维生素C会促进血液中癌细胞的死亡

皇后

Vitamin C may encourage blood cancer stem cells to dieAugust 17, 2017[size=1.4]

[size=1.6]Vitamin C may "tell" faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers. This is the finding of a study led by researchers from Perlmutter Cancer Center at NYU Langone Health, and published online August 17 in the journal Cell.

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Certain genetic changes are known to reduce the ability of an enzyme called TET2 to encourage stem cells to become mature blood cells, which eventually die, in many patients with certain kinds of leukemia, say the authors. The new study found that vitamin C activated TET2 function in mice engineered to be deficient in the enzyme.

"We're excited by the prospect that high-dose vitamin C might become a safe treatment for blood diseases caused by TET2-deficient leukemia stem cells, most likely in combination with other targeted therapies," says corresponding study author Benjamin G. Neel, MD, PhD, professor in the Department of Medicine and director of the Perlmutter Cancer Center.

Changes in the genetic code (mutations) that reduce TET2 function are found in 10 percent of patients with acute myeloid leukemia (AML), 30 percent of those with a form of pre-leukemia called myelodysplastic syndrome, and in nearly 50 percent of patients with chronic myelomonocytic leukemia. Such cancers cause anemia, infection risk, and bleeding as abnormal stem cells multiply in the bone marrow until they interfere with blood cell production, with the number of cases increasing as the population ages.

Along with these diseases, new tests suggest that about 2.5 percent of all U.S. cancer patients - or about 42,500 new patients each year - may develop TET2 mutations, including some with lymphomas and solid tumors, say the authors.

Cell Death Switch

The study results revolve around the relationship between TET2 and cytosine, one of the four nucleic acid "letters" that comprise the DNA code in genes. Every cell type has the same genes, but each gets different instructions to turn on only those needed in a given cellular context.

These "epigenetic" regulatory mechanisms include DNA methylation, the attachment of a small molecule termed a methyl group to cytosine bases that shuts down the action of a gene containing them.

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Researchers from Perlmutter Cancer Center at NYU Langone Health discuss their discovery that vitamin C may "tell" faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers. Credit: NYU Langone Health

The back- and-forth attachment and removal of methyl groups also fine-tunes gene expression in stem cells, which can mature, specialize and multiply to become muscle, bone, nerve, or other cell types. This happens as the body first forms, but the bone marrow also keeps pools of stem cells on hand into adulthood, ready to become replacement cells as needed. In leukemia, signals that normally tell a blood stem cell to mature malfunction, leaving it to endlessly multiply and "self-renew" instead of producing normal white blood cells needed to fight infection.

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The enzyme studied in this report, Tet methylcytosine dioxygenase 2 (TET2), enables a change in the molecular structure (oxidation) of methyl groups that is needed for them to be removed from cytosines. This "demethylation" turns on genes that direct stem cells to mature, and to start a count-down toward self-destruction as part of normal turnover. This serves as an anti-cancer safety mechanism, one that is disrupted in blood cancer patients with TET2 mutations, says Neel.

To determine the effect of mutations that reduce TET2 function in abnormal stem cells, the research team genetically engineered mice such that the scientists could switch the TET2 gene on or off.

Similar to the naturally occurring effects of TET2 mutations in mice or humans, using molecular biology techniques to turn off TET2 in mice caused abnormal stem cell behavior. Remarkably, these changes were reversed when TET2 expression was restored by a genetic trick. Previous work had shown that vitamin C could stimulate the activity of TET2 and its relatives TET1 and TET3. Because only one of the two copies of the TET2 gene in each stem cell is usually affected in TET2-mutant blood diseases, the authors hypothesized that high doses of vitamin C, which can only be given intravenously, might reverse the effects of TET2 deficiency by turning up the action of the remaining functional gene.

Indeed, they found that vitamin C did the same thing as restoring TET2 function genetically. By promoting DNA demethylation, high-dose vitamin C treatment induced stem cells to mature, and also suppressed the growth of leukemia cancer stem cells from human patients implanted in mice.

"Interestingly, we also found that vitamin C treatment had an effect on leukemic stem cells that resembled damage to their DNA," says first study author Luisa Cimmino, PhD, an assistant professor in the Department of Pathology at NYU Langone Health. "For this reason, we decided to combine vitamin C with a PARP inhibitor, a drug type known to cause cancer cell death by blocking the repair of DNA damage, and already approved for treating certain patients with ovarian cancer."

Researchers found that the combination had an enhanced effect on leukemia stem cells, further shifting them from self-renewal back toward maturity and cell death. The results also suggest that vitamin C might drive leukemic stem cells without TET2 mutations toward death, says Cimmino, given that it turns up any TET2 activity normally in place.

"Our team is working to systematically identify genetic changes that contribute to risk for leukemia in significant groups of patients," says corresponding author Iannis Aifantis, PhD, professor and chair of the Department of Pathology at NYU Langone Health. "This study adds the targeting of abnormal TET2-driven DNA demethylation to our list of potential new treatment approaches."

皇后

维生素C会诱导骨髓中产生病变的造血干细胞成熟、死亡，降低人们患上血癌的风险。这一结果是由来自珀尔马特癌症研究中心(附属于纽约大学兰戈恩医疗研究中心)的研究人员发现的，并于8月17日在线发表在《Cell》杂志上。

该研究的作者表示，在许多白血病病例中，某些基因突变降低了TET2酶诱导造血干细胞分化为成熟血细胞的能力。患者的这些造血干细胞直接就死去了，导致血细胞不足，从而患上白血病。而新的研究发现，维生素C成功激活了小鼠(通过基因工程被设计为TET2酶有缺陷的小鼠)身上TET2酶的功能。

“我们对这一发现的前景很激动，这意味着：高剂量的维生素C与其他靶向治疗相结合，也许可以安全地治疗由于TET2酶缺陷而导致的白血病。” 该研究的通讯作者——珀尔马特癌症研究中心的主任和医学系教授Benjamin G. Neel对此说道。

他们表示，10%的急性髓细胞样白血病患者、30%的骨髓增生异常综合征患者以及将近50%的慢性骨髓单核细胞性白血病患者体内都被发现有降低TET2酶功能性的基因突变。上述的三种疾病都会导致人体贫血、感染或出血。这些病的起因是骨髓中癌变的干细胞迅速繁殖，进而开始干扰正常血细胞的生成。随着人口老龄化，病例数量也在不断增加。

该研究的作者还说道，除了上述那些疾病，新的测试表明，每年约有2.5%的美国癌症患者(包括淋巴瘤和实体肿瘤)——或者说是每年约有42500个新的患者体内会发生TET2基因突变。

细胞死亡“开关”
研究结果围绕着TET2酶和胞嘧啶(用来组成DNA密码的四个核酸“字母”之一)之间的关系展开。众所周知，每一种细胞都有着相同的基因，但是每种细胞会接收不同的指令来表达在特定细胞环境中需要的基因。这些“表观遗传”的调控机制包括DNA甲基化——被称为甲基的小分子与胞嘧啶碱基连接，从而使含有这些胞嘧啶碱基的基因失去作用。

甲基来回的连接和脱离能很好地调节干细胞中的基因表达，这些干细胞会慢慢地成熟、繁殖并分化成肌肉细胞、骨骼细胞、神经细胞或其他类型的细胞。这种情况发生在身体第一次形成的时候，但骨髓也会将一些干细胞保存到成年，以便于它们随时可以成为人体所需要的替代细胞。而在白血病患者体内，常常会有生物信号使得造血干细胞发育异常，使其不断繁殖并“自我更新”，而不是产生正常的白细胞用于抵抗感染。

而本研究报告中所提到的TET2酶，能使甲基的分子结构发生改变(氧化)从而与胞嘧啶分离。作为细胞正常生理活动的一部分，这个“去甲基化”的过程将使得干细胞直接成熟，并开始走向自我毁灭。Neel对此说道，这是一种抗癌的安全机制，而在那些TET2酶有缺陷的白血病患者身上，这种机制被扰乱了。

为了确定异常干细胞中降低TET2功能性的基因突变的影响，该研究团队通过基因工程对小鼠进行了改造，以便于科学家们可以随时打开或关闭控制TET2基因表达的“开关”。

就像小鼠和人类身上自然发生的TET2基因突变的影响一样，利用分子生物学技术使TET2基因无法表达也引起了小鼠的干细胞行为异常。值得注意的是，当TET2基因的表达被恢复时，小鼠身上出现的那些变化也被逆转了。此前已经有研究表示，维生素C对TET2及其相关的TET1和TET3的活动有促进作用。因为在由TET2基因突变引起的血液病中，通常只有两份TET2基因中的一份产生了突变，所以该研究的作者推测：通过静脉注射的高剂量维生素C，可能会通过表达剩余的基因来逆转TET2缺陷所带来的影响。

事实上，他们发现在恢复TET2基因的功能性时，维生素C也做了和TET2同样的事——通过促进DNA去甲基化，高剂量的维生素C不仅诱导干细胞成熟，并抑制了被注入小鼠体内的癌变干细胞(属于人类患者的)的生长。

“有趣的是，我们还发现，维生素C对由DNA损伤导致的白血病干细胞也有治疗作用。”该研究的第一作者——纽约大学兰戈恩医疗研究中心病理学部门的助理教授Luisa Cimmino说道：“为此，我们决定将维生素C与PARP抑制剂(一种通过抑制DNA损伤的修复而导致癌细胞死亡的药物)一起使用，并且这种药物已经被批准用于治疗某些卵巢癌患者。”

研究人员发现，这两种药物的结合对白血病干细胞很有效，能够进一步将它们从自我更新转变为成熟和死亡。研究结果还表明，考虑到维生素C会出现在任何有TET2活动的地方，维生素C还会使没有TET2突变的白血病干细胞走向死亡。

“我们的研究小组正在系统地识别会显著增加人群患上白血病的风险的基因变化。”该研究的通信作者——纽约大学兰戈恩医疗研究中心病理学部门的教授Lannis Aifantis说道：“我们后面的研究也会把由TET2酶引起的DNA去甲基化异常的治疗作为目标清单的一部分。”