本帖最后由 sunsong7 于 2012-7-13 23:37 编辑 6 v% J5 X3 l" m) r
: w6 R$ m; |2 b c
5 j5 ]" |( m5 f4 q+ a' F) sUniversity 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)
) |7 R6 W% B5 M! S$ C/ y) ]' M7 A
' R F' X$ f N3 L3 x【摘要】 基因突变及分子异常如此稀少，哪能解释癌症的高发病率呢？根据手头掌握的文献，肿瘤细胞的产生至少要满足以下三个条件：一是必须有5个以上的基因发生突变才有可能致癌；二是突变基因必须是肿瘤相关基因（如抗癌基因、抑癌基因等）；三是基因突变必须是双等位性的，即变成基因纯合子。因此，我们一直认为，无基因突变细胞的增生只能长成良性肿瘤（belign tumor），而有基因突变细胞的增生才会长成恶性肿瘤（malignant timor），即癌（cancer）。也就是说，由于细胞的快速生长，激活了DNA的应急修复机制，从而增大基因突变，抑制细胞凋亡，促进血管形成。http://blog.sciencenet.cn/blog-281238-591598.html# S; H8 H. B% a! P8 k
9 X) T3 X5 e. J, T3 x6 v+ X& e/ J/ h( F$ g' U3 W
& g6 S! j; N; }作者：徐鹰等 来源：JMCB 发布时间：2012-7-11 14:04:33
6 ~, }, B5 G U' q7 `" d | 4 P8 I5 l! O" w! t
《分子细胞生物学期刊》（Journal of Molecular Cell Biology）2012年第3期“复杂疾病的系统生物学研究”专辑中发表了一篇美国佐治亚大学生物化学与分子生物学系徐鹰教授题为“Hypoxia and miscoupling between reduced energy efficiency and signaling to cell proliferation drive cancer to grow increasingly faster”的论文，报道了细胞内低氧引起能量效率与控制细胞增殖的关系的失调，从而促进肿瘤的快速生长。这一假设与传统认为的“基因突变导致肿瘤生长”观点有着很大的区别。此文在线出版后，立即受到包括ScienceDaily在内的国际媒体广泛关注。3 a0 x9 _" m; Z( X/ U. h5 R
8 Z M' L, h, S1 ~) P过去的研究将细胞内低氧水平看作癌症发展的促进因素之一，但并不是肿瘤生长的驱动因素。徐教授说，随机的基因突变单独无法解释全球癌症的高发病率。他又说，将数学和计算机知识应用于生物学而形成的生物信息学使研究人员可以从一种新的角度看待癌症。基因突变可能使癌细胞在竞争中优于健康细胞，但这样的话新生癌细胞生长的模式就不需要癌变前兆的出现，如原癌基因突增等常见的不良变化。“癌症治疗药物力求达到根源——在分子水平上——一个特定的突变，但往往不能根治，”徐教授说：“所以我们想基因突变可能并不是癌症的主要驱动因素。”的确，徐教授的分析发现，长期的细胞内缺氧可能是癌生长的一个关键驱动因素。+ `3 Z4 L* x* o
( j0 z# L. x+ i8 P) U5 e% k
目前大多数的癌症研究希望通过药物对抗与某种特定癌症相关的基因突变，进而达到治疗癌症的目的。徐教授课题组从Stanford Microarray Database数据库下载了7种癌症（乳腺癌、肾癌、肝癌、肺癌、卵巢癌、胰腺癌及胃癌）的相关数据，通过一款软件程序分析这7种癌症中异常的基因表达模式。他们以基因HIF1A作为一个细胞氧含量的标记物，所有被实验的7种癌细胞中，HIF1A水平都有显著的升高，这表明这些癌细胞中氧含量显著的降低。
R5 F% J6 P) k8 `. f4 z/ c; d5 ^* f' z: O+ K' S
细胞内氧含量降低，导致氧化磷酸化反应的中断，而氧化磷酸化反应是细胞将食物转化为能量的一种高效途径。随着氧含量的降低，细胞切换到糖酵解途径生产能量单位，即ATP，这是一种效率非常低的能量获取方式，所以为了存活癌细胞必须努力得到更多的食物，尤其是葡萄糖。当氧含量水平下降到极限时，血管新生——即生成新血管的过程——启动了。新生血管提供新鲜的氧气，提高细胞内和肿瘤的氧含量水平，并延缓癌细胞的生长，但这都是暂时的。
/ ^ D* w/ |' |4 Y0 G- {: C' O* [) F# i2 ~4 a$ J# u
“得到更多的食物后，癌细胞就会生长；这就会导致整个肿瘤实体增长而更加缺氧。反过来，能量转换效率将更加低下，从而使细胞更加饥饿，促使细胞从血液循环中获得更多的食物，形成一个恶性循环。这或许是肿瘤形成的一个关键驱动因素，”徐说。这个全新的癌细胞生长模式可能用于解释为什么很多肿瘤很快（3-6个月以内）产生耐药性。他强调了未来非常有必要通过大量的癌症实验研究来论证这一新模式。如果这一模式得以成立，研究人员的首要任务是探索防止细胞内低氧的办法，从而使肿瘤治疗的手段发生巨大改变。（来源：中科院上海生命科学研究院）
) t. t: { `5 C" k" g0 Y1 Y1 A
+ n; E7 X$ O* [6 N2 d1 D" |6 ]6 v |
( \: ^ F0 s+ K! @' ]) M2 R' k$ Q2 T5 U* M8 @# o
Low Oxygen Levels Could Drive Cancer Growth, Research Suggests ScienceDaily (May 3, 2012) — 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.
: Z6 F! j; _ h4 v% S L5 `0 d
8 K# n+ s+ _( B+ WIf 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.
: B% I) q5 W% g( V$ WThe 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.5 R# T' i' R) m0 k# J/ U
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.
% B9 y0 I" C8 j) h, ~6 z7 E! B"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."
7 L2 `2 }* _) l! dMuch 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.1 _% V$ K. z* s4 Q- F0 t
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.& k- a9 h3 J% C6 ]2 Y+ t3 y
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.9 i+ f$ `: U2 }7 H6 P. S
"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.
& }- V' D& N+ ~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./ t& W" l; j% V
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./ B! X- p" R( n2 i: |! Y# B
" _+ `& b$ y. Z
http://www.sciencedaily.com/releases/2012/05/120503194219.htm% B6 q! I D" F/ Y
% O# D* Z7 O5 ~5 w
$ z$ B1 b6 {# L7 n; N6 u |
发表于 2012-7-13 23:29
发表于 2012-8-7 11:35
