Expression Of Hyaluronic Acid Receptors Research Articles

Hypoxia modulates human mast cell adhesion to hyaluronic acid

Hypoxia is an inherent factor in the inflammatory process and is important in the regulation of some immune cell functions, including the expression of mast cell pro- and anti-inflammatory mediators. Hypoxia also influences cell adhesion to the extracellular matrix (ECM). Hyaluronic acid is one of the major components of the ECM that is involved in inflammatory and tissue regeneration processes in which mast cells play a prominent role. This prompted us to investigate the effects of hypoxia on the expression of hyaluronic acid receptors in mast cells and mast cell adhesion to this ECM component. We found that human LAD2 mast cells spontaneously adhered to hyaluronic acid in a CD44-dependent manner and that reduced oxygen concentrations inhibited or even completely abolished this adhesion process. The mechanism of hypoxia downregulation of mast cell adhesion to hyaluronic acid did not involve a decrease in CD44 expression and hyaluronidase-mediated degradation of adhesion substrates but rather conformational changes in the avidity of CD44 to hyaluronic acid. Hypoxia-mediated regulation of mast cell adhesion to extracellular matrix components might be involved in the pathogenic accumulation of mast cells observed in the course of certain diseases including rheumatoid arthritis and cancer.

Diverse Roles for Hyaluronan and Hyaluronan Receptors in the Developing and Adult Nervous System.

Hyaluronic acid (HA) plays a vital role in the extracellular matrix of neural tissues. Originally thought to hydrate tissues and provide mechanical support, it is now clear that HA is also a complex signaling molecule that can regulate cell processes in the developing and adult nervous systems. Signaling properties are determined by molecular weight, bound proteins, and signal transduction through specific receptors. HA signaling regulates processes such as proliferation, differentiation, migration, and process extension in a variety of cell types including neural stem cells, neurons, astrocytes, microglia, and oligodendrocyte progenitors. The synthesis and catabolism of HA and the expression of HA receptors are altered in disease and influence neuroinflammation and disease pathogenesis. This review discusses the roles of HA, its synthesis and breakdown, as well as receptor expression in neurodevelopment, nervous system function and disease.

Zika Virus Nonstructural Protein 1 Disrupts Glycosaminoglycans and Causes Permeability in Developing Human Placentas.

During pregnancy, the Zika flavivirus (ZIKV) infects human placentas, inducing defects in the developing fetus. The flavivirus nonstructural protein 1 (NS1) alters glycosaminoglycans on the endothelium, causing hyperpermeability in vitro and vascular leakage in vivo in a tissue-dependent manner. The contribution of ZIKV NS1 to placental dysfunction during ZIKV infection remains unknown. We examined the effect of ZIKV NS1 on expression and release of heparan sulfate (HS), hyaluronic acid (HA), and sialic acid on human trophoblast cell lines and anchoring villous explants from first-trimester placentas infected with ZIKV ex vivo. We measured changes in permeability in trophoblasts and stromal cores using a dextran-based fluorescence assay and changes in HA receptor expression using immunofluorescent microscopy. ZIKV NS1 in the presence and absence of ZIKV increased the permeability of anchoring villous explants. ZIKV NS1 induced shedding of HA and HS and altered expression of CD44 and lymphatic endothelial cell HA receptor-1, HA receptors on stromal fibroblasts and Hofbauer macrophages in villous cores. Hyaluronidase was also stimulated in NS1-treated trophoblasts. These findings suggest that ZIKV NS1 contributes to placental dysfunction via modulation of glycosaminoglycans on trophoblasts and chorionic villi, resulting in increased permeability of human placentas.

Abstract 1146: Biomarker-driven targeted oral treatment strategy for bladder cancer

Abstract INTRODUCTION AND OBJECTIVE: Hyaluronic acid (HA) family of molecules, HA-synthases (HAS-1,2,3), HA-receptors (CD44, RHAMM) and hyaluronidase (HYAL-1) are markers for bladder cancer (BCa) diagnosis and predicting prognosis. HA-family promotes tumor growth and metastasis by inducing epithelial mesenchymal transition (EMT). 4-Methylumbelliferone (4-MU) is an orally bioavailable dietary supplement that inhibits HA synthesis. We evaluated the expression of HA family and EMT markers in bladder tissues as well as the antitumor effects of 4-MU as a potential targeted therapeutic agent in preclinical models of BCa. METHODS: Quantitative PCR was used to measure mRNA expression of HA-family and EMT genes (β-catenin, Twist, and Snail) in 72 bladder tissue specimens (28 normal; 44 tumor); follow-up: 20.3±2.5 months; median 17 months. The effect of 4-MU (0-0.6 mM) on cell proliferation, apoptosis, intracellular signaling, and the expression of HA receptors, and EMT genes were examined in BCa cell lines by Q-PCR, immunoblotting, proximal ligation and PI-3K activity assays. Mechanism of action was analyzed by HA addition and mAkt overexpression. Effect of oral administration of 4-MU (100, 200-mg/kg) on tumor growth was analyzed in subcutaneous xenografts. RESULTS: HAS-1, -2 -3, HYAL-1 and Snail levels were 10-20-fold elevated in BCa tissues as compared to normal bladder (P<0.001). In univariate analysis, HAS-1, -2, HYAL-1 and Twist levels correlated with metastasis (P<0.001); HYAL-1 was an independent predictor of metastasis. 4-MU inhibited cell proliferation, chemotactic motility and invasion in a dose-dependent manner; 50-70% inhibition at IC50 (0.4 mM) for HA-synthesis inhibition. 4-MU induced apoptosis (>3-fold) via the death receptor pathway. 4-MU downregulated HA-signaling, specifically transcript and/or protein levels of CD44, RHAMM, p-Akt, β-catenin, pβ-catenin(S552). Snail and twist were downregulated by 2-5-fold, but pβcatenin((T41/S45), pGSK-3α/β and E-cadherin levels were increased. 4-MU also inhibited CD44/PI-3K complex formation and PI-3K activity. HA addition or myristoylated Akt expression attenuated 4-MU effects. In xenograft studies, 4-MU oral treatment abrogated tumor growth of established tumors (vehicle, day 50: 766±221 mm3; 4-MU: 128±61, day 50) by abrogating HA-synthesis. No weight loss or serum or organ toxicity was observed in treated mice. CONCULUSION: This study demonstrates that HA-family signaling is upregulated in BCa and can be specifically targeted for treatment by a non-toxic dietary supplement. Support: 7R01 CA072821-16; 7R01CA176691-03 Citation Format: Daley S. Morera, Andre Jordan, Vinata B. Lokeshwar. Biomarker-driven targeted oral treatment strategy for bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1146. doi:10.1158/1538-7445.AM2017-1146

Cross-linked hyaluronic acid gel inhibits metastasis and growth of gastric and hepatic cancer cells: in vitro and in vivo studies.

Cross-linked hyaluronic acid gel (CHAG) has been used to prevent postoperative adhesion of abdominal tumorectomy. However, its effect on tumor cells is still unknown. This paper was designed to investigate the effect of CHAG on metastasis and growth of tumor cells. Migration and invasion assays, Western blotting, pull down assay, siRNA interference, and nude mice implantation tumor model were applied in this study. The results of in vitro experiments with gastric cancer cell line AGS and hepatic cancer cell line HepG2 showed that CHAG inhibited the migration and invasion activities, the MAPK and PI3K/Akt mediated signaling, the activation of small G proteins Rac1 and RhoA, and the expression of MMPs and PCNA initiated by EGF, through blocking the activation of EGFR. CHAG also had inhibitory effect on activation of other membrane receptors, including integrin and VEGFR. When the expression of hyaluronic acid receptors (CD44 or RHAMM) was interfered, the above inhibitory effects of CHAG still existed. In vivo experimental results showed that CHAG suppressed colonization, growth and metastasis of gastric cancer cell line SGC-7901 in peritoneal cavity of nude mice. In conclusion, CHAG had inhibitory effect on tumor cells, through covering cell surface and blocking the interaction between extracellular stimulative factors and their receptors.

Abstract 1033: Inhibiting bladder cancer metastasis with a dietary supplement

Abstract INTRODUCTION AND OBJECTIVE: Hyaluronic acid (HA) and HYAL-1 hyaluronidase (HAase) family molecules are potential markers for BCa diagnosis and prognosis and promote tumor growth and metastasis. 4-Methylumbelliferone (4-MU) is an orally bioavailable dietary supplement that inhibits HA synthesis. Epithelial-to-mesenchymal transition (EMT) is the hallmark of invasion and metastasis. Since HA promotes tumor metastasis and EMT, we evaluated the expression of EMT markers in bladder tissues and antitumor effects of 4-MU in BCa models. METHODS: Quantitative PCR was used to measure mRNA expression of EMT genes (β-catenin, Twist, and Snail) in 66 bladder tissue specimens (27 normal; 39 tumor); follow-up: 26±4.3 months; median 20 months. The effect of 4-MU (40 - 120 µg/ml) on cell proliferation, apoptosis, intracellular signaling, and the expression of HA receptors and EMT genes were examined in BCa cell lines, 253J-Lung and HT1376. Effect of 4-MU on tumor growth was analyzed in subcutaneous xenografts. RESULTS: Among the EMT genes, Snail and Twist were differentially expressed in BCa tissues when compared to normal bladder (P<0.001). Furthermore, elevated Twist expression significantly correlated with metastasis (2-fold increase; P=0.028). β-catenin expression negatively correlated with survival (chi square=4.3, p=0.038). At IC50 for HA synthesis, 4-MU inhibited proliferation (∼ 2.5-fold) and induced apoptosis (3-fold) in BCa cells. 4-MU induced caspase-8, -9 and -3 activation and up-regulation of Fas and FADD. 4-MU caused 4-10-fold downregulation of HA-receptors (CD44, RHAMM), and EMT promoters - β-catenin, Snail and Twist, but increased E-cadherin expression by 2-fold. In xenograft studies, 4-MU significantly decreased tumor growth (> 3-fold) when treatment was started either on the day of tumor cell injection or after tumors became palpable. No weight loss or serum or organ toxicity was observed in treated mice. Tumors showed reduced microvessel density (∼3-fold) and HA expression but increased TURNEL positive cells. CONCLUSION: This study shows that expression of EMT determinants correlates with clinical outcome. Furthermore, the non-toxic dietary supplement 4-MU has potent antitumor activity and reverses EMT. Support: R01 CA 123063-04 (VBL); R01 CA 72821-11 (VBL). Citation Format: Kelly T. Hoye, Travis Yates, David Alonzo, Vinata B. Lokeshwar. Inhibiting bladder cancer metastasis with a dietary supplement. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1033. doi:10.1158/1538-7445.AM2014-1033

Polyethyleneimine/DNA polyplexes with reduction-sensitive hyaluronic acid derivatives shielding for targeted gene delivery

The natural anionic polysaccharide hyaluronic acid (HA) was modified by introducing reduction-sensitive disulfide bond between the carboxyl groups and the backbone of HA (HA-SS-COOH). HA-SS-COOH and its corresponding unmodified stable analog HA were used to shield DNA/PEI polyplexes (DP) to form ternary complexes (DPS and DPH complexes). The shielding/deshielding effect was tested along with size, zeta potential, cell viability and transfection. Both DPS and DPH complexes showed increase in size, decrease in zeta potential and low cytotoxicity in physiological conditions due to the anionic shielding. In the reductive environment, only HA-SS-COOH coated ternary complexes (DPS) demonstrated the size increase and recovered high positive zeta potential. DPS complexes showed an up to 14-fold higher transfection than the stable coated one, indicating the efficiency of the reduction-responsive deshielding design. Moreover, the presence of extra free HA inhibited the transfection of DPS on HepG2 and B16F10 cells with HA receptor expression, while displaying no effect on non-targeted NIH3T3 cells. More rapid cellular association of DPS with HepG2 was observed, thus confirming the targeting reservation of disulfide bond modified HA. Intratumoral injection of DPS complexes resulted in much higher accumulation and luciferase expression in the tumor bearing C57BL/6 mice. Both in vitro and in vivo results demonstrated the successful combination of deshielding and target functions in HA derivatives for gene delivery.

Abstract 336: 4-methylumbeliferone, an HA synthesis inhibitor, inhibits EMT determinants in bladder cancer cell lines

Abstract INTRODUCTION AND OBJECTIVE: Elevated Hyaluronic Acid (HA) levels are a molecular determinant of bladder cancer (BCa) metastasis. Furthermore, HA, HYAL-1 hyaluronidase and HA-synthesizing enzymes are potential markers for BCa diagnosis and predicting prognosis. 4-Methylumbelliferone (4-MU) is an orally bioavailable dietary supplement that inhibits HA synthesis. Epithelial mesenchymal transition (EMT) is the hallmark of invasion and metastasis, in which cancer cells acquire an invasive phenotype. Since HA promotes tumor metastasis, we evaluated the antitumor effects of 4-MU in vitro and in vivo and examined whether 4-MU can reverse the EMT by inhibiting HA synthesis. METHODS: Quantitative PCR was used to measure mRNA expression of EMT genes (β-catenin, Twist, and Snail) in 66 bladder tissue specimens (27 normal; 39 tumor); follow-up: 26±4.3 months; median 20 months. The effect of 4-MU (0.2 - 0.6 mM) on cell proliferation, apoptosis, intracellular signaling, and the expression of HA receptors and EMT genes were examined in BCa cell lines, 253J-Lung and HT1376. Effect of 4-MU on tumor growth was analyzed in subcutaneous xenografts. RESULTS: Among the EMT genes, both Snail and Twist were differentially expressed in BCa tissues when compared to normal bladder (P<0.001). Furthermore, Twist expression significantly correlated with metastasis (+: 0.25+0.15, -: 0.12+0.14; P=0.028). β-catenin expression negatively correlated with survival (chi square=4.3, p=0.038). 4-MU inhibited proliferation and induced apoptosis in the BCa cells. Following a 48 h exposure at the IC50 for HA synthesis (0.4 mM), 4-MU inhibited proliferation by 61% and increased apoptosis by 73%. 4-MU induced caspase-8, -9 and -3 activation and up-regulation of Fas and FADD. 4-MU downregulated the expression of HA-receptors - CD44, RHAMM, EMT promoters - β-catenin, Snail and Twist by 4-10-fold, but increased the expression of E-cadherin by 2-fold, suggesting EMT-reversal. In xenograft studies, 4-MU significantly decreased tumor growth (> 3-fold) when treatment was started either on the day of tumor cell injection or after tumors became palpable. No weight loss or serum or organ toxicity was observed in treated mice. Tumors showed reduced microvessel density (∼3-fold) and HA expression but increased TURNEL positive cells. CONCLUSION: This is the first study that shows inhibition of HA synthesis by an orally bioavailable, non-toxic supplement potentially reverses EMT and has potent anti-tumor activity. Support: R01 CA 123063-04 (VBL); R01 CA 72821-11 (VBL). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 336. doi:1538-7445.AM2012-336

894 4-METHYLUMBELIFERONE A POTENTIAL ANTI-METASTATIC ORAL AGENT FOR BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Basic Research II1 Apr 2012894 4-METHYLUMBELIFERONE A POTENTIAL ANTI-METASTATIC ORAL AGENT FOR BLADDER CANCER Michael Garcia-Roig, Travis Yates, Anaid Benitez, and Vinita Lokeshwar Michael Garcia-RoigMichael Garcia-Roig Miami, FL More articles by this author , Travis YatesTravis Yates Miami, FL More articles by this author , Anaid BenitezAnaid Benitez Miami, FL More articles by this author , and Vinita LokeshwarVinita Lokeshwar Miami, FL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.989AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Elevated Hyaluronic Acid (HA) levels are a molecular determinant of bladder cancer (BCa) metastasis. Furthermore, HA, HYAL-1 hyaluronidase and HA-synthesizing enzymes are potential markers for BCa diagnosis and predicting prognosis. 4-Methylumbelliferone (4-MU) is an orally bioavailable dietary supplement that inhibits HA synthesis. Epithelial mesenchymal transition (EMT) is the hallmark of invasion and metastasis, in which cancer cells acquire an invasive phenotype. Since HA promotes tumor metastasis, we evaluated the antitumor effects of 4-MU in vitro and in vivo and examined whether 4-MU can reverse the EMT by inhibiting HA synthesis. METHODS Quantitative PCR was used to measure mRNA expression of EMT genes (β;-catenin, Twist, and Snail) in 66 bladder tissue specimens (27 normal; 39 tumor); follow-up: 26±4.3 months; median 20 months. The effect of 4-MU (0.2 – 0.6 mM) on cell proliferation, apoptosis, intracellular signaling, and the expression of HA receptors and EMT genes were examined in BCa cell lines, 253J-Lung and HT1376. Effect of 4-MU on tumor growth was analyzed in subcutaneous xenografts. RESULTS Among the EMT genes, both Snail and Twist were differentially expressed in BCa tissues when compared to normal bladder (P<0.001). Furthermore, Twist expression significantly correlated with metastasis (+: 0.25+0.15, - : 0.12+0.14; P=0.028). β-catenin expression negatively correlated with survival (chi square=4.3, p=0.038). 4-MU inhibited proliferation and induced apoptosis in the BCa cells. Following a 48 h exposure at the IC50 for HA synthesis (0.4 mM), 4-MU inhibited proliferation by 61% and increased apoptosis by 73%. 4-MU induced caspase-8, -9 and -3 activation and up-regulation of Fas and FADD. 4-MU downregulated the expression of HA-receptors - CD44, RHAMM, EMT promoters - β;-catenin, Snail and Twist by 4-10-fold, but increased the expression of E-cadherin by 2-fold, suggesting EMT-reversal. In xenograft studies, 4-MU significantly decreased tumor growth (> 3-fold) when treatment was started either on the day of tumor cell injection or after tumors became palpable. No weight loss or serum or organ toxicity was observed in treated mice. Tumors showed reduced microvessel density (∼3-fold) and HA expression but increased TURNEL positive cells. CONCLUSIONS This is the first study that shows inhibition of HA synthesis by an orally bioavailable, non-toxic supplement that potentially reverses EMT and has potent anti-tumor activity. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e364 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Garcia-Roig Miami, FL More articles by this author Travis Yates Miami, FL More articles by this author Anaid Benitez Miami, FL More articles by this author Vinita Lokeshwar Miami, FL More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract 523: Three-dimensional hyaluronic acid-based hydrogel systems for studies of cancer invasion

Abstract Currently available invasion assays for study of cancer metastasis have limitations that led us to develop a novel system that provides a more flexible, quantifiable, and physiologically relevant method to study cancer cell invasion. The three-dimensional (3D) hyaluronic acid (HA) hydrogel invasion assay then was used to study HA receptor signaling as it occurs during prostate cancer metastasis to bone marrow. Our invasion assay uses the HA hydrogel which reflects the prevalence of HA in the bone marrow and its key role in the promotion of cancer cell motility and tissue invasion. The HA hydrogel spontaneously crosslinks via interaction of aldehyde and hydrazide groups, allowing for direct encapsulation of cells within the gel. This cell/gel construct is plated in a 12 mm tissue culture insert for construction of the invasion assay. The cells are situated on a single plane so that individual cell movement from that plane can be tracked. We show that our 3D HA hydrogel invasion assay allows for cell migration/invasion in response to a chemoattractant, fetal bovine serum (FBS), and that this movement is easily quantified using confocal microscopy techniques over a distance of up to 1 mm. The ability of cancer cells to invade the HA hydrogel depends on their expression of HA receptors and hyaluronidases; more highly invasive cell lines express HA receptors and hyaluronidases at higher levels. We will show that culture in the HA hydrogel triggers differential expression and/or compartmental translocation of HA receptor proteins and downstream effectors, all of which contribute to motility and metastasis. Ongoing work examines the role that a specific HA receptor, RHAMM, plays in prostate cancer metastasis, specifically how it activates Rho GTPases that increase cell motility. We will show how these physiologically relevant 3-D HA hydrogel invasion assays can be used to study such pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 523.

Differences in Hyaluronic Acid-mediated Functions and Signaling in Arterial, Microvessel, and Vein-derived Human Endothelial Cells

Hyaluronic acid (HA), a nonsulfated glycosaminoglycan, regulates cell adhesion and migration. Small HA fragments (3-25 disaccharide units) induce neovascularization. We investigated the effect of HA and a HA fragment (10-15 disaccharide units, F1) on primary human endothelial cells (ECs). Human pulmonary ECs (HPAEC) and lung microvessel ECs (HMVEC-L) bound HA (K(d) approximately 1 and 2.3 nm, respectively) and expressed 17,780 and 16,690 HA binding sites, respectively. Both ECs showed HA-mediated cell adhesion; however, HMVEC-L was 1.5-fold better. Human umbilical vein ECs neither bound HA nor showed HA-mediated adhesion. All three ECs expressed CD44 ( approximately 110 kDa). The expression of receptor for HA-mediated motility (RHAMM) (approximately 80 kDa) was the highest in HMVEC-L, followed by HPAEC and human umbilical vein ECs. RHAMM, not CD44, bound HA in all three ECs. F1 was better than HA and stimulated a 2. 5- and 1.8-fold mitogenic response in HMVEC-L and HPAEC, respectively. Both HA and F1 induced tyrosine phosphorylation of p125(FAK), paxillin, and p42/44 ERK in HMVEC-L and HPAEC, which was blocked by an anti-RHAMM antibody. These results demonstrate that RHAMM is the functional HA receptor in primary human ECs. Heterogeneity exists among primary human ECs of different vascular origins, with respect to functional HA receptor expression and function.

Biology of fetal wound healing: Hyaluronate receptor expression in fetal fibroblasts

Fetal tissue repair is rapid, relatively scarless, and proceeds in an environment rich in hyaluronic acid. Understanding the interaction of hyaluronic acid (HA) with the reparative cells may provide important insight into the remarkable process of fetal wound healing. Therefore, the purpose of this study was to characterize the HA receptor (a member of the CD44 family of cell surface glycoproteins) and its density on the cell surface of fetal fibroblasts. HA receptor expression on both adult and fetal fibroblasts was first studied by Western blot analysis. Autoradiographs of the blots were assessed by densitometry to quantitate the relative amounts of the HA receptor. It appears that the HA receptor expressed on both adult and fetal rabbit dermal fibroblasts is a 56-kd protein. After normalizing for total protein concentration using the Bradford protein assay, the fetal HA receptor density was found to be approximately four-fold greater than that of the adult. The same adult and fetal fibroblasts were then studied by flow cytometry, using a fluorescence-activated cell sorter (FACS). Relative fluorescence was representative of HA receptor density. Corroborating the authors' earlier result with the Western blot analysis, the FACS analysis showed that the fetal fibroblasts had 2.5 times the fluoresence of the adult cells. It is concluded that, in comparison to adult fibroblasts, fetal fibroblasts have an increased density of cell-surface HA receptor.

Differential binding of anti-CD44 on human gliomas in vitro

Recent studies have shown that the membrane glycoprotein, CD44, is expressed on both normal and neoplastic astrocytes. Moreover, CD44 has been shown to recognise the receptor for hyaluronic acid (HA), an extracellular matrix protein thought to be involved in tumour invasion. The present study has established, by immunocytochemical staining, that CD44 is present on the majority of cells in long and short term cultures derived from astrocytic gliomas. In glioblastoma multiforme, medulloblastoma, ependymoma and dysembryoplastic neuroepithelial tumour, however, staining is either absent or restricted to isolated cells. This differential binding suggests that HA receptor expression may be related to (a) the cell cycle and (b) local invasiveness of brain tumours.