事件记录
面试官: 这是一种思考癌症起源的不同方式. 接下来是《大发娱乐》.
播音员: 检查最新的研究，告诉你最新的突破. 科学研究展正在进行中.
面试官: 我正在和医生谈话. 查理·莫塔夫. 犹他大学人类遗传学教授和内森·克拉. 他们刚刚在《大发娱乐提供》杂志上发表了一篇论文."
Dr. 莫塔夫, 据我所知, 你的研究结果让大发娱乐对癌症的起源有了不同的认识.
Dr. 莫塔夫: The standard model for how cancer starts is that you have a cell that accumulates a bunch of different mutations until that cell becomes sufficiently abnormal that it turns into a cancer cell and stops behaving like a normal cell. 大发娱乐对如何将其应用于胰腺癌很感兴趣. 和 we and others have found that the genetic mutations that occur in pancreatic cancer in the model that we use are not enough to actually trigger the beginning of the disease. 所以大发娱乐知道肯定有别的事情在发生. 大发娱乐现在认为细胞的分化状态.
那么细胞是如何知道它通常应该做什么. In this, case the cells are cells that make digestive enzymes to break down food. 他们通常会百分之百地专注于这项任务. 它们并没有分裂. 但后来, a change happens and those cells forget what they're supposed to do and then in that context then those mutations that can cause cancer can become hyperactive and the cells start to become transformed and move toward cancer.
面试官: Nathan, maybe you can tell me why you're focusing on pancreatic cancer in the first place.
慧慧: 肯定是的. So pancreatic cancer is one of the deadliest solid tumors that patients can have. It has one of the poor survival rates of just about any cancer with a five-year survival of only about 5%. 所以, any clues that we can get that push toward earlier detection or better treatment options would be good.
面试官: 你在暗示发展原理来理解癌症. 这到底是什么意思?
Dr. 莫塔夫: 正确的. 我对微分过程一直很感兴趣. 这可能要追溯到20年前. So it just how cells learn to adopt the mature fates that they're supposed to achieve, 从胚胎开始，分化在成体中继续. So, 当然, we are continually shedding skin so we have to differentiate new skin all the time, 新头发, 等等. 和 it was through studies of differentiation in the pancreas and trying to understand how the different cell types, 内分泌细胞和外分泌细胞, how they get to differentiate that we began to be interested in how that might apply in cancer.
因为根据经典研究，这似乎是可能的. That in fact cancer might start from not only genetic mutations that we know are important, 但非遗传的变化，比如分化的丧失.
面试官: 当细胞分化的时候, 它是成熟的，被认为是固定的, 这样比较稳定. 如果你破坏了它，事情就会出错?
Dr. 莫塔夫: 是的,完全. 完全.
面试官: 你是如何把它应用到癌症研究中去的? 我想你研究PTF1基因已经有一段时间了?
Dr. 莫塔夫: 正确的. PTF1是一种被称为转录因子的基因. 转录因子是调节其他基因的蛋白质. So a lot of what differentiation involves is turning on expression of genes that are important for the carrying out the function of the cells. So, for example, the exocrine cells that we study, they make hundreds of digestive enzymes. 比如高浓度.
在成熟细胞中，PTF1A通常会激活这些基因. So without PTF1A during development, you can never make the cells that normally digest food. 和 what we found is that once you are a mature cell you still require PTF1A in order to continue making those enzymes and in order to repress alternative choices.
所以细胞不喜欢无所事事. 如果你去掉像PTF1A这样的因素，它会迫使它们进入一个特定的身份, if you take that away they will kind of cast around and look for an alternative identity. 在一个健康的细胞中，这可能不是什么大问题. 事实上，大发娱乐发现仅仅去除PTF1A并不足以导致癌症.
但是在一个有潜在致癌突变的细胞中, 当细胞开始试图改变它应该做的事情时, 这些突变可以自我表达，然后细胞非常, 很快就不正常了.
面试官: You've done these experiments in an environment where there's already something wrong? 因此，这就像是又迈出了一步，打破了骆驼的背部?
Dr. 莫塔夫: 是的,完全.
面试官: 内森，你这么做的时候看到了什么?
慧慧: 当大发娱乐在致癌基因或致癌基因的背景下去除PTF1A, 大发娱乐看到这些细胞迅速转化为癌前病变. 和 what's really interesting is that if we just express these oncogenes or cancer-causing genes alone, 这真的不足以做太多. 它们偶尔会形成癌前病变, 而是在PTF1A缺失的情况下, 几乎每个失去PTF1A的细胞都会导致癌症.
面试官: 有没有迹象表明这种情况发生在人类胰腺癌中?
Dr. 莫塔夫: 正确的. 这是个很好的问题. So one of the things that we were able to show is that in fact in the lesions of humans, 这些早期癌前病变, PTF1A也被关闭了. 事实上, 还有一些其他的研究并没有关注PTF1A, but have all sort of implied the same thing that this must be happening at a very early stage in cancer. 和 so it does look like it probably does happen to humans and one of the things we're really interested in going forward is sort of doing the reverse, 那就是如果大发娱乐能在人类细胞中重新激活它, 大发娱乐能阻止癌细胞的生长吗.
面试官: 正确的. 我是说，这是否意味着另一种治疗方法?
Dr. 莫塔夫: 我想是的. I mean, most cancer therapies in pancreatic and other cancers are targeted to cell division. 和, 当然, that's what conventional chemotherapy does and it has limitations because it can kill the normal dividing cells. 和 there are other therapies that are targeted at the mutated signals that occur in the cancer and in some cases like lung cancer, 这些都是非常有效的治疗方法. 但在胰腺癌中，这样做是非常具有挑战性的. 所以致癌基因, the cancer-causing mutation that is so central to pancreatic cancer is one that is in a protein that is very hard to make drugs against.
这是这个领域长期存在的问题. But we do feel that differentiation is something that there's almost no disadvantage. 在理论上, 至少, there are no side effects from having too much differentiation in the pancreas because it's an organ that is normally very differentiated. 所以如果有办法重新激活这些细胞的正常分化, 它本身应该不会有什么大的副作用. 问题是它作为一种疗法是否有效.
面试官: 是的,迷人的. 我的意思是，有没有迹象表明这种情况也会发生在其他癌症中?
慧慧: 是的，这是个很好的问题. So one thing I think that's exciting to us is if we really look throughout the GI tract, there are a lot of cancers that undergo this process called metaplasia or a change in cell fate, which almost always precedes cancer and is usually associated with chronic inflammation.
一个很好的例子就是食道, a lot of people have the acid reflex and that can lead to changes in the cell populations in the lower esophagus. 人们认为这些变化实际上是癌症形成所必需的. 大发娱乐在胰腺中展示了一个非常相似的故事. We think that this actually a broadly applicable principle where you need a loss of differentiation in order to actually initiate cancer.
播音员: 有趣，内容丰富，而且都是为了更好的健康. 大发娱乐是Scope健康科学广播.