探討活性氧化物質與循環性缺氧在多型性神經膠質瘤的發展以及對放射線治療抵抗性的影響

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Title:	探討活性氧化物質與循環性缺氧在多型性神經膠質瘤的發展以及對放射線治療抵抗性的影響 The effect of Reactive Oxygen Species Related to Cycling Hypoxia in Glioblastoma Multiforme Progression and Resistance to Radiation Therapy
Authors:	李政鴻;Cheng-Hung Lee
Contributors:	醫學院基礎醫學研究所
Keywords:	循環性缺氧;多型性神經膠質瘤;放射線治療;Cycling Hypoxia;GBM;Radiotherapy
Date:	2009
Issue Date:	2010-09-29 12:13:31 (UTC+8)
Abstract:	一直以來，相對於循環性缺氧，持續性缺氧在癌症腫瘤的發展以及對於放射線及化學治療的效果是扮演著主要的角色。主要的原因在於持續性缺氧的環境造成腫瘤細胞的表現型轉變，造成對放射線治療及化學治療的抵抗性，進而造成腫瘤的侵襲性與轉移性。然而，與過去研究成果矛盾的是，在放射線治療之後腫瘤的復發往往存在於間歇性血管鬱積的地方。因此，循環性缺氧區域的細胞可能才是真正的抗放射線治療的部分，也就是造成腫瘤復發的主因。我們研究的主要目的是去探討在多形惡性神經膠質(glioblastoma Multiforme)當中，持續性缺氧或者循環性缺氧在腫瘤生長發展以及腫瘤對於放射性的感受性的影響。我們將神經膠質瘤細胞以及帶有腫瘤的裸鼠暴露在不同的缺氧環境中，並且使用放射線照射，探討腫瘤細胞在體內及體外實驗中的結果。在此研究中，我們探討了：(1)非間歇性缺氧與循環性缺氧在細胞增殖、轉移、侵犯和放射敏感度的比較，(2)活性氧化物質在兩種組別的差異為何？(3)活性氧化物質在循環性缺氧中扮演的角色。而實驗結果表示，我們在神經膠質瘤中確定了循環性缺氧與放射線感受性的直接關係，並且比較了循環性缺氧以及持續性缺氧所造成的效果。而在循環性缺氧的組別中，細胞的增殖、遷移、侵襲和對放射線抵抗性是經由活性氧化物質產生所促進。這樣的結果提供了一個臨床上潛在的重要影響：在癌症病患使用活性氧化物質的清除劑，可能會是抑制腫瘤生長發展以及降低放射線治療抵抗性的有效方法。 It has long been considered that chronic hypoxia, rather than cycling hypoxia, plays the main role in promotion of cancer progression and in the efficacy of radiation therapy or chemotherapy. This is because the major phenotypic shift associated with chronic hypoxia involves tumor cell resistance to chemotherapy or radiotherapy in addition to more invasive and metastatic features. However, this concept contradicts previous findings that tumor recurrence after radiation therapy tended to occur more frequently in regions where there was a high incidence of intermittent vascular stasis. Therefore, cyclically hypoxic cells might be the most radio-resistant cells and could therefore be responsible for tumor re-growth. The purpose of this study is to investigate the differential effect and mechanism of chronic and cycling hypoxia on tumor progression and tumor radio-sensitivity in the human glioblastoma tumor model. We exposed GBM cells and mice bearing glioma to experimentally imposed cycling or chronic hypoxic stress in vitro and in vivo prior to treatment with ionizing irradiation. Cell proliferation assay, migration assay, invasion assay, clonogenic survival assay and tumor growth measurements were performed to determine tumor progression and tumor radiosensitivity. Furthermore, Tempol, a membrane-permeable radical scavenger, was used to determine the impact of reactive oxygen species (ROS) on hypoxia-induced tumor progression and radioresistance. In the present study, we identified a direct causal link between cycling hypoxia and tumor radiosensitivity in GBM and documented the differential effects of chronic versus cycling hypoxia in this process. Here, our results demonstrate that cycling hypoxia increases tumor cell proliferation, migration, invasion and radioresistance by inducing ROS production. Tempol treatment during cycling hypoxia suppressed cycling hypoxia-induced tumor progression and radioresistance. These results have potentially important clinical implications and suggest that ROS scavengers may be an effective approach by which to suppress hypoxia-induced tumor progression and radioresistance.
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