令人討厭的癌細胞就像是無政府主義者一樣。它們游蕩到不應該去的地方，顛覆秩序，拉攏守規矩的健康細胞加入它們肆意破壞，打破無數生物學規則。

癌細胞還很古怪。關于它們破壞規則的特性，一個最令人匪夷所思的例子就是它們代謝糖分的方式。在像人類身體這樣氧氣充足的環境下，正常細胞通過氧化過程分解葡萄糖，從中吸取能量。通過這種生物化學轉化機制，細胞可以從1分子葡萄糖中提取出36分子三磷酸腺苷（ATP）。ATP就相當于人體內的現金。（就像比特幣一樣：細胞解開復雜的方程式，作為回報，它們獲得了可以消耗的物質。）

而（多數）癌細胞進行大量的生化反應，卻得到較少的報酬。它們通過一種古老的糖酵解代謝過程分解葡萄糖，經過10個步驟，1分子葡萄糖只能產生2分子ATP。

細胞通過糖酵解過程，甚至可以在無氧環境下產生能量，就像我們黏糊糊的原始祖先一樣。厭氧菌和酵母也是如此，它們通過發酵從糖中提取能量。而在有氧環境下，從糖中提取能量就像是用熨斗熨襪子一樣：付出巨大的努力，收益卻少得可憐。

與此同時，癌細胞需要大量的能量來支持它們肆意“作亂”；畢竟細胞快速分裂需要大量生物化學燃料。所以癌細胞會瘋狂吞噬糖分。（所以通常在PET掃描過程中，注射氟脫氧葡萄糖，可以明顯看出哪些組織正在快速吸收這種葡萄糖，從而幫助我們發現腫瘤。）

上世紀20年代，德國生物化學家奧托·瓦伯格最早發現了癌細胞這種有悖直覺的異常行為，他將之歸咎于癌細胞線粒體存在的缺陷。線粒體相當于癌細胞的能量工廠（也是我最喜歡的細胞器）。事實上，瓦伯格認為這種異常的有氧糖酵解是癌癥發生的真正原因，但他并不確定它的發生機制或原因。這種現象后來被稱為“瓦氏效應”。

后來數十年間，這種觀點逐漸被人們所遺忘，因為研究人員開始關注癌癥的其他理論框架，試圖梳理出哪些基因變異轉化了細胞，導致癌癥發生。但近幾年，瓦氏效應和更廣泛的癌癥新陳代謝理論再度興起。

雖然癌癥研究界對于癌癥的新陳代謝因素再次產生了興趣，但目前仍存在兩個重要問題使許多人很難全部接受這種觀點。首先是為什么？為什么需要大量能量的癌細胞，經過進化會適應這種效率低下的代謝過程？第二個問題是怎么樣？有氧糖酵解通過哪種機制促進癌變（或者這只是細胞惡性轉化的副作用）？

第一個問題仍是個迷。但關于第二個問題，三個比利時研究組織最近發表了一篇研究報告，揭示了一種可能被遺漏的分子聯系或者至少是一種候選聯系。研究團隊經過九年努力，在酵母模型系統中發現了糖酵解途徑中一個關鍵糖分子（果糖-1,6-雙磷酸）與ras基因之間的聯系。ras基因是決定細胞增殖和生存能力的關鍵。重要的是，ras就是所謂的致癌基因，如果這種基因出現變異，會導致細胞惡性轉化。在近一半癌癥中都發現了ras基因的變異形式。

不久前，《自然通訊》期刊的網站上發表了這篇論文。論文的作者表示，ras基因與所發現的糖分子之間“互惠的”相互關系“可能在惡性循環中活化癌細胞，持續刺激細胞增殖，使糖酵解過程持續過度活躍。這可以解釋癌細胞增殖速度和侵襲強度與其發酵異常活躍之間的密切聯系。”

研究的資深作者之一約翰·泰韋林在隨后的一份新聞稿中表示，這是一種“持續刺激癌癥發展與增長的惡性循環”，這種相互關系可以“解釋瓦式效應與腫瘤侵襲的強度之間的相關性。”

這項發現當然令人興奮，并且可能對癌癥患者的飲食療法有重要意義。對于其他人而言，這項研究提供了又一項證據，證明過多攝入糖分的危害。因為現在有一種潛在的作用機制可以解釋這種危害的原因。（財富中文網）

譯者：劉進龍/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.