糖与癌症之间的致命联系

令人讨厌的癌细胞就像是无政府主义者一样。它们游荡到不应该去的地方，颠覆秩序，拉拢守规矩的健康细胞加入它们肆意破坏，打破无数生物学规则。

癌细胞还很古怪。关于它们破坏规则的特性，一个最令人匪夷所思的例子就是它们代谢糖分的方式。在像人类身体这样氧气充足的环境下，正常细胞通过氧化过程分解葡萄糖，从中吸取能量。通过这种生物化学转化机制，细胞可以从1分子葡萄糖中提取出36分子三磷酸腺苷（ATP）。ATP就相当于人体内的现金。（就像比特币一样：细胞解开复杂的方程式，作为回报，它们获得了可以消耗的物质。）

而（多数）癌细胞进行大量的生化反应，却得到较少的报酬。它们通过一种古老的糖酵解代谢过程分解葡萄糖，经过10个步骤，1分子葡萄糖只能产生2分子ATP。

细胞通过糖酵解过程，甚至可以在无氧环境下产生能量，就像我们黏糊糊的原始祖先一样。厌氧菌和酵母也是如此，它们通过发酵从糖中提取能量。而在有氧环境下，从糖中提取能量就像是用熨斗熨袜子一样：付出巨大的努力，收益却少得可怜。

与此同时，癌细胞需要大量的能量来支持它们肆意“作乱”；毕竟细胞快速分裂需要大量生物化学燃料。所以癌细胞会疯狂吞噬糖分。（所以通常在PET扫描过程中，注射氟脱氧葡萄糖，可以明显看出哪些组织正在快速吸收这种葡萄糖，从而帮助我们发现肿瘤。）

上世纪20年代，德国生物化学家奥托·瓦伯格最早发现了癌细胞这种有悖直觉的异常行为，他将之归咎于癌细胞线粒体存在的缺陷。线粒体相当于癌细胞的能量工厂（也是我最喜欢的细胞器）。事实上，瓦伯格认为这种异常的有氧糖酵解是癌症发生的真正原因，但他并不确定它的发生机制或原因。这种现象后来被称为“瓦氏效应”。

后来数十年间，这种观点逐渐被人们所遗忘，因为研究人员开始关注癌症的其他理论框架，试图梳理出哪些基因变异转化了细胞，导致癌症发生。但近几年，瓦氏效应和更广泛的癌症新陈代谢理论再度兴起。

虽然癌症研究界对于癌症的新陈代谢因素再次产生了兴趣，但目前仍存在两个重要问题使许多人很难全部接受这种观点。首先是为什么？为什么需要大量能量的癌细胞，经过进化会适应这种效率低下的代谢过程？第二个问题是怎么样？有氧糖酵解通过哪种机制促进癌变（或者这只是细胞恶性转化的副作用）？

第一个问题仍是个迷。但关于第二个问题，三个比利时研究组织最近发表了一篇研究报告，揭示了一种可能被遗漏的分子联系或者至少是一种候选联系。研究团队经过九年努力，在酵母模型系统中发现了糖酵解途径中一个关键糖分子（果糖-1,6-双磷酸）与ras基因之间的联系。ras基因是决定细胞增殖和生存能力的关键。重要的是，ras就是所谓的致癌基因，如果这种基因出现变异，会导致细胞恶性转化。在近一半癌症中都发现了ras基因的变异形式。

不久前，《自然通讯》期刊的网站上发表了这篇论文。论文的作者表示，ras基因与所发现的糖分子之间“互惠的”相互关系“可能在恶性循环中活化癌细胞，持续刺激细胞增殖，使糖酵解过程持续过度活跃。这可以解释癌细胞增殖速度和侵袭强度与其发酵异常活跃之间的密切联系。”

研究的资深作者之一约翰·泰韦林在随后的一份新闻稿中表示，这是一种“持续刺激癌症发展与增长的恶性循环”，这种相互关系可以“解释瓦式效应与肿瘤侵袭的强度之间的相关性。”

这项发现当然令人兴奋，并且可能对癌症患者的饮食疗法有重要意义。对于其他人而言，这项研究提供了又一项证据，证明过多摄入糖分的危害。因为现在有一种潜在的作用机制可以解释这种危害的原因。（财富中文网）

译者：刘进龙/汪皓 

Cancer cells are nasty little anarchists. They go where they shouldn’t, subvert authority, co-opt law-abiding cells around them, and break a ton of biological rules in their mindless quest for destruction.

They’re also weird. And one of the most bizarre examples of their rule breaking is how they metabolize sugar. When oxygen is readily available, as it is in the human body, normal cells break down and draw energy from glucose through a process called oxidation. By way of this biochemical machination, cells can extract 36 molecules of ATP, which is like cash money in the body. (Think of it like Bitcoin: Cells do some complex equation-solving and, as a reward, they get something they can spend.)

But cancer cells (mostly) do lots of biochemical work to get less coin. They break down glucose through an ancient 10-step process called glycolysis—which yields them a mere two molecules of ATP for every one of glucose.

With glycolysis, cells can produce energy even in the absence of oxygen, which is what our primordial slime ancestors had to do. It’s also what anaerobic bacteria and yeasts do. They derive energy from sugar by way of fermentation. But in the presence of oxygen, extracting energy from sugar by glycolysis is the equivalent of ironing your socks: It would seem to involve expending a lot of effort for little benefit.

What’s more, cancer cells need gobs of energy to fuel their mad rebellion; rapid cell division, after all, requires plenty of biochemical fuel. And cancer cells gobble up sugar like nobody’s business. (That’s why we’re often able to see tumors on a PET scan, which highlights tissues that rapidly take up an injected sugar called FDG.)

A German biochemist named Otto Warburg, back in the 1920s, was the first to observe these oddball, counterintuitive facts about cancer cells, which he blamed on a defect in their mitochondria, the cell’s energy factories (and my all-time favorite organelles). Indeed, the biochemist believed this aberrant aerobic glycolysis—which later became known as the “Warburg effect”—actually caused cancer, though it wasn’t clear how or why.

The notion was somewhat forgotten for decades, as researchers focused on other theoretical frameworks for cancer and tried to tease out the genetic mutations that transformed cells and drove the disease. But in recent years, the Warburg effect—and the broader metabolic theory of cancer—has had a reawakening.

Still, as much as the cancer research community has rekindled interest in the metabolic aspects of the disease, there are two big questions that have kept some from embracing it whole hog. The first is why? Why would cancer cells, which require so much energy, evolve to adapt such an inefficient process? And the second is how? By what mechanism would aerobic glycolysis drive the cancer process (or is it, rather, a side effect of the malignant transformation of a cell)?

The first question remains a mystery. But as to the second, a new study published by three Belgian research groups has revealed the possible missing molecular link—or at least a candidate for one of them. Working in the model system of yeast, the teams, after a nine-year effort, identified a connection between a key sugar molecule in the glycolytic pathway (fructose-1,6-bisphosphate) and a critical gene called ras that’s central to a cell’s ability to proliferate and survive. Ras, importantly, is a so-called oncogene—a gene that, when mutated, can help turn a cell malignant. Mutated forms of ras are found in as many as half of all cancers.

In the paper, published online Friday in the journal Nature Communications, the authors report that a “reciprocal” interaction between ras and the identified sugar molecule “may lock cancer cells in a vicious cycle causing both persistent stimulation of cell proliferation and continued maintenance of overactive glycolysis. This would explain the close correlation between the proliferation rate and aggressive character of cancer cells and their fermentation hyperactivity.”

It’s a “vicious cycle of continued stimulation of cancer development and growth,” said one of the study’s senior authors, Johan Thevelein, in a follow-up press statement—an interaction that seems to “explain the correlation between the strength of the Warburg effect and tumor aggressiveness.”

The finding is a provocative one, surely, and one that may have implications for the diets of cancer patients. For the rest of us, this study is one more piece of evidence about the dangers of excessive sugar consumption. And now, there’s a potential mechanism of action to explain it.