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Title: Selective endothelin receptor involvement in the development of colorectal cancer and liver metastases
Author: Dawas, K. I.
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2007
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Endothelin-1 (ET-1), a vasoactive peptide with mitogenic qualities, is over-expressed in the plasma of patients with colorectal cancer (CRC) and liver metastases. Its actions are mediated via two G-protein linked receptors, ETA and ETB. This study (i) examined the effect of ET-1 and its receptor antagonists as well as a G-protein blocker on CRC cell line growth (ii) investigated tET receptor distribution in human CRC and liver metastases by autoradiography (iii) recorded the effect on tumour growth of an oral ETA receptor antagonist to an in vivo model of colorectal cancer liver metastases. ET-1 stimulated significant growth in the cancer cells. This effect was reversed by the ETA, but not the ETB, receptor antagonist. Apoptosis was similar in controls and ET-1 antagonist treated cells. BrDU staining demonstrated an ET-1 dependent increase in mitosis, reversed by the ETA receptor antagonist. Blocking the G-protein subunits also reversed growth. In human cancer tissues ETA was over-expressed while ETB was under- expressed compared to controls. There was no significant difference in weight or number of liver metastases between control and experimental rats in vivo. In summary, ET-1 stimulates human CRC growth in vitro via ETA receptors by mechanisms that include stimulation of mitosis but not alteration of apoptosis. Thi signal is transduced via the G-protein subunits Go or Gi. Human CRC liver metastases tissue over-express ETA receptors compared to normal tissue. ET receptor antagonists may have a therapeutic role in primary and metastatic CRC.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available