华盛顿大学：癌细胞利用乳酸作为燃料和合成细胞生长的材料
Metabolomics Study Reveals another Energy Source for Cancer Cells

一项新的研究表明，癌细胞中的线粒体可以利用乳酸（Lactate)来促进生化反应，并产生细胞生长所需的化合物。

资料来源:华盛顿大学帕蒂实验室
研究人员发现了癌细胞产生生存和生长所需能量的另一种方式。

利用新的代谢组学技术，研究人员发现，癌细胞可以利用乳酸这种化合物来促进生化反应，并生成细胞生长所需的其他化合物，如脂质来构建新的细胞膜。代谢组学是一门测量生物样品中葡萄糖、氨基酸和胆固醇等小分子的科学。

这一发现出乎意料，因为乳酸，一种部分被消化的葡萄糖，被认为是细胞分泌的废物。

“我们的研究表明，在某些癌症细胞中，乳酸可以有效地制造细胞所需的其他营养物质，”圣路易斯华盛顿大学的Gary J. Patti博士说，他领导了这项研究。

通过追踪癌细胞内乳酸的化学转化，研究人员发现，乳酸不是被细胞排出体外，而是被线粒体吸收，线粒体被认为是细胞的能量工厂。帕蒂博士说:“乳酸的有效利用可能发生在线粒体中。”

研究结果发表在9月12日的《自然化学生物学》杂志上。

新陈代谢的差异
当健康细胞癌变时，它们的新陈代谢也随之改变。健康细胞通过吸收和代谢葡萄糖分子在一个两阶段的过程中产生能量。第一阶段发生在细胞质中，不依赖氧气;第二种发生在线粒体中，需要氧气。

线粒体产生细胞生存所需的大部分能量。只有一小部分葡萄糖的能量可以在没有氧气的情况下被提取出来(厌氧的)——也就是说，在细胞质中——而绝大多数是在线粒体中被提取出来的。

癌细胞被认为在很大程度上放弃了线粒体阶段的能量生产。癌细胞的生长和分裂速度很快，而癌细胞只依赖于葡萄糖代谢效率较低的阶段，这一发现长期以来一直令研究人员感到困惑。

“我们想知道为什么癌细胞会如此浪费，”帕蒂博士说。他指出，癌症细胞被认为是通过“加速”第一阶段和快速分解葡萄糖来弥补能量损失，从而分泌出相对大量的乳酸。

当葡萄糖在细胞质中快速代谢时，就会产生乳酸。没有参与这项研究的NCI癌症生物学部门的Michael Espey博士指出，这项新研究表明，加速的厌氧代谢产生的乳酸可以在进入线粒体后被进一步代谢，而不是像在非癌细胞中那样被排出体外。

新的发现表明，“在癌细胞中，线粒体可以以一种不同于在细胞质中使用乳酸的方式使用乳酸，”埃斯佩博士补充说。

一个意想不到的发现
帕蒂博士的团队是在测试一种标记癌细胞分子的方法，并使用一种被称为非靶向代谢组学(untargeted metabolomics)的技术来跟踪它们的运动时发现这一现象的。在实验中，研究人员选择了乳酸盐，假设乳酸盐不会像其他化合物一样在细胞中广泛分布。

结果令人惊讶——细胞中几乎所有的脂质最终都被标记为乳酸代谢产物。“我们看到了成千上万的标记信号，”帕蒂博士实验室的博士后研究员、共同作者Amanda Ying-Jr Chen博士说，“这非常令人意外和兴奋。”

为了证实这一发现，研究人员对癌细胞中的单个线粒体进行了额外的实验。这些实验表明，乳酸可以被运输到线粒体中，并被用来为细胞产生营养。

结果提出了许多新问题。“我们仍然需要弄清楚乳酸何时以及如何进入线粒体，”帕蒂博士说。

埃斯皮博士补充说，一个更广泛的问题是:是什么机制控制着细胞如何利用它们的资源来满足它们的需求?“我们还不知道如何确定每个单元的主资源分配，”他说。

乳酸和肺肿瘤
“这项研究提供了一个例子，说明癌细胞在如何利用燃料方面具有极大的灵活性，”医学博士拉尔夫·德贝拉尔迪尼斯(Ralph DeBerardinis)说他是德克萨斯大学西南分校(UT southwest)儿童医学中心研究所(Children’s Medical Center Research Institute)遗传和代谢疾病项目的负责人，没有参与这项研究。

他和他的同事最近发表的一项研究表明，乳酸是人类肺部肿瘤的一种能量来源。“我们的发现与新研究一致，”德贝拉尔迪尼斯博士说。“但这项新研究比我们的研究走得更远，它提供了一种癌细胞利用乳酸的机制。”

DeBerardinis博士继续说，新的研究表明线粒体可以包含一种与乳酸代谢相关的酶。在对肺肿瘤的研究中，德贝拉尔迪尼斯博士假设乳酸会在细胞质中代谢，而不是在线粒体中。

“如果乳酸是一种废物，那么它就不应该存在于线粒体中，”他补充说。“但如果像新的研究表明的那样，乳酸被用作一种燃料，那么它存在于线粒体中是有道理的。”

德贝拉尔迪尼斯博士指出，帕蒂博士的研究是在培养的细胞中进行的，观察这个过程是否发生在体内的肿瘤中非常重要。“我们对小鼠肺部肿瘤的研究表明，这种情况可能存在。”

埃斯皮博士预测，未来的研究将针对其他类型癌症的新发现的普遍性。

他补充说:“这些研究还可以确定线粒体乳酸代谢在多大程度上是癌细胞抵御生存压力的工具之一。”

Metabolomics Study Reveals another Energy Source for Cancer Cells

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October 20, 2016, by NCI Staff

ENLARGE
A new study suggests that mitochondria in cancer cells can use lactate to fuel biochemical reactions and generate compounds needed for cell growth.
Credit: Patti Lab, Washington University
Researchers have discovered another way that cancer cells may produce the energy they need to survive and grow.

Using new metabolomics technologies, the researchers found that cancer cells can use the compound lactate to fuel biochemical reactions and to generate other compounds needed for cell growth, such as lipids to build new cellular membranes. Metabolomics is the science of measuring small molecules, such as glucose, amino acids, and cholesterol, within a biological sample.

The finding was unexpected because lactate, a partially digested form of glucose, is thought to be secreted by cells as a waste product.

“Our study shows that—at some times in some cancer cells—lactate can be used productively to make other nutrients the cell needs,” said Gary J. Patti, Ph.D., of Washington University in St. Louis, who led the research.

By tracking the chemical transformations of lactate within cancer cells, the researchers found that, rather than being expelled from cells, lactate was being taken up by mitochondria, which are considered the energy factories of cells. “It’s possible that the productive use of lactate is occurring in the mitochondria,” said Dr. Patti.

The study results appeared in Nature Chemical Biology on September 12.

Differences in Metabolism
As healthy cells become cancerous, their metabolism changes. Healthy cells produce energy by taking in and metabolizing glucose molecules during a two-phase process. The first phase occurs in the cytoplasm and does not rely upon oxygen; the second takes place in mitochondria and requires oxygen.

Mitochondria produce most of the energy that cells need to live. Only a small percentage of glucose’s energy can be extracted without oxygen (anaerobically)—that is, in the cytoplasm—whereas the vast majority is extracted in the mitochondria.

Cancer cells have been thought to largely forgo the mitochondrial phase of energy production. The observation that cancer cells, which are growing and dividing rapidly, would rely only on the less-efficient phase of glucose metabolism has long been a puzzle to researchers.

“We have wondered why a cancer cell would be so wasteful,” said Dr. Patti. Cancer cells have been thought to compensate for the lost energy by “revving up” the first phase and breaking down glucose rapidly, as a result secreting relatively large quantities of lactate, he noted.

Lactate is produced when glucose is metabolized rapidly in the cytoplasm. The new work suggests that the lactate produced by the revved-up anaerobic metabolism can be further metabolized following transport into the mitochondria rather than being excreted, as happens in noncancerous cells, noted Michael Espey, Ph.D., of NCI’s Division of Cancer Biology, who was not involved in the study.

The new findings suggest that “in cancer cells, mitochondria can use lactate in a manner that is distinct from how it is used in the cytoplasm,” added Dr. Espey.

An Unexpected Finding
Dr. Patti’s team made its discovery while testing a way to tag molecules in cancer cells and use a technology known as untargeted metabolomics to track their movements. For the test, the investigators selected lactate, assuming that it would not be as widely distributed in cells as other compounds.

The results were surprising—nearly every lipid in the cell ended up being tagged as a metabolic product of lactate. “We saw thousands of labeled signals,” said coauthor Amanda Ying-Jr Chen, Ph.D., who is a postdoctoral fellow in Dr. Patti’s lab. “It was very unexpected and exciting.”

To confirm the findings, the researchers conducted additional experiments with individual mitochondria in cancer cells. These experiments showed that lactate can be transported into mitochondria and used to generate nutrients for the cell.

The results have raised many new questions. “We still need to figure out when and how lactate is getting into mitochondria,” Dr. Patti said.

A broader question, Dr. Espey added, is: What mechanisms govern how cells use their resources to meet their needs? “We don’t yet know how the master allocation of resources for each cell is determined,” he said.

Lactate and Lung Tumors
“This study provides an example of the tremendous flexibility of cancer cells in terms of how they utilize fuel,” said Ralph DeBerardinis, M.D., Ph.D., who directs the Genetic and Metabolic Disease Program at the Children’s Medical Center Research Institute at UT Southwestern and who was not involved in the research.

He and his colleagues published a recent study showing that lactate is an energy source for human lung tumors in mice. “Our findings are consistent with the new study,” said Dr. DeBerardinis. “But the new research goes quite a bit further than our study by providing a mechanism by which cancer cells utilize lactate.”

The new study shows that mitochondria can contain one of the enzymes associated with lactate metabolism, Dr. DeBerardinis continued. In his study of lung tumors, Dr. DeBerardinis had assumed that lactate would be metabolized in the cytoplasm rather than the mitochondria.

“If lactate is a waste product, then it should not be in the mitochondria,” he added. “But if lactate is to be used as a fuel, as the new study suggests, then it makes sense that it would be in the mitochondria.”

Dr. Patti’s study was conducted in cultured cells, and it will be important to see whether the process takes place in tumors in the body, Dr. DeBerardinis noted. “Our study of lung tumors in mice suggests that it probably does.”

Future studies will address the generality of the new findings for other types of cancer, Dr. Espey predicted.

“These studies can also determine the degree to which mitochondrial lactate metabolism is part of the cancer cell’s toolkit to withstand stresses for their survival,” he added.

Another Cancer Cell Energy Source - National Cancer Institute https://www.cancer.gov/news-events/cancer-currents-blog/2016/cancer-metabolism-lactate

　

参考文献：

Another Cancer Cell Energy Source - National Cancer Institute https://www.cancer.gov/news-events/cancer-currents-blog/2016/cancer-metabolism-lactate