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The role of endothelin in colorectal cancer and liver metastases

Asham, Emad Hakeem; (2002) The role of endothelin in colorectal cancer and liver metastases. Doctoral thesis (M.D), UCL (University College London). Green open access

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Abstract

Cancer is regarded as a disease in which normal growth signalling pathways are deregulated. Growth regulatory molecules are overproduced, mutated, expressed at inappropriate stages of development or lost due to inheritance or aberrant mitotic division. Endothelin-1 (ET-1), a vasoactive molecule which acts via two receptors ETA and ETb, was found to be a mitogenic factor that enhances growth in a variety of cancer cells in vitro. Raised levels of ET-1 have also been detected in tissues from patients with different types of tumours. This thesis is concerned with the putative role of ET-1 in colorectal cancer from three perspectives: Firstly, to study the effects of intraportal infusion of ET receptor antagonist on tumour growth in a rat model of colorectal liver metastases. Secondly, to assess the expression of ET-1 in surgical specimens of colorectal cancer and their liver metastases by immunohistochemistry. Thirdly, to confirm previous work suggesting that production of ET-1 by cancer cells is reflected in raised plasma levels in colorectal cancer patients with and without metastases. Early intraportal infusion of ETA receptor antagonist following tumour inoculation was found to significantly reduce the tumour weight in the liver (p = 0.03). On the other hand antagonism of ETB receptor did not affect tumour growth. Using Immunohistochemistry, ET-1 was found to be abundantly expressed in colorectal cancer cells with over spillage in the stroma unlike normal colon where the epithelium was mostly negative for ET-1. ET-1 plasma levels were significantly elevated in patients with and without metastases compared to the control group (p = 0.0001, p = 0.002 respectively). ETA receptor antagonism may be a potential pharmacological tool for manipulation of colorectal cancer growth.

Type: Thesis (Doctoral)
Qualification: M.D
Title: The role of endothelin in colorectal cancer and liver metastases
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Cancer cells
URI: https://discovery.ucl.ac.uk/id/eprint/10104050
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