Robertson, JHP;
(2008)
The role of integrins in early colonic cancer liver metastases development.
Doctoral thesis , UCL (University College London).
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Abstract
Annually, almost one million cases of colorectal cancer are diagnosed and almost half a million deaths are attributed to this disease worldwide. The liver is the most common and critical site of distant metastasis. The primary locus of the colorectal tumour can frequently be managed by surgery alone or with neoadjuvant and adjuvant oncological therapy. Management of the metastatic spread is more difficult. For more effective oncological management of disseminated colorectal cancer, therapies must be devised that target the different individual stages of metastasis development. This theory is supported by the survival benefit shown using Bevacizumab, a selective inhibitor of Vascular Endothelial Growth Factor, as an adjuvant to standard chemotherapy for metastatic colorectal cancer. Recent work showed that specific integrin subunits a2, a6 and p4 played a role in vivo in human HT29 colorectal cancer cell migration and extravasation. Through the techniques of Immuncytochemistry and Western Blotting, these three integrins were shown to be expressed not only in the control HT29 cell line but also in the unrelated rat DHDK12 colonic cancer cell line - a novel finding. Functional blocking by antibodies of these integrin subunits, in the rat DHDK12 cell line, was studied in vivo using intravital video microscopy. This produced a significant reduction in tumour cell extravasation compared to control groups - wild type and wild type with non specific IgG. Serial measurements were used and then compared using ANOVA with Bonferroni's Multiple Comparison. Analysis of current established in vivo models of early colorectal liver metastasis development were performed using the intravital video microscopy. The results showed colorectal cancer cell line-host selection and biological compatibility had a significant effect on early metastasis development. The in vivo model of BDIX rat with DHDK12 cell provides a highly biologically accurate system to allow the study of the early events of colonic cancer liver metastasis. In conclusion, integrins play an important role in the early development of colonic cancer cell liver metastasis. Functional blocking of integrin subunits a2, a6 and p4, expressed in unrelated colorectal cancer strains, reduce colonic cancer cell migration. Colorectal cancer cell line-host selection and biological compatibility had a significant effect on early colorectal liver metastasis establishment.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | The role of integrins in early colonic cancer liver metastases development |
| Identifier: | PQ ETD:593256 |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity. |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1445932 |
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