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Title: Regulation of lymphangiogenesis by interleukin-7 (IL7) and the association with lymphatic metastasis in human breast cancer
Author: Al-Rawi, Mahir Ali Ahmed
ISNI:       0000 0004 2750 6554
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2004
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The lymphatic system constitutes a major route for cancer cells to spread to the regional lymph nodes. Lymph node metastasis is considered to be a key prognostic factor in determining patients' prognosis in many solid tumours including breast cancer. However, studies on the lymphatic system had been very limited mainly due to the lack of biological and molecular markers that distinguish between blood and lymphatic vessels. The last few years however, have witnessed the identification of several novel molecular markers that are considered to be specific to the lymphatic endothelium. The detection of these specific lymphatic markers has lead to the identification of the existence of intra- tumoural lymphatics and lymphangiogenesis (formation and growth of new lymphatic vessels) within tumours. Lymphangiogenesis is now considered to play a major role in cancer lymphatic spread in many tumours including breast cancer. It is thought that the production of some vascular endothelial growth factors (VEGFs) like VEGF-D, by cells within tumours could stimulate the generation of new or existing lymphatic vessels thereby provide a direct conduit for cancer cells to spread to the regional lymph nodes. The current knowledge of the regulation of lymphangiogenesis and the production of the vascular endothelial growth factors within the tumour microenvironment is still very poor. To this end, we sought to identify a potential regulator of lymphangiogenesis. The results presented here demonstrated that amongst the many cytokines and growth factors tested, Interleukin-7 (IL-7) could indeed regulate lymphangiogenesis either directly via stimulating endothelial cell growth or indirectly via upregulating the expression of VEGF-D in these cells. The specificity of this effect of IL-7 was demonstrated by using neutralising antibodies and ribozyme trangenes. In addition to endothelial cells, IL-7 was also found to have a direct effect on breast cancer cells. The detection of a fully functional receptor for IL-7, IL-7R, in these cells had enabled us to study the effects of IL-7 on breast cancer cells as well. IL-7 induced the growth of breast cancer cells and also upregulated the expression of VEGF-D in these cells. Dissection of the signalling pathways of IL-7 in both endothelial and breast cancer cells revealed that IL-7 exerts these effects mainly via a Wortmannin sensitive pathway. Clinically, IL-7 and its downstream signalling pathway signalling molecules levels of expression were correlated with higher lymphatic metastatic rate in human breast cancer. Additionally, breast cancers with higher levels of IL-7 were found in patients with the poorer prognosis and worst survival. Therefore, it is concluded from these data that IL-7 plays an adverse effect in breast cancer metastasis. This effect of IL-7 is mediated via two arms acceleration of lymphangiogenesis and stimulating breast cancer cells growth. Inhibition of IL-7 signalling by using monoclonal antibodies, blocking agents to IL-7 or to one of its main intermediates could indeed be used as a way of targeted therapy to tackle metastatic spread of tumours particularly by the lymphatic route.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available