The integrins play a crucial role in cancer cell proliferation, migration,
differentiation, survival and angiogenesis. It has been shown that integrin
expression is positively correlated to cancer dissemination, this suggests
targeting selected integrins as an anti-metastatic strategy. The aim of this study
is to investigate the effect of novel antagonists of α5β1, αvβ3 and αvβ5 integrins
on cancer cell migration, a key process in tumour cell dissemination.
Immunohistochemistry was used to evaluate the expression of α5, αv, β3 and
β5 integrin subunits in prostate cancer tissues. Furthermore the expression of
these integrin subunits in tumour and normal human head and neck tissues was
compared. The expression profile of these integrin subunits in established
human cancer cell lines was subsequently evaluated using immunodetection
methods in cells and xenograft tumour samples. The effect of integrin inhibition
on cell migration was then assessed using neutralizing antibodies against αvβ3,
αvβ5, and α5β1 integrins in the scratch-wound healing assay. This assay was
then used to evaluate the potential of novel small molecule integrin antagonists in preventing tumour cell migration. In H & N tissues, αvβ3, αvβ5 and α5β1
integrins are extensively expressed in tumour tissues but weakly expressed in normal tissue from the same patient. Further, prostate cancer tissues expressed
variable levels of αvβ3, αvβ5 and α5β1 integrins. αvβ3 and αvβ5 integrins were
expressed in variable levels in OSC-19, PC-3, DU145, DLD-1, HT-29, HUVEC,
MCF-7, MCF-7ADR and M14 human tumour cell lines and in OSC-19, PC-3,
HT-29 and MCF-7 xenografts. α5β1 integrin was expressed in all cell lines and
xenografts except in MCF-7 cell line and HT-29 cell line and xenograft. Overall,
the expression was elevated in xenografts compared to the corresponding
cultured cells. Based on the expression profile and ability of cells to migrate,
three cell lines (DLD-1 colon, DU145 prostate and OSC-19 HNSCC) were
selected as models to further evaluate the potential of novel small molecule
integrin antagonists to inhibit cell migration. The cell lines were characterized by
using neutralizing antibodies against αvβ3, αvβ5, and α5β1 integrins to
determine which of these three integrins were primarily involved in tumour cell
migration. In DLD-1 and DU145, blocking αvβ5 and αvβ3 significantly inhibited migration, whilst the migration of OSC-19 was 50% inhibited by a multi-integrin
inhibitor combination. Among the antagonists, ICT9055 and ICT9072
significantly decreased DLD-1 cell migration by 70% and 60% respectively while
ICT9023, ICT9024, and ICT9026 significantly decreased DU145 cell migration
by 60%, 60% and 50% respectively. The findings suggest that single integrin
inhibition is not sufficient to prevent cell migration whereas dual or multiple
inhibition is more effective. Two novel anti-migratory agents were identified in
colon cancer and three in prostate cancer which would warrant further
investigation. / Princess Nora Bint Abdul Rahman University
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/14284 |
| Date | January 2015 |
| Creators | Ahmedah, Hanadi T.A. |
| Contributors | Sheldrake, Helen M., Shnyder, Steven, Patterson, Laurence H. |
| Publisher | University of Bradford, Institute of Cancer Therapeutics |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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