Roles of macrophages on acquired radio-resistance and the invasiveness of brain tumor

 

Abstract:

Glioblastoma multiforme (GBM) is the most malignant and lethal form of primary brain tumor.  They are also recognized as high radio-chemo-resistance and destructive invasion. The idea for the design of new therapeutic approaches to overcome both radio-chemo-resistance and invasion of GBM initially arises from our molecular knowledge about frequent genetic and epigenetic alterations. Of similar importance is the tumor microenvironment consisting of a myriad of different factors such as the immune system, growth factors, and extracellular matrix (ECM).  Previous project (2013 Aug. ~ 2016 July) on studying brain tumor microenvironment had discovered that tumor cells secret factors, such as SDF-1a and MMP2, to drive macrophages into pro-tumor function and assisting radiation-induced brain tumor invasion.  During the last 1.5 years without specific grant support for this topic, we further found that macrophages are actually the key cells for acquired radio-chemo-resistance and invasiveness of brain tumors.  However, the molecular mechanisms of how macrophages involve these effects are still unknown.  Therefore, the overall aim of this research proposal is to unravel the molecular circuitry of how macrophages regulate brain tumor cells for survival and invasion and prove their clinical potential in the orthotopic brain tumor model in immune-competent mice. To achieve this goal, three specific aims are proposed.  They are:

1.    To delineate the mechanisms involved in macrophage-mediated acquired radio-resistance and invasiveness of brain tumor in vitro.

2.    To examine the potential of macrophage blockade therapy for lowering macrophages-mediated acquired radio-resistance and invasiveness of brain tumor in vivo.

3.    To evaluate the potential of combining macrophage blockade therapy with radiation therapy and immunotherapy.

Throughout this project, we anticipate developing a macrophage blockade therapy to unleash the protective circuit of macrophages for invasive brain tumor cells and enhance the efficacy of radiation therapy for treating brain tumors.

 

Key words: Brain tumor, macrophages, radiation therapy, radio-resistance, invasiveness

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探討巨噬細胞於後天性輻射抗性與侵襲性腦瘤中所扮演的角色

摘要

多形性膠質母細胞瘤(GBM)是一種最惡性且致命型的原發性腦瘤，也已被確認為對放射線/化療藥物具有高度抵抗性，以及具有高度破壞性的侵襲力。欲克服多形性膠質母細胞瘤對放射線/化療之高抗性與侵襲力，除了應用分子生物學中的遺傳學與外遺傳學的概念來設計新的治療方式外，應用腫瘤微環境因子，特別是腫瘤相關巨噬細胞，來對抗此一抗性也扮演著同要的重要性。本實驗室於先前的三年期科技部研究計畫(2013.08~2016.07旨在探討腦癌腫瘤微環境)已發現腦腫瘤細胞會分泌如SDF-1 and MMP2等因子來調控腫瘤相關巨噬細胞，使其具有幫助腫瘤生長同時在放射線誘發的腦腫瘤侵襲現象中扮演關鍵的角色。在最近一年半內即使沒有相關研究計畫經費支持這個研究計畫，我們仍投入研究人力，而更進一步發現巨噬細胞本身在腦癌細胞的後天性輻射抗性與腦組織侵襲性上扮演著重要的角色，但巨噬細胞是經由何種的分子機制調控腦癌細胞的後天性輻射抗性與腦組織侵襲性仍然不清楚。因此，本研究計畫將從細胞層面與應用免疫完全的小鼠原位腦癌(多形性膠質母細胞瘤/星狀細胞瘤)模式進行探討，主要目標為探討巨噬細胞調控多形性膠質母細胞瘤之後天性輻射抗性與侵襲現象的分子機制。為了達到此目標，本計畫中規劃三個研究方向，

1. 探討影響巨噬細胞導引的後天性輻射抗性與腫瘤侵襲之相關機制。

2. 應用臨床前動物模式驗證巨噬細胞阻斷劑在降低腦瘤的後天性輻射抗性與腫瘤侵襲的應用潛力。

3. 評估合併巨噬細胞阻斷劑與放射治療於腦腫瘤治療中結合免疫檢查點阻斷劑的可行性。

經由此一計畫的執行，我們期望能發展出應用巨噬細胞阻斷劑來降低腦腫瘤的輻射抗性與侵襲性，並進一步發展成能與免疫檢查點阻斷劑結合的治療平台。

 

關鍵字：腦瘤、巨噬細胞、放射治療、輻射抗性、侵襲性