腫瘤缺氧在固體腫瘤當中是一種很常見的特徵。缺氧可以導致局部和系統性腫瘤的發展，並且缺乏對化學治療及放射治療的敏感性，也因此導致腫瘤復發之機率提高。腫瘤缺氧目前可分為兩種類型，其一為因不充分之血流供給所造成，稱急性、間歇性或循環性缺氧；而慢性缺氧則是因為腫瘤不斷的擴增，導致氧氣擴散距離不足所形成。在近幾年來普遍已知，擁有缺氧影響的腫瘤細胞會造成更強的抗化療性。然而，這些研究主要著重於慢性缺氧所造成之抗化療效應，只有少數的實驗結果指出這些抗凋亡的腫瘤細胞可能與反覆的缺氧有關係。這些腫瘤細胞已經被知道可以抵抗不同型態之細胞毒素，例如疊氮化物(azide)、順鉑(cisplatin)、星形孢菌素(staurosporine)等。但是，在動物體內腫瘤微環境一直缺乏直接的證據顯示腫瘤細胞的形成與反覆的缺氧的關相關性。可以確定的是，在目前的某些研究指出在腫瘤形成當中循環性缺氧及慢性缺氧有著不同的機制與型態。因此，循環性缺氧媒介腫瘤形成之生物標誌與機轉對於臨床醫師與生物學家來說，也變得越來越有興趣。然而，缺乏合適的轉譯分子影像去監控循環性缺氧在活體腫瘤內空間和時間上的特性，是目前缺氧相關研究面臨的難題。在我們的研究中發展出一核磁共振影像平台，藉由觀察血氧濃度及血液灌注情形，能動態的觀察活體腫瘤內循環性缺氧的特性。此外，我們也更進一步的探索腫瘤循環性缺氧調控之多重抗藥性及其生物標記與機轉，希望能更深入了解循環性缺氧在腫瘤抗藥性當中扮演的角色，並應用於臨床治療上。
Hypoxia is a common characteristic of solid tumors. It contributes to local and systemic tumor progression, as well as the lack of response to radio and chemotherapy, therefore increasing the probability of tumor recurrence. Tumor hypoxia has been classified into two models. Acute, intermittent or cycling hypoxia is associated with inadequate blood flow while chronic hypoxia is the consequence of the increased oxygen diffusion distance due to tumor expansion. It has known for many years that hypoxia renders cells to become more chemoresistance. However, these studies focused mainly on the effects of chronic hypoxia on drug resistance. Only a few results derived from in vitro studies demonstrated that the possibility of death-resistant cell selection by the repetition of hypoxia episodes. Such selected cells were shown to be resistant to cell death induced by different types of cytotoxicity drugs, such as azide, cisplatin and staurosporine. However, the lack of direct evidence from in vivo tumor microenvironment is a significant impediment for supporting this notion. Furthermore, some of the recent results suggest that some differences in mechanisms and phenotypes can be seen between chronic hypoxia and cycling hypoxia in tumor progression. Therefore, the biosignatures and mechanisms of cycling hypoxia-mediated tumor progression are interesting for oncologist and biologist. However, the lack of technologies for translational imaging of the dynamics and spatial heterogeneity of cycling hypoxic area in vivo is a significant impediment for such studies. In our study, we develop the magnetic resonance imaging(MRI) based-translational imaging platform for monitoring the dynamics and spatial characteristics of cycling hypoxia within tumors in living subjects. Furthermore we also explore the biosignatures of cycling hypoxia-mediated tumor progression in glioma.
