在未来几个月，来自三家医学中心的研究者将首次在病人中启动一项最有希望而又很有争议的实验，该试验是关于肿瘤的病因和治疗的。该试验是针对一些科学家所说的肿瘤干细胞——即能使恶性肿瘤维持和扩增的变异细胞。
尽管许多科学家相信肿瘤细胞是永生的，可无限分裂和生长，多数还是会在分裂若干代后死亡。干细胞假说认为：肿瘤本身由于不断被肿瘤干细胞“喂养”而不会死去。这些数目极少，特别危险的细胞通过分裂可不断更新自己并分裂出更多细胞从而形成肿瘤体。更糟糕的是，干细胞也许对多数标准肿瘤治疗是抵抗的。
并非所有人都接受肿瘤干细胞的假说，怀疑者认为，支持者因为太迷恋这一假说，以致排斥或忽视不利的证据。例如，霍普金斯大学胰腺癌领衔研究者Dr. Scott E. Kern，认为这一假说的信仰成分要大于科学成分。
这一争议最相关的是肿瘤研究的方向问题。如果干细胞假说的支持者是正确的，这将引导进入一个新时代——曾经不可治愈的肿瘤将被治愈。如果怀疑者是对的，那么干细胞热心者正在走向一个死胡同，而这将成为医学研究史上又一个具有警告性的故事。但同时，支持者正在寻找能杀死干细胞的途径，并认为某些新的药物可能解决这一问题。
“明年,我们会看到许多医学中心将针对几乎所有的肿瘤开展干细胞治疗的探索。”密西根大学综合肿瘤中心主任Dr. Max S. Wicha说到。该中心是参与在未来几个月开始的预试验的单位之一，另两家是休斯敦的Baylor医学院和波斯顿的Dana-Farbe肿瘤研究所。“对此我们非常兴奋。这已经成为我们肿瘤中心的主要推动力。” Dr. Wicha说到。
NIH的管理者们也兴奋无比，“假如这是真的，它会立即产生影响。”NIH的肿瘤免疫和血液学的主任Dr. R. Allan Mufson说到。NIH的肿瘤研究所将资助这项研究，并授权Dr. R. Allan Mufson提出议案请求，以请求投资者将肿瘤研究所的资金用于研究肿瘤干细胞和将研究应用到肿瘤患者的途径。研究所已同意提供$5,400,000.考虑到当前极差的财政形势,这是令人惊奇的一笔.“我们实际上没要求这么多,但是肿瘤研究所的执行委员要求增加数目.”
假说的支持者喜欢用点缀蒲公英的草坪进行比喻:割草坪似乎将杂草都割掉了,但是杂草根还完好无损,蒲公英又会长回.肿瘤也是这样的.化疗和放疗通常只能杀死大部分肿瘤细胞,但不能杀死干细胞,而干细胞是肿瘤细胞的根,能卷土重来.
肿瘤干细胞与胚胎干细胞不同，后者在发育早期，可以分化成任一种体细胞。前者转化成肿瘤细胞,特点是有特殊的分子标记物。
干细胞的假设或许能回答一个长期困扰科学家的问题, 肿瘤内的细胞是否都一样具备让肿瘤不断生长的能力? 一个简单而经典的实验证明,不是这么回事. 研究者把肿瘤细胞移植到没有免疫系统的小鼠身上,发现不是所有的细胞都能形成肿瘤.
要再深入研究这一现象, 科学家需要一种好的方法来分离出那些能形成肿瘤的细胞.直到最近,整个事情都在苦思中,因为科学家没有用于研究的分子工具.
但当1990s早期出现那些工具时, Dr. Dick在急性髓系白血病中发现了干细胞.他报道这些细胞只占白血病细胞的1%,它们正是能够在小鼠上形成肿瘤的那一些.
然而Dr. Wicha 说到,Dr. Dick的研究极大地被忽视了.肿瘤研究者没有被说服,即使他们接受这个研究,仍然怀疑这个结果是否适用于实体瘤如乳腺、结肠、前列腺或脑的肿瘤。
这种情形在1994年发生改变,当时Dr. Wicha 和同事, Dr. Michael Clarke报道在乳腺癌患者中发现肿瘤干细胞。
Robert Weinberg说，“这篇文章非常令我震惊.对我来说,这是十多年来肿瘤方面，在概念上最重要的文章. Dr. Weinberg是MIT的生物学教授,同时是肿瘤研究的领导者.Dr. Weinberg和其他人开始从事干细胞假说的研究。现在研究者已经在结肠、头颈、肺、前列腺、脑和胰腺肿瘤上发现肿瘤干细胞。
相关的专题讨论会已举行，而领衔期刊的报道也是一篇接一篇。
但是难题继续。怀疑者说，有个问题是数学上加算不一致。Dr. Bert Vogelstein是Johns Hopkins大学的结肠癌研究者。他说，假说只能说明肿瘤中一小部分是干细胞,自己对假说的有效性尚有怀疑.
但是一些研究认为干细胞占肿瘤细胞的10%或40%甚至50%,至少是通过分子标记标准.如果治疗能缩小肿瘤99%,通常临床情况也是这样的,而干细胞占10%,那么干细胞也必须受到怀疑.怀疑者也质疑在小鼠上的研究.同样的细胞如果移植到小鼠的某一部位能够长肿瘤,不一定能够在其他部分形成肿瘤.
Johns Hopkins的研究者Dr. Kern说，许多因素影响移植,移植在老鼠上能长肿瘤的细胞，并不表示就是肿瘤干细胞.
Dana-Farber肿瘤研究所的Dr. Kornelia Polyak也持有疑问,是否乳腺肿瘤细胞能够维持真正的原型即干细胞仍是干细胞,其他仍是非干细胞?她已经发现答案并不一定是.肿瘤细胞似乎是移动的靶,从干细胞变到非干细胞,然后又变回来.这一发现是非预期的,因为以前认为细胞的发展是单向的——从干细胞到肿瘤细胞——没有能够变回的.“你想杀掉肿瘤中所有的细胞.” Dr. Polyak说，“所有人都假设目前用的药物不是靶向干细胞群的,但这并没有被证实.”
Dr. Weinberg说怀疑是有道理的.但是他仍受肿瘤干细胞假说的支配。他说，“有许多尚未回答的问题存在。许多人认为肿瘤干细胞存在,但那并不意味着它们就存在.我们的相信是建立在一些非常零碎的证据上,而我恰恰相信总的来说还是很有说服力的证据。”他说自己相信肿瘤干细胞假说是正确的,它比医生和患者已知的其他假说更好。“不仅是我们所采取的一些方法并没有达到预期的目的,而且我们评估药物的方法的模式很糟糕.他提到抗肿瘤药物如果能缩小肿瘤就能被批准,即使它们不能延长生存期.这是割蒲公英草地的医学等价物.”
他说，随着如计划在乳腺癌妇女中开展的研究的进行,真理将很快到来。这种药物本来是由Merck公司开发用于治疗Alzheimer病的.它对Alzheimer’没效,却在实验室研究中能杀死乳腺癌干细胞.这项研究将首先开始在30名晚期乳腺癌患者中进行安全试验.期望是这项研究将被扩展,以发现药物是否能延长生命.
“患者生存是最终的目的.”Dr. Wicha说到。
Scientists Weigh Stem Cells’ Role as Cancer Cause
在未来几个月，来自三家医学中心的研究者将首次启动一项最有希望（也是很有争议）的临床实验，试验癌症的发病和治疗。
Within the next few months, researchers at three medical centers expect to start the first test in patients of one of the most promising — and contentious — ideas about the cause and treatment of cancer.
这项试验的核心设想是，利用某些科学家所说的肿瘤干细胞-即能使恶性肿瘤维系和不断扩增的变异细胞，来解答医学界的悬念。
The idea is to take aim at what some scientists say are cancerous stem cells — aberrant cells that maintain and propagate malignant tumors.
尽管许多科学家相信癌细胞不死，可无限制分裂，多数还是会在分裂若干代后死亡。干细胞假设认为：肿瘤本身由于不断被肿瘤干细胞“喂养”提携不会死去。这些数目极少，特别危险的细胞通过分裂可不断更新自己并分裂出更多细胞从而形成肿瘤体。更可怕的是，干细胞也许是许多肿瘤标准治疗的大敌。
Although many scientists have assumed that cancer cells are immortal — that they divide and grow indefinitely — most can only divide a certain number of times before dying. The stem-cell hypothesis says that cancers themselves may not die because they are fed by cancerous stem cells, a small and particularly dangerous kind of cell that can renew by dividing even as it spews out more cells that form the bulk of a tumor. Worse, stem cells may be impervious to most standard cancer therapies.
并非所有的人都接受癌性干细胞的假设，怀疑者说，这一理论的相信者因为太迷恋者一假说，以致或略所有不利的证据，甚至霍普金斯大学Dr. Scott E. Kern说，这一假设的宗教色彩要大于科学成分
Not everyone accepts the hypothesis of cancerous stem cells. Skeptics say proponents are so in love with the idea that they dismiss or ignore evidence against it. Dr. Scott E. Kern, for instance, a leading pancreatic cancer researcher at Johns Hopkins University, said the hypothesis was more akin to religion than to science.
At stake in the debate is the direction of cancer research. If proponents of the stem-cell hypothesis are correct, it will usher in an era of hope for curing once-incurable cancers.
If the critics are right, the stem-cell enthusiasts are heading down a blind alley that will serve as just another cautionary tale in the history of medical research.
In the meantime, though, proponents are looking for ways to kill the stem cells, and say that certain new drugs may be the solution.
“Within the next year, we will see medical centers targeting stem cells in almost every cancer,” said Dr. Max S. Wicha, director of the University of Michigan Comprehensive Cancer Center, one of the sites for the preliminary study that begins in the next few months (the other participating institutions are Baylor College of Medicine in Houston and the Dana-Farber Cancer Institute in Boston).
“We are so excited about this,” Dr. Wicha said. “It has become a major thrust of our cancer center.”
At the National Cancer Institute, administrators seem excited, too.
NIH的管理者们也兴奋无比，假如这是真的，马上会产生重大临床影响。
“If this is real, it could have almost immediate impact,” said Dr. R. Allan Mufson, chief of the institute’s Cancer Immunology and Hematology Branch.
美国肿瘤研究所将资助这项研究
The cancer institute is financing the research, he said, and has authorized Dr. Mufson to put out a request for proposals, soliciting investigators to apply for cancer institute money to study cancer stem cells and ways to bring the research to cancer patients. The institute has agreed to contribute $5.4 million.
“Given the current fiscal situation, which is terrible, it’s a surprising amount,” Dr. Mufson said. “We actually asked for less,” he added, but the cancer institute’s executive committee asked that the amount be increased.
Proponents of the hypothesis like to use the analogy of a lawn dotted with dandelions: Mowing the lawn makes it look like the weeds are gone, but the roots are intact and the dandelions come back.
So it is with cancer, they say. Chemotherapy and radiation often destroy most of a tumor, but if they do not kill the stem cells, which are the cancer’s roots, it can grow back.
化疗和放疗通常能杀死大部分肿瘤细胞，但这些治疗手段无发杀死干细胞，这些是肿瘤细胞的根，能很快卷土重来。
Cancerous stem cells are not the same as embryonic stem cells, the cells present early in development that can turn into any cell of the body. Cancerous stem cells are different. They can turn into tumor cells, and they are characterized by distinctive molecular markers.
癌性干细胞与胚胎干细胞不同，后者在发育早期，可以分化成任何一种体细胞。前者有不同的分子标记物，只是转化成癌细胞。
The stem-cell hypothesis answered a longstanding question: does each cell in a tumor have the same ability to keep a cancer going? By one test the answer was no. When researchers transplanted tumor cells into a mouse that had no immune system, they found that not all of the cells could form tumors.
To take the work to the next step, researchers needed a good way to isolate the cancer-forming cells. Until recently, “the whole thing languished,” said Dr. John E. Dick, director of the stem cell biology program at the University of Toronto, because scientists did not Scientists Weigh Stem Cells’ Role as Cancer Cause
Times Health Guide: CancerThe idea is to take aim at what some scientists say are cancerous stem cells — aberrant cells that maintain and propagate malignant tumors.
Although many scientists have assumed that cancer cells are immortal — that they divide and grow indefinitely — most can only divide a certain number of times before dying. The stem-cell hypothesis says that cancers themselves may not die because they are fed by cancerous stem cells, a small and particularly dangerous kind of cell that can renew by dividing even as it spews out more cells that form the bulk of a tumor. Worse, stem cells may be impervious to most standard cancer therapies.
Not everyone accepts the hypothesis of cancerous stem cells. Skeptics say proponents are so in love with the idea that they dismiss or ignore evidence against it. Dr. Scott E. Kern, for instance, a leading pancreatic cancer researcher at Johns Hopkins University, said the hypothesis was more akin to religion than to science.
At stake in the debate is the direction of cancer research. If proponents of the stem-cell hypothesis are correct, it will usher in an era of hope for curing once-incurable cancers.
If the critics are right, the stem-cell enthusiasts are heading down a blind alley that will serve as just another cautionary tale in the history of medical research.
In the meantime, though, proponents are looking for ways to kill the stem cells, and say that certain new drugs may be the solution.
明年,我们会看到许多医学中心将针对几乎所有的肿瘤开展干细胞治疗的探索.
“Within the next year, we will see medical centers targeting stem cells in almost every cancer,” said Dr. Max S. Wicha, director of the University of Michigan Comprehensive Cancer Center, one of the sites for the preliminary study that begins in the next few months (the other participating institutions are Baylor College of Medicine in Houston and the Dana-Farber Cancer Institute in Boston).
“We are so excited about this,” Dr. Wicha said. “It has become a major thrust of our cancer center.”
At the National Cancer Institute, administrators seem excited, too.
“If this is real, it could have almost immediate impact,” said Dr. R. Allan Mufson, chief of the institute’s Cancer Immunology and Hematology Branch.
The cancer institute is financing the research, he said, and has authorized Dr. Mufson to put out a request for proposals, soliciting investigators to apply for cancer institute money to study cancer stem cells and ways to bring the research to cancer patients. The institute has agreed to contribute $5.4 million.
“Given the current fiscal situation, which is terrible, it’s a surprising amount,” Dr. Mufson said. “We actually asked for less,” he added, but the cancer institute’s executive committee asked that the amount be increased.
Proponents of the hypothesis like to use the analogy of a lawn dotted with dandelions: Mowing the lawn makes it look like the weeds are gone, but the roots are intact and the dandelions come back.
So it is with cancer, they say. Chemotherapy and radiation often destroy most of a tumor, but if they do not kill the stem cells, which are the cancer’s roots, it can grow back.
Cancerous stem cells are not the same as embryonic stem cells, the cells present early in development that can turn into any cell of the body. Cancerous stem cells are different. They can turn into tumor cells, and they are characterized by distinctive molecular markers.
干细胞的假设或许能回答一个长期困扰科学家的问题, 肿瘤内的细胞是否都一样具备让肿瘤不断生长的能力? 一个简单而经典的实验证明,不是这么回事. 把肿瘤移植到没有免疫功能的老鼠身上,发现不是所有的细胞都能形成肿瘤.
The stem-cell hypothesis answered a longstanding question: does each cell in a tumor have the same ability to keep a cancer going? By one test the answer was no. When researchers transplanted tumor cells into a mouse that had no immune system, they found that not all of the cells could form tumors.
要再深入研究这一现象, 科学家需要分离出那些能形成肿瘤的细胞.
To take the work to the next step, researchers needed a good way to isolate the cancer-forming cells. Until recently, “the whole thing languished,” said Dr. John E. Dick, director of the stem cell biology program at the University of Toronto, because scientists did not have the molecular tools to investigate.
But when those tools emerged in the early 1990s, Dr. Dick found stem cells in acute myelogenous leukemia, a blood cancer. He reported that such cells made up just 1 percent of the leukemia cells and that those were the only ones that could form tumors in mice.
Yet Dr. Dick’s research, Dr. Wicha said, “was pretty much ignored.” Cancer researchers, he said, were not persuaded — and even if they had accepted the research — doubted that the results would hold for solid tumors, like those of the breast, colon, prostate or brain.
1994年Dr. Wicha 和同事, Dr. Michael Clarke在乳腺癌中发现肿瘤形成细胞
That changed in 1994, when Dr. Wicha and a colleague, Dr. Michael Clarke, who is now at Stanford, reported finding cancerous stem cells in breast cancer patients.
“The paper hit me like a bombshell,” said Robert Weinberg, a professor of biology at M.I.T. and a leader in cancer research. “To my mind, that is conceptually the most important paper in cancer over the past decade.”
MIT的Robert Weinberg教授高度评介这一发现,认为这是十多年来最重要的肿瘤生物学发现. 现在大部分器官组织中都已找到和发现肿瘤形成细胞.
Dr. Weinberg and others began pursuing the stem-cell hypothesis, and researchers now say they have found cancerous stem cells in cancers of the colon, head and neck, lung, prostate, brain, and pancreas.
Symposiums were held. Leading journals published paper after paper.
But difficult questions persisted. One problem, critics say, is that the math does not add up. The hypothesis only makes sense if a tiny fraction of cells in a tumor are stem cells, said Dr. Bert Vogelstein, a colon cancer researcher at Johns Hopkins who said he had not made up his mind on the validity of the hypothesis.
But some studies suggest that stem cells make up 10 percent or even 40 percent or 50 percent of tumor cells, at least by the molecular-marker criterion. If a treatment shrinks a tumor by 99 percent, as is often the case, and 10 percent of the tumor was stem cells, then the stem cells too must have been susceptible, Dr. Vogelstein says.
Critics also question the research on mice. The same cells that can give rise to a tumor if transplanted into one part of a mouse may not form a tumor elsewhere.
许多事影响移植, 移植到老鼠的肿瘤并不表示这些就是干细胞.
“A lot of things affect transplants,” Dr. Kern, the Johns Hopkins researcher, said, explaining that transplanting tumors into mice did not necessarily reveal whether there were stem cells.
Other doubts have been raised by Dr. Kornelia Polyak, a researcher at the Dana-Farber Cancer Institute. Dr. Polyak asked whether breast cancer cells remain true to type, that is, whether stem cells remain stem cells and whether others remain non-stem cells? The answer, she has found, is “not necessarily.”
Cancer cells instead appear to be moving targets, changing from stem cells to non-stem cells and back again. The discovery was unexpected because it had been thought that cell development went one way — from stem cell to tumor cell — and there was no going back.
“You want to kill all the cells in a tumor,” Dr. Polyak said. “Everyone assumes that currently-used drugs are not targeting stem cell populations, but that has not been proven.”
“To say you just have to kill the cancer stem cell is oversimplified,” she added. “It’s giving false hope.”
The criticisms make sense, Dr. Weinberg said. But he said he remained swayed by the stem cell hypothesis.
“There are a lot of unanswered questions, mind you,” he said. “Most believe cancer stem cells exist, but that doesn’t mean they exist. We believe it on the basis of rather fragmentary evidence, which I happen to believe in the aggregate is rather convincing.”
Dr. Wicha said he was convinced that the hypothesis was correct, and said it explained better than any other hypothesis what doctors and patients already know.
“Not only are some of the approaches we are using not getting us anywhere, but even the way we approve drugs is a bad model,” he said. Anti-cancer drugs, he noted, are approved if they shrink tumors even if they do not prolong life. It is the medical equivalent, he said, of mowing a dandelion field.
He said the moment of truth would come soon, with studies like the one planned for women with breast cancer.
The drug to be tested was developed by Merck to treat Alzheimer’s disease. It did not work on Alzheimer’s but it kills breast cancer stem cells in laboratory studies, Dr. Wicha says.
The study will start with a safety test on 30 women who have advanced breast cancer. Hopes are that it will be expanded to find out if the drug can prolong lives.
“Patient survival,” Dr. Wicha said, “is the ultimate endpoint.”
http://www.nytimes.com/2007/12/21/science/21stem.html?_r=1&ref=health&oref=slogin
Dr. Max S. Wicha, a leading researcher of cancerous stem cells.
TAG: 肿瘤细胞