Investigations into therapeutic discovery and delivery of heparin-like glycosaminoglycans

Heparin-like glycosaminoglycans (HLGAGs) are complex polysaccharides found both in extracellular matrix (ECM) and at the cell surface where they, in a sequence-specific manner, bind to and regulate the biological activity of numerous proteins. Due to a lack of effective tools to study structure-function relationship of these complex molecules, the role(s) of HLGAGs in cancer remains largely indirect and poorly understood. To study the role(s) of HLGAGs in cancer growth, metastasis and angiogenesis, tumor systems were studied using heparinases I and III which have distinct substrate specificities. Studies, focusing on the biochemistry of the heparinase active site, elucidated key interactions important for enzymatic activities, thus enabling the biological studies presented here. In vitro cell culture study with heparinases as tools clearly showed that cell surface HLGAGs are involved in regulating fundamental cellular activities including cell proliferation, invasion and adhesion. Significantly, heparinase I and III demonstrated distinct effect on these cellular activities with heparinase III inhibiting tumor cell proliferation, invasion and adhesion in selected model systems and heparinase I inhibiting these processes. Further in vivo studies in animal tumor models confirmed and expanded the distinct responses to heparinase I and III treatment. HLGAG fragments generated from heparinase treatment were found to be responsible for the effect of heparinase treatment in tumor models. Moreover, cell surface HLGAGs containing cryptic activatory and inhibitory sequence information were identified and characterized. In contrast to heparinase I- generated HLGAG fragments, heparinase III- generated HLGAG fragments were shown here to inhibit both primary tumor growth and secondary lung metastasis.

Department dc:contributor.department

Massachusetts Institute of Technology. Division of Bioengineering and Environmental Health

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2001

Author dc:creator

• Liu, Dongfang, 1969-

Advisor dc:contributor.advisor

• Ram Sasisekharan.

• Division of Bioengineering and Environmental Health.

Statement dc:rights

• MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/29952

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/29952