion, Migration and Growth Regulation

  2003cited by this paper
• EGF upregulates, whereas TGF-beta downregulates, the hyaluronan synthases Has2 and Has3 in organotypic keratinocyte cultures: correlations with epidermal proliferation and differentiation.

  2003cited by this paper
• Genetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor)

  2003cited by this paper
• Elevated Hyaluronan Production Induces Mesenchymal and Transformed Properties in Epithelial Cells*

  2003cited by this paper
• Keratinocyte Growth Factor Stimulates Migration and Hyaluronan Synthesis in the Epidermis by Activation of Keratinocyte Hyaluronan Synthases 2 and 3*

  2003cited by this paper
• Integrins: bidirectional, allosteric signaling machines.

  2002cited by this paper
• Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis.

  2002cited by this paper
• Regulation of Hyaluronidase Activity by Alternative mRNA Splicing*

  2002cited by this paper
• Codon 12 and codon 13 mutations at the K‐ras gene induce different soft tissue sarcoma types in nude mice

  2002cited by this paper
• Expression of hyaluronan synthase 2 or hyaluronidase 1 differentially affect the growth rate of transplantable colon carcinoma cell tumors

  2002cited by this paper
• Gains of 12q are the most frequent genomic imbalances in adult fibrosarcoma and are correlated with a poor outcome

  2002cited by this paper
• Proteoglycans and tumor progression: Janus-faced molecules with contradictory functions in cancer.

  2002cited by this paper
• Testicular hyaluronidase induces tubular structures of endothelial cells grown in three‐dimensional colagen gel through a CD44‐mediated mechanism

  2002cited by this paper
• CD44 in Cancer

  2002cited by this paper
• Mammalian Hyaluronan Synthases

  2002cited by this paper
• Hyaluronan-Cell Interactions in Cancer and Vascular Disease*

  2002cited by this paper
• Signaling Properties of Hyaluronan Receptors*

  2002influential reference
• Hyaluronan and Homeostasis: A Balancing Act*

  2002cited by this paper
• Hyaluronan-binding Proteins: Tying Up the Giant*

  2002cited by this paper
• Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration

  2002cited by this paper

• Hyaluronic Acid: A Comprehensive Review of Its Osteogenic Potential and Diverse Biomedical Applications

  2025cites this paper
• Microenvironment-based immunotherapy in oral cancer: a comprehensive review

  2025cites this paper
• Microbial hyaluronic acid production by integrating molecular structure, biological function, purification, and application.

  2025cites this paper
• Advances in Hyaluronic Acid-Based Therapies

  2025cites this paper
• Breaking down physical barriers: strategies to improve lymphocyte infiltration for effective neoantigen-based therapies

  2025cites this paper
• Optimized quercetin-loaded glycerohyalurosome hydrogel: an innovative nanoplatform for enhanced wound healing

  2025cites this paper
• Elevated RHAMM as a biomarker for predicting diabetic kidney disease in patients with type 2 diabetes

  2024cites this paper
• From oncogenes to tumor suppressors: The dual role of ncRNAs in fibrosarcoma.

  2024cites this paper
• Recent advances in exploring the properties and applications of hyaluronan

  2024cites this paper
• [Hyaluronan receptors: role in aging and age-associated processes.]

  2024cites this paper
• The bioengineering application of hyaluronic acid in tissue regeneration and repair.

  2024cites this paper
• Selective adhesion inhibition and hyaluronan envelope reduction of dermal tumor cells by cold plasma-activated medium

  2023cites this paper
• Etiology of Delayed Inflammatory Reaction Induced by Hyaluronic Acid Filler

  2023cites this paper
• RHAMM/hyaluronan inhibit β-catenin degradation, enhance downstream signaling, and facilitate fibrosarcoma cell growth

  2023cites this paper
• Functional organization of extracellular hyaluronan, CD44, and RHAMM

  2023cites this paper
• Making Sense of Late Tissue Nodules Associated With Hyaluronic Acid Injections

  2023cites this paper
• HSOA Journal of Angiology & Vascular Surgery Hyaluronic Acid: An Old Molecule with New Perspectives

  2022cites this paper
• EMMPRIN is an emerging protein capable of regulating cancer hallmarks.

  2022cites this paper
• Heparanase 2 (Hpa2) attenuates the growth of human sarcoma.

  2022cites this paper
• Cancer and Apoptosis.

  2022cites this paper
• Hyaluronan network: a driving force in cancer progression.

  2022cites this paper
• Hyaluronic Acid: Known for Almost a Century, but Still in Vogue

  2022cites this paper
• Complex Interplay of Genes Underlies Invasiveness in Fibrosarcoma Progression Model

  2021cites this paper
• SnapshotDx Quiz: June 2021.

  2021cites this paper
• Transcriptome profile of Haemaphysalis longicornis (Acari: Ixodidae) exposed to Cymbopogon citratus essential oil and citronellal suggest a cytotoxic mode of action involving mitochondrial Ca2+ overload and depolarization.

  2021cites this paper
• CD44 and Tumor-Derived Extracellular Vesicles (TEVs). Possible Gateway to Cancer Metastasis

  2021cites this paper
• Hyaluronic Acid: A Key Ingredient in the Therapy of Inflammation

  2021influential citation
• The Fibroblast Growth Factor 9 (Fgf9) Participates in Palatogenesis by Promoting Palatal Growth and Elevation

  2021cites this paper
• Understanding Hyaluronan Receptor (CD44) Interaction, HA-CD44 Activated Potential Targets in Cancer Therapeutics

  2020cites this paper
• Hyaluronic Acid: Redefining Its Role

  2020cites this paper
• TGFβ and Hippo Pathways Cooperate to Enhance Sarcomagenesis and Metastasis through the Hyaluronan-Mediated Motility Receptor (HMMR)

  2020cites this paper
• Co-localization and crosstalk between CD44 and RHAMM depend on hyaluronan presentation.

  2020cites this paper
• A review on the wide range applications of hyaluronic acid as a promising rejuvenating biomacromolecule in the treatments of bone related diseases.

  2020cites this paper
• Hyaluronic acid containing scaffolds ameliorate stem cell function for tissue repair and regeneration.

  2020cites this paper
• The enhancement of glycolysis regulates pancreatic cancer metastasis

  2019cites this paper
• CD44-dependent inflammation, fibrogenesis, and collagenolysis regulates extracellular matrix remodeling and tensile strength during cutaneous wound healing.

  2019cites this paper
• Bioengineered tumor microenvironments with naked mole rats high-molecular-weight hyaluronan induces apoptosis in breast cancer cells

  2019cites this paper
• The Effect of Function-blocking RHAMM Peptides in a Mouse Model of Bleomycin-induced Systemic Sclerosis

  2018cites this paper
• ADAMTS‐1 disrupts HGF/c‐MET signaling and HGF‐stimulated cellular processes in fibrosarcoma

  2018cites this paper
• Modulating Three-Dimensional Microenvironment with Hyaluronan of Different Molecular Weights Alters Breast Cancer Cell Invasion Behavior.

  2017cites this paper
• Technologies to Engineer Cell Substrate Mechanics in Hydrogels

  2017cites this paper
• HEPATIC WOUND HEALING FOLLOWING ACUTE AND CHRONIC LIVER INJURY: A POTENTIAL ROLE FOR THE HYALURONAN NETWORK

  2017cites this paper
• An invasive tumor cell subpopulation as a therapeutic target in breast cancer

  2017cites this paper
• The Promotion of Adipogenesis in a Rat Model of Radiation-Induced Mammary Fat Pad Fibrosis

  2017cites this paper
• Receptor for hyaluronan mediated motility (RHAMM/HMMR) is a novel target for promoting subcutaneous adipogenesis.

  2017cites this paper
• Receptor for hyaluronic acid- mediated motility (RHAMM) regulates HT1080 fibrosarcoma cell proliferation via a β-catenin/c-myc signaling axis.

  2016cites this paper
• Hyaluronan in cancer - from the naked mole rat to nanoparticle therapy.

  2016cites this paper
• A reciprocal regulatory circuit between CD44 and FGFR2 via c-myc controls gastric cancer cell growth

  2016cites this paper
• Hyaluronic Acid in Inflammation and Tissue Regeneration.

  2016cites this paper
• Advances in Hyaluronic Acid-Based Drug Delivery Systems.

  2016cites this paper
• Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed

  2016cites this paper
• Hyaluronan based hydrogels provide an improved model to study megakaryocyte-matrix interactions.

  2016cites this paper
• Receptor for hyaluronic acid-mediated motility (RHAMM, CD168) expression is prognostically important in both nodal negative and nodal positive large cell lung cancer

  2015cites this paper
• Hyaluronan regulates chemical allergen-induced IL-18 production in human keratinocytes.

  2015cites this paper
• Hypoxia and cancer metabolism : genetic and functional analysis of H+/lactate symporters and their chaperone, BASIGIN

  2015cites this paper
• Comparative proteomic analysis of fibrosarcoma and skin fibroblast cell lines

  2015cites this paper
• Identification, design and synthesis of tubulin-derived peptides as novel hyaluronan mimetic ligands for the receptor for hyaluronan-mediated motility (RHAMM/HMMR).

  2015cites this paper
• Hyaluronic acid as a potential boron carrier for BNCT: Preliminary evaluation.

  2015cites this paper
• Interactions between Hyaluronan and Its Receptors (CD44, RHAMM) Regulate the Activities of Inflammation and Cancer

  2015cites this paper
• Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters

  2015cites this paper
• Lactate as an insidious metabolite due to the Warburg effect

  2015cites this paper
• Interplay of Matrix Stiffness and c-SRC in Hepatic Fibrosis

  2015cites this paper
• Autoantibody Profiling of Glioma Serum Samples to Identify Biomarkers Using Human Proteome Arrays

  2015cites this paper
• Hyaluronan, Inflammation, and Breast Cancer Progression

  2015cites this paper
• High and low molecular weight hyaluronic acid differentially influence macrophage activation.

  2015cites this paper
• Uncovering the dual role of RHAMM as an HA receptor and a regulator of CD44 expression in RHAMM-expressing mesenchymal progenitor cells

  2015influential citation
• The Role of CD44 in Disease Pathophysiology and Targeted Treatment

  2015cites this paper
• The Effects of RHAMM on Cell Division, Cell Motility, and Tumorigenesis

  2014influential citation
• The Motile Breast Cancer Phenotype Roles of Proteoglycans/Glycosaminoglycans

  2014cites this paper
• Hyaluronic Acid: A Key Facilitator of Cancer Evolution

  2014cites this paper
• Hyaluronan: biosynthesis and signaling.

  2014cites this paper
• Cancer Bioinformatics

  2014cites this paper
• Hyaluronan and RHAMM in Wound Repair and the “Cancerization” of Stromal Tissues

  2014cites this paper
• Spatially restricted hyaluronan production by Has2 drives epithelial tubulogenesis in vitro.

  2014cites this paper
• Stimulation of TLR4 by LMW-HA Induces Metastasis in Human Papillary Thyroid Carcinoma through CXCR7

  2013cites this paper