乔治亚大学 低氧水平可促进肿瘤的生长

Low oxygen levels could drive cancer growth, research suggests

 

 

来源: 佐治亚大学

简介:

一项新的研究表明,细胞中的低氧水平可能是某些癌症中无法控制的肿瘤生长的主要原因。作者的发现与人们普遍认为的基因突变导致癌症生长的观点背道而驰。

 

完整的故事

佐治亚大学的徐颖教授和他的同事分析了微阵列芯片的信息,微阵列芯片是一种含有大量基因物质的小玻璃片,他们发现细胞中的低氧水平可能是某些癌症中无法控制的肿瘤生长的主要原因。

 

 

图片由乔治亚大学提供

 

乔治亚大学的一项新研究表明,细胞中的低氧水平可能是某些癌症中无法控制的肿瘤生长的主要原因。作者的发现与人们普遍认为的基因突变导致癌症生长的观点背道而驰。

 

如果缺氧,或者细胞内低氧水平,是被证明是某些类型癌症的一个关键驱动因素, 治疗肿瘤恶性生长的治疗方案可能有重大改变,徐应说,他是Regents-Georgia生物信息学和计算生物学研究联盟和富兰克林艺术与科学学院著名的学者和教授。

 

 

研究小组分析了信使RNA数据的样本,这些数据也被称为转录组数据,来自一个公共数据库中7种不同的癌症类型。他们发现,细胞中长期缺乏氧气可能是癌症生长的关键驱动力。这项研究发表在分子细胞生物学杂志的网络版上。

 

先前的研究表明,细胞内低氧水平是导致癌症发展的一个因素,但不是癌症生长的驱动力。世界范围内癌症的高发病率不能仅仅用偶然的基因突变来解释,徐说。他补充说,生物信息学融合了生物学和计算科学,让研究人员从新的角度看待癌症。基因水平的突变可能使癌细胞比健康细胞具有竞争优势,但新提出的癌症生长模型不需要出现常见的故障,比如致癌基因的突然增殖,即癌细胞的前体。

 

“抗癌药物试图从分子层面深入到特定突变的根源,但癌症往往会绕过它,”许志永说。“所以我们认为基因突变可能不是癌症的主要诱因。”

 

到目前为止,许多癌症研究都集中在设计药物治疗,以对抗与特定类型癌症相关的基因突变。在他们的研究中,研究人员通过一个软件程序分析了从斯坦福微阵列数据库下载的数据,以检测7种癌症的异常基因表达模式:乳腺癌、肾癌、肝癌、肺癌、卵巢癌、胰腺癌和胃癌。该在线数据库允许科学家检查来自微阵列芯片的信息,微阵列芯片是包含大量基因材料的小玻璃片。

 

徐依赖HIF1A基因作为细胞中氧分子数量的生物标志物。所有七种癌症都显示出HIF1A的增加,表明癌细胞中的氧气水平下降。

 

 

细胞内的低氧水平会干扰氧化磷酸化的活性,氧化磷酸化是细胞将食物转化为能量的高效方式。随着氧气的减少,细胞转而进行糖酵解,产生能量单位,称为ATP。糖酵解是一种非常低效的获取能量的方法,因此癌细胞必须更加努力地工作以获得更多的食物,特别是葡萄糖,才能存活。当氧气水平下降到危险的低水平时,血管生成或新生血管的过程就开始了。新的血管提供新鲜的氧气,从而提高细胞和肿瘤中的氧气水平,减缓癌症的生长——但只是暂时的。

 

“当癌细胞获得更多的食物时,它就会生长;这使得肿瘤生物量更大,更缺氧。反过来,能量转换效率进一步下降,使细胞更加饥饿,并触发细胞从血液循环中获得更多的食物,形成一个恶性循环。这可能是癌症的主要诱因。

 

 

徐解释说,这种新的癌症生长模型可以帮助解释为什么许多癌症在三到六个月内就会迅速产生抗药性。他强调了通过未来的癌症实验研究来测试新模型的重要性。如果这个模型成立,研究人员首先需要寻找防止细胞缺氧的方法,这可能导致癌症治疗的巨大变化。

 

这项研究的其他作者包括崔娟、毛希增和奥尔曼,都来自佐治亚大学,还有贝勒医学院的菲尔·哈斯廷斯。许志永还与中国吉林大学有合作关系。

 

期刊引用:

崔志杰,毛新民,伍文华,P. J.哈斯廷斯,许玉仪。低氧和能量效率降低和细胞增殖信号的混淆导致癌症增长越来越快。分子细胞生物学杂志,2012;DOI:10.1093 / jmcb / mjs017

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Low oxygen levels could drive cancer growth, research suggests

Date:

May 3, 2012

Source:

University of Georgia

Summary:

Low oxygen levels in cells may be a primary cause of uncontrollable tumor growth in some cancers, according to a new study. The authors' findings run counter to widely accepted beliefs that genetic mutations are responsible for cancer growth.

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FULL STORY

 

University of Georgia Professor Ying Xu and his colleagues analyzed information from microarray chips, which are small glass slides containing large amounts of gene material, and have found that low oxygen levels in cells may be a primary cause of uncontrollable tumor growth in some cancers.

Credit: Image courtesy of University of Georgia

Low oxygen levels in cells may be a primary cause of uncontrollable tumor growth in some cancers, according to a new University of Georgia study. The authors' findings run counter to widely accepted beliefs that genetic mutations are responsible for cancer growth.

 

If hypoxia, or low oxygen levels in cells, is proven to be a key driver of certain types of cancer, treatment plans for curing the malignant growth could change in significant ways, said Ying Xu, Regents-Georgia Research Alliance Eminent Scholar and professor of bioinformatics and computational biology in the Franklin College of Arts and Sciences.

 

The research team analyzed samples of messenger RNA data-also called transcriptomic data-from seven different cancer types in a publicly available database. They found that long-term lack of oxygen in cells may be a key driver of cancer growth. The study was published in the early online edition of the Journal of Molecular Cell Biology.

 

Previous studies have linked low oxygen levels in cells as a contributing factor in cancer development, but not as the driving force for cancer growth. High incidence rates of cancer around the world cannot be explained by chance genetic mutations alone, Xu said. He added that bioinformatics, which melds biology and computational science, has allowed researchers to see cancer in a new light. Gene-level mutations may give cancer cells a competitive edge over healthy cells, but the proposed new cancer growth model does not require the presence of common malfunctions such as a sudden proliferation of oncogenes, precursors to cancer cells.

 

"Cancer drugs try to get to the root -- at the molecular level -- of a particular mutation, but the cancer often bypasses it," Xu said. "So we think that possibly genetic mutations may not be the main driver of cancer."

 

Much of cancer research so far has focused on designing drug treatments that counteract genetic mutations associated with a particular type of cancer. In their study, the researchers analyzed data downloaded from the Stanford Microarray Database via a software program to detect abnormal gene expression patterns in seven cancers: breast, kidney, liver, lung, ovary, pancreatic and stomach. The online database allows scientists to examine information from microarray chips, which are small glass slides containing large amounts of gene material.

 

Xu relied on the gene HIF1A as a biomarker of the amount of molecular oxygen in a cell. All seven cancers showed increasing amounts of HIF1A, indicating decreasing oxygen levels in the cancer cells.

 

Low oxygen levels in a cell interrupt the activity of oxidative phosphorylation, a term for the highly efficient way that cells normally use to convert food to energy. As oxygen decreases, the cells switch to glycolysis to produce their energy units, called ATP. Glycolysis is a drastically less efficient way to obtain energy, and so the cancer cells must work even harder to obtain even more food, specifically glucose, to survive. When oxygen levels dip dangerously low, angiogenesis, or the process of creating new blood vessels, begins. The new blood vessels provide fresh oxygen, thus improving oxygen levels in the cell and tumor and slowing the cancer growth-but only temporarily.

 

"When a cancer cell gets more food, it grows; this makes the tumor biomass bigger and even more hypoxic. In turn, the energy-conversion efficiency goes further down, making the cells even more hungry and triggering the cells to get more food from blood circulation, creating a vicious cycle. This could be a key driver of cancer," Xu said.

 

Xu explained that this new cancer-growth model could help explain why many cancers become drug resistant so quickly-often within three to six months. He stressed the importance of testing the new model through future experimental cancer research. If the model holds, researchers will need to search for methods to prevent hypoxia in cells in the first place, which could result in a sea change in cancer treatment.

 

Additional authors of this study include Juan Cui, Xizeng Mao and Victor Olman, all of UGA, and Phil Hastings of Baylor College of Medicine. Xu also has a joint appointment with Jilin University in China.

 

Story Source:

 

Materials provided by University of Georgia. Original written by Kathleen Raven. Note: Content may be edited for style and length.

 

Journal Reference:

 

J. Cui, X. Mao, V. Olman, P. J. Hastings, Y. Xu. Hypoxia and miscoupling between reduced energy efficiency and signaling to cell proliferation drive cancer to grow increasingly faster. Journal of Molecular Cell Biology, 2012; DOI: 10.1093/jmcb/mjs017

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