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This dissertation, Study of the Role of {221}-adrenoceptors in the Promotion of Colon Cancer Growth by 黃佩珊, Pui-shan, Helen, Wong, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled STUDY OF THE ROLE OF β-ADRENOCEPTORS IN THE PROMOTION OF COLON CANCER GROWTH Submitted by WONG PUI SHAN HELEN for the degree of Doctor of Philosophy at The University of Hong Kong in November 2007 Cigarette smoking is a risk factor for colon cancer. Studies suggested that stress increases the incidence and promotes the development of cancers. Cigarette smoking and stress are closely associated, as people often smoke under stressful conditions and both of them can activate the adrenergic nervous system. Furthermore, activation of β-adrenoceptors has been implicated in the carcinogenesis in various kinds of cancers. Therefore, the present study aims to investigate the interactions between cigarette smoking and stress on colon cancer growth and the modulating role of β-adrenoceptors in these pathological processes. 4% cigarette smoking together with restraint stress one hour daily promoted tumor growth in nude mice bearing HT-29 human colon cancer xenograft. This was accompanied by the increase of plasma levels of cotinine, a metabolite of nicotine, and adrenaline in these animals. The results suggest that the promotion of colon tumor growth by cigarette smoke together with restraint stress treatment could be attributed to the increase of nicotine and adrenaline in the animals. Further studies were performed to determine the effects of nicotine on colon cancer growth in vivo. Results showed that oral nicotine administration stimulated growth of HT-29 human colon cancer xenograft in nude mice. Nicotine also elevated cotinine and adrenaline plasma levels. Intraperitoneal injection of atenolol or ICI 118,551, a β -selective antagonist and β -selective 1 2 antagonist respectively, blocked the stimulatory action of nicotine on tumor growth. β-Adrenoceptors blockade also abrogated the promoting action of nicotine on microvessel densities as well as cellular expression of cyclooxygenase-2 (COX-2), prostaglandin E (PGE ), and vascular endothelial 2 2 growth factor (VEGF). Nicotine could also directly increase adrenaline production and stimulate colon cancer cell growth in vitro. The stimulatory action of nicotine was reversed by atenolol or ICI 118,551. The action of nicotine on adrenaline release was affirmed by upregulation of catecholamine-synthesizing enzymes in colon cancer cells. Methyllycaconitine, an α7-nicotinic acetylcholine receptor antagonist, reversed the stimulatory actions of nicotine on cell proliferation and adrenaline production. The direct action of adrenaline was further studied in colon cancer cells in vitro. Adrenaline stimulated colon cancer growth which was accompanied by the enhanced expression of COX-2, PGE, matrix metalloproteinase-9 (MMP-9) and VEGF in HT-29 cells. The stimulatory action of adrenaline on HT-29 colon cancer growth was reversed by atenolol and ICI 118,551. In addition, both antagonists also abrogated the stimulating actions of adrenaline on COX-2, PGE, MMP-9 and VEGF expression. 24-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), an active metabolite of nicotine, also stimulated HT-29 cell proliferation which was abolished by atenolol and ICI 118,551. They also significantly decreased COX-2 expression, cytosolic phospholipase A (cPLA ) expression and PGE release 2 2 2 induced by NNK. All these findings indicate the importance of β-adrenoceptor activat

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