VIB生命科学研究院：肿瘤氧供应正常化可能是对抗癌症的关键因素

Normalizing tumor oxygen supply could be key factor in the fight against cancer

 

日期: 2016年8月17日

来源: VIB(佛兰德生物技术研究所)

VIB ( the Flanders Institute for Biotechnology) is a research center with 1100 scientists, professionals and support staff and headquartered in Gent, Belgium. VIB's main objective is gathering innovative basic knowledge on the normal and abnormal or pathological processes occurring in a cell, an organ, and an organism (humans, plants and micro-organisms) utilizing gene technology research methods. VIB has made many breakthrough discoveries. VIB operates in four Flemish universities, Ghent University, K.U. Leuven, University of Antwerp, and Vrije Universiteit Brussel.

简介:

研究人员认为，肿瘤细胞中缺乏氧气会改变细胞的基因表达，从而促进癌症的生长。这一发现意义深远，因为研究还证明，在肿瘤中维持适当的氧气供应可以抑制这些所谓的“表观遗传畸变”。

 

完整的故事

肿瘤细胞缺氧改变了细胞的基因表达，从而促进了肿瘤的生长。这是由Diether Lambrechts教授和Bernard Thienpont博士(VIB-KU Leuven)领导的一项研究项目的主要结论，该项目发表在科学杂志《自然》上。这一发现意义深远，因为该研究还证明，在肿瘤中维持适当的氧气供应可以抑制这些所谓的“表观遗传畸变”。这篇论文的见解最终可能导致针对血管或表观遗传变异的新型抗癌药物。

 

癌症的发生是众所周知的:由于偶然或致癌因素，单个细胞的DNA发生突变，然后异常细胞迅速膨胀。这些基因突变破坏了正常的细胞功能，但有利于癌细胞的生长和生存。但除了这些基因变化，肿瘤细胞也表现出不同的表观遗传，这与基因的表达方式有关，而不是基因本身。

 

与广泛的癌症相关

尽管表观遗传变化不会影响遗传密码，但它们会以类似的方式强烈干扰基因功能，从而对癌细胞有利。但直到现在，这些表观遗传变化的起源仍是一个谜。Lambrechts教授实验室的科学家研究了一种常见的表观遗传改变:高甲基化，或甲基在DNA中过量添加。高甲基化抑制肿瘤抑制基因的表达，从而导致细胞异常行为和肿瘤过度生长。

 

Diether Lambrechts (VIB-KU Leuven):“我们的研究表明，这些表观遗传改变是由肿瘤环境引起的，更确切地说，是由缺氧引起的，我们称之为‘缺氧’。通常从DNA中去除甲基的酶需要氧气。当缺氧时，过多的甲基化被保留，导致高甲基化。更重要的是，缺氧可以解释肿瘤中高达一半的高甲基化。在我们致力于乳腺肿瘤研究的同时，我们也证明了这种机制对膀胱、结直肠、头颈、肾、肺和子宫肿瘤也有广泛的影响。

 

诊断和治疗使用

通过对3000多例患者肿瘤的分析，发现了缺氧与肿瘤生长之间的联系。作为下一步，研究人员验证了另一个假设:干扰肿瘤氧供应是否会对癌症的进展造成打击?他们很高兴地看到这个假设得到了证实:用老鼠，他们证明了正常的血液供应足以阻止表观遗传改变的发生。

 Bernard Thienpont (VIB-KU Leuven):我们的新见解可能对癌症治疗产生巨大影响。首先，我们可以利用表观遗传畸变来监测肿瘤的供氧情况，使我们能够更好地预测肿瘤的行为并做出更明智的治疗决定。其次，它为现有的血管靶向治疗提供了新的思路。它们不仅有助于肿瘤化疗，还能抑制新的表观遗传畸变。这反过来有助于降低复发的侵袭性，从而证明对治疗有益。

 

下一个计划

第一个目标已经达到了高潮:VIB实验室正在测试分析肿瘤DNA是否可以用于预测肿瘤氧化。科学家们还在从事一项新的研究，重点是血管正常化疗法。“我们想知道是否不仅可以抑制，甚至可以逆转这些表观遗传变异。”通过这些和其他新的研究途径，我们对癌症研究的未来充满信心。

 

故事来源:

VIB(佛兰德斯生物技术研究所)提供的材料。注意:内容可以根据样式和长度进行编辑。

期刊引用:

Bernard Thienpont, Jessica Steinbacher, Hui Zhao, Flora D 'Anna, Anna Kuchnio, Athanasios Ploumakis, Bart Ghesquiere, Laurien Van Dyck, Bram Boeckx, Luc Schoonjans, Els Hermans, Frederic Amant, Vessela N. Kristensen, Kian Peng Koh, Massimiliano Mazzone, Mathew L. Coleman, Thomas Carell, Peter Carmeliet, Diether Lambrechts。肿瘤缺氧通过降低TET活性导致DNA高甲基化。自然,2016;DOI:10.1038 / nature19081

 

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Normalizing tumor oxygen supply could be key factor in the fight against cancer

Date:

August 17, 2016

Source:

VIB (the Flanders Institute for Biotechnology)

Summary:

The lack of oxygen in tumor cells changes the cells' gene expression, thereby contributing to the growth of cancer, suggest researchers. The findings are far-reaching, as the study also proved that maintaining a proper oxygen supply in tumors inhibits these so-called 'epigenetic aberrations.'

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FULL STORY

The lack of oxygen in tumor cells changes the cells' gene expression, thereby contributing to the growth of cancer. This is the main conclusion of a research project led by professor Diether Lambrechts and Dr. Bernard Thienpont (VIB-KU Leuven), which was published in the scientific journal Nature. The findings are far-reaching, as the study also proved that maintaining a proper oxygen supply in tumors inhibits these so-called 'epigenetic aberrations'. The paper's insights could eventually lead to new anti-cancer drugs that target blood vessels or the epigenetic aberrations.

 

Cancer onset is generally well-understood: due to chance or carcinogenic factors, a single cell's DNA mutates, followed by the rapid expansion of the abnormal cell. These genetic mutations disturb normal cell function, but are beneficial for the growth and survival of cancer cells. But apart from these genetic changes, tumors cells also differ epigenetically, which has to do with how genes are expressed rather than the genes themselves.

 

Pertinent to a wide range of cancers

 

Although epigenetic changes don't affect the genetic code, they can strongly disturb gene function in a similar way, to the benefit of cancer cells. But until now, the origins of these epigenetic changes mostly remained a mystery. Scientists from the lab of professor Lambrechts investigated one frequent epigenetic alteration: hypermethylation, or the excessive addition of methyl groups to DNA. Hypermethylation silences the expression of tumor suppressing genes, thereby enabling the aberrant behavior of cells and the excessive growth of tumors.

 

Diether Lambrechts (VIB-KU Leuven): "Our study shows that these epigenetic alterations are caused by the environment of the tumor, and more specifically by oxygen shortage -- which we call 'hypoxia'. Oxygen is required by the enzymes that normally remove the methyl groups from the DNA. When there is oxygen shortage, too much methylation is retained, causing hypermethylation. Even more, hypoxia explains up to half of the hypermethylation in tumors. While we dedicated much of our efforts to breast tumors, we also demonstrated that this mechanism has a similarly broad impact in bladder, colorectal, head and neck, kidney, lung and uterine tumors."

 

Diagnostic and therapeutic uses

 

Uncovering the link between oxygen shortage and tumor growth was the result of the analysis of over 3,000 patient tumors. As a next step, the researchers verified another assumption: would interfering with tumor oxygen supply strike a blow against the progression of cancer? They were pleased to see this hypothesis confirmed: using mice, they proved that normalizing the blood supply is sufficient to stop the epigenetic alterations from occurring.

 

Bernard Thienpont (VIB-KU Leuven): "Our new insights can have a potentially huge impact on cancer management. First of all, we could use epigenetic aberrations to monitor the oxygen supply to a tumor, allowing us to better predict tumor behavior and make more informed treatment decisions. Secondly, it sheds new light on existing blood vessel targeting therapies. They don't only help deliver chemotherapy to the tumor, but also inhibit new epigenetic aberrations. This could in turn help make relapses less aggressive, and thus prove to be therapeutically beneficial."

 

Next steps

 

The first ambition is already in full swing: the VIB lab is now testing whether analyzing tumor DNA can be used to predict tumor oxygenation. The scientists are also engaged in new research that focuses on blood vessel normalizing therapies. "We want to know whether it's not just possible to inhibit, but maybe even to reverse some of these epigenetic aberrations. Following through on these and other new research avenues gives us great faith in the future of cancer research," concludes prof. Lambrechts.

 

Story Source:

 

Materials provided by VIB (the Flanders Institute for Biotechnology). Note: Content may be edited for style and length.

 

Journal Reference:

 

Bernard Thienpont, Jessica Steinbacher, Hui Zhao, Flora D’Anna, Anna Kuchnio, Athanasios Ploumakis, Bart Ghesquière, Laurien Van Dyck, Bram Boeckx, Luc Schoonjans, Els Hermans, Frederic Amant, Vessela N. Kristensen, Kian Peng Koh, Massimiliano Mazzone, Mathew L. Coleman, Thomas Carell, Peter Carmeliet, Diether Lambrechts. Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature, 2016; DOI: 10.1038/nature19081

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VIB (the Flanders Institute for Biotechnology). "Normalizing tumor oxygen supply could be key factor in the fight against cancer." ScienceDaily. ScienceDaily, 17 August 2016. <www.sciencedaily.com/releases/2016/08/160817142914.htm>.