Investigation of the effect of structured hyaluronic acid surfaces on cell proliferation and expression of HA cellular receptors:CD44 and RHAMM

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dc.contributor.advisor Morgan, Sarah
dc.contributor.advisor Cullen, David C. Marques, Ana Catia Ferrao 2012-01-18T14:57:20Z 2012-01-18T14:57:20Z 2011-03
dc.description.abstract Hyaluronic acid (HA) is one of the major components of the extracellular matrix; and may exhibit different biological functions, dependent on polymer molecular weight (MW). The signalling events performed by HA are mediated through interactions with its main cell receptors: CD44 and RHAMM. However, the direct effect between the HA MW and the expression of CD44 and RHAMM remains unclear. This study aimed to investigate whether different HA polymer MW alters the proliferation of tumour-derived cell lines, and whether different HA-sized has an effect on the regulation of the expression of CD44 and RHAMM. In order to determine size-specific responses of tumour cells of defined fragment MW, this investigation was undertaken using HA-tethered culture surfaces. Four surfaces were constructed, coated with polymers of different MWs. HA (4, 234, 2590 kDa) and an oligomer mixture were tethered onto an aminosilane (AHAPTMS)-treated glass surfaces using a carbodiimide reaction. Surfaces were analysed using a toolbox of in situ characterisation techniques, including wettability measurements, QCM, AFM and confocal microscopy. Using the constructed surfaces was demonstrated that HA-polymer MW modulates cell proliferation of human bladder (RT112 and T24) and prostate (PC3 and PNT1A) cell lines, with low HA MW (HA4) increasing proliferation, whereas a decrease is seen in the presence of medium (HA234) and high MW fragments (HA2590). The proliferation stimulus performed by HA was found to be phenotype dependent, with HA4 surfaces stimulating an increased proliferation in those less invasive cell lines (T24 and PNT1A), while HA234 and HA2590 inducing a sharper decrease in the most malignant tumour cell lines (RT112 and PC3). It was also demonstrated that the regulation of CD44 and RHAMM transcripts expression appears to be phenotype dependent but not HA-MW dependent. HA down-regulates CD44 and RHAMM in the most malignant cell lines; with up-regulation of the expression of the cell receptors in the less invasive cell lines. In addition, the presence of exogenous HA was shown to be involved in the regulation of the expression of CD44 variants expression. The results obtained for the CD44 and RHAMM protein expression were also found to be correlated with the obtained transcripts expression. However, the significance of these findings in tumourigenesis remains unclear. Findings from this investigation may help in the design and development of biocompatible implants with controlled surface properties to be used in cancer therapeutics; with medium and large HA polysaccharides being potential biopolymer candidates, useful for the development of novel therapies for highly invasive cancer. In addition, implications from this work can serve as a base for future research, and can lead to ideas for drugs and methods to be used in cancer therapeutic approaches. en_UK
dc.language.iso en en_UK
dc.publisher Cranfield University en_UK
dc.rights © Cranfield University 2011. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright owner. en_UK
dc.subject CD44 en_UK
dc.subject extracellular matrix en_UK
dc.subject hyaluronic acid en_UK
dc.subject proliferation en_UK
dc.subject RHAMM en_UK
dc.subject surface en_UK
dc.subject tumour en_UK
dc.title Investigation of the effect of structured hyaluronic acid surfaces on cell proliferation and expression of HA cellular receptors:CD44 and RHAMM en_UK
dc.type Thesis or dissertation en_UK
dc.type.qualificationlevel Doctoral en_UK
dc.type.qualificationname PhD en_UK

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