[2007.2.15][转贴][APTX青山病院]寻求癌症与衰老之间的联系

wangyuankai

[U]http://www.medicalnewstoday.com/medicalnews.php?newsid=62416[/U]

FISH-ing For Links Between Cancer And Aging

Article Date: 07 Feb 2007 - 7:00 PST

Wielding a palette of chromosome paints, scientists at the Salk Institute for Biological Studies have taken a step closer to understanding the relationship between aging and cancer by visualizing chromosomes of cells from patients with a heritable premature aging disease known as Werner Syndrome.

In a study to be published in this week's online edition of the Proceedings of the National Academy of Sciences researchers led by Jan Karlseder, Ph.D., assistant professor in Salk's Regulatory Biology Laboratory, showed that rebuilding structures called telomeres, which are found at the tips of each chromosome, significantly blocks the type of genetic damage seen in cells of patients with Werner Syndrome.

Patients with Werner Syndrome manifest signs of aging, such as skin wrinkling, baldness, or hair graying, in their teens. Most die in their 40's or 50's due to a predisposition to diseases like cancer. "Cancer is almost always related to chromosomal instability," explains Karlseder. "If telomeres are lost on individual chromosomes, then chromosomes are not protected and can fuse with other nonprotected chromosomes. Then when cells divide, chromosomes randomly break, leading to genome instability."

The current study extended work published in 2004 by Karlseder and first author Laure Crabbe, Ph.D., who was a graduate student in the Karlseder lab at the time. In that work, the team used a technique called FISH-short for fluorescent in situ hybridization-to microscopically visualize both the telomeres and chromosomal DNA from Werner Syndrome patients. They reported that some protective telomeres were actually missing on patients' chromosomes, a finding Karlseder describes as "a fairly catastrophic event for a cell."

For the current study, Salk researchers grew cells from Werner Syndrome patients in tissue culture dishes and, aided by colleagues at the Institute of Human Genetics in Heidelberg, Germany, evaluated DNA damage using a highly colorful variation of the FISH technique called chromosome painting. This technique "paints" or labels every pair of the 46 chromosomes with a different colored fluorescent dye, enabling investigators to easily see breakage or fusion of chromosomes that are characteristic of damaged DNA under the microscope.

Then they artificially supplied the cultured cells with one of two genes-either a functional copy of the WRN gene, which is mutant or nonfunctional in Werner Syndrome, or a gene encoding the protein telomerase, which elongates short or missing telomeres. After cells divided several times, their DNA was reexamined for the type of damage associated with both aging and cancer.

Cells supplied with a functional WRN gene showed decreased DNA damage compared to untreated cells, which was predictable: the WRN gene encodes a protein called a helicase that unwinds tightly coiled DNA strands when cells divide. Loss of WRN protein in individuals with Werner Syndrome is responsible for the disease. Explains Crabbe, now a postdoctoral fellow at The Institute of Human Genetics in Montpellier, France, "The lack of a single protein (WRN) induced loss of some telomeres, leading to a premature cellular growth arrest."

However, the most interesting finding was what the scientists observed in cells supplied with added telomerase. "When we put telomerase into cells, we suppressed accumulation of mutations to the same degree as when we put the WRN protein back," reports Karlseder. "It fixed the defect by elongating short telomeres seen in Werner Syndrome cells."

Crabbe, who is continuing to study DNA replication as a postdoc, concludes that these findings not only provide a mechanism underlying accelerated aging seen in Werner Syndrome but establish a link to cancer predisposition, saying, "These results indicate that the telomere dysfunction in Werner Syndrome cells is a major cause of genomic instability and could explain the high incidence of cancer seen in this disease."

Translating these findings into a treatment for Werner Syndrome will be extremely difficult. However, Karlseder feels optimistic about what these investigations show. "We study this disease because it is an excellent model for aging, and we show here a direct relation between aging, telomere loss, and cancer occurrence," he says. "I predict that cancer in older people has precisely the same basis as that seen in Werner Syndrome patients. That is why this was such a satisfying study."

wangyuankai

FISH-ing For Links Between Cancer And Aging
寻找癌症与衰老之间的联系
Article Date: 07 Feb 2007 - 7:00 PST
文章日期：2007年2月7日- 7:00 PST

Wielding a palette of chromosome paints, scientists at the Salk Institute for Biological Studies have taken a step closer to understanding the relationship between aging and cancer by visualizing chromosomes of cells from patients with a heritable premature aging disease known as Werner Syndrome.
Salk生物研究所的科学家们通过利用染色体彩涂板来观察Werner综合征（一种遗传性早衰疾病）患者细胞中的染色体，使我们对于衰老与癌症之间的关系有了进一步的认识。

In a study to be published in this week's online edition of the Proceedings of the National Academy of Sciences researchers led by Jan Karlseder, Ph.D., assistant professor in Salk's Regulatory Biology Laboratory, showed that rebuilding structures called telomeres, which are found at the tips of each chromosome, significantly blocks the type of genetic damage seen in cells of patients with Werner Syndrome.
Salk生物研究所调节生物学实验室助理教授Jan Karlseder博士领导的研究小组在本周的《美国国家科学院学报》网络版上发表的一项研究表明，端粒（每个染色体的末端都有的重建结构）可以阻断Werner综合征患者细胞中的这种基因损害。
Patients with Werner Syndrome manifest signs of aging, such as skin wrinkling, baldness, or hair graying, in their teens. Most die in their 40's or 50's due to a predisposition to diseases like cancer. "Cancer is almost always related to chromosomal instability," explains Karlseder. "If telomeres are lost on individual chromosomes, then chromosomes are not protected and can fuse with other nonprotected chromosomes. Then when cells divide, chromosomes randomly break, leading to genome instability."
Werner综合征患者会出现一些衰老的体征，比如在少年时出现皮肤皱纹，秃头，或灰发。大部分患者由于疾病（如癌症）的易感性在40多岁或50多岁是时死亡。Karlseder解释说：“癌症几乎总是和染色体不稳定联系，如果端粒在人的染色体中丢失，染色体就不会受保护，它可能与其它不受保护的染色体融合。当细胞分裂时，染色体随机分开，导致基因组的不稳定。”
The current study extended work published in 2004 by Karlseder and first author Laure Crabbe, Ph.D., who was a graduate student in the Karlseder lab at the time. In that work, the team used a technique called FISH-short for fluorescent in situ hybridization-to microscopically visualize both the telomeres and chromosomal DNA from Werner Syndrome patients. They reported that some protective telomeres were actually missing on patients' chromosomes, a finding Karlseder describes as "a fairly catastrophic event for a cell."
Karlseder的最近相关研究发表于2004年（第一作者为当时在Karlseder实验室读研究生的Laure Crabbe博士）在那项研究中，研究人员用叫做FISH（荧光素原位杂交）的技术使Werner综合症患者的端粒和染色体DNA在显微镜下可视。他们报道在患者的染色体中有些保护性的端粒实际上丢失了，Karlseder把这个发现描述为“细胞的灾难性事件”。
For the current study, Salk researchers grew cells from Werner Syndrome patients in tissue culture dishes and, aided by colleagues at the Institute of Human Genetics in Heidelberg, Germany, evaluated DNA damage using a highly colorful variation of the FISH technique called chromosome painting. This technique "paints" or labels every pair of the 46 chromosomes with a different colored fluorescent dye, enabling investigators to easily see breakage or fusion of chromosomes that are characteristic of damaged DNA under the microscope.
目前的研究，Salk的研究人员在组织培养皿中培养来自Werner综合症患者的细胞，并由德国爱得堡人类基因研究所的同事们帮助，用叫做染色体彩涂的高度彩色变化的FISH技术评估DNA损伤。这种技术用不同的彩色荧光染料“彩涂”或标记46条染色体的每一对，从而研究者在显微镜下很容易看到被损伤DNA特征性的染色体的断裂和融合。
Then they artificially supplied the cultured cells with one of two genes-either a functional copy of the WRN gene, which is mutant or nonfunctional in Werner Syndrome, or a gene encoding the protein telomerase, which elongates short or missing telomeres. After cells divided several times, their DNA was reexamined for the type of damage associated with both aging and cancer.
然后他们人为地在培养细胞中供给下述两种基因的其中之一，一种是WRN基因的功能性拷贝，它在Werner综合症患者中是突变的或无功能的。在细胞分裂几次之后，再检查与衰老和癌症均有关的DNA损伤类型。
Cells supplied with a functional WRN gene showed decreased DNA damage compared to untreated cells, which was predictable: the WRN gene encodes a protein called a helicase that unwinds tightly coiled DNA strands when cells divide. Loss of WRN protein in individuals with Werner Syndrome is responsible for the disease. Explains Crabbe, now a postdoctoral fellow at The Institute of Human Genetics in Montpellier, France, "The lack of a single protein (WRN) induced loss of some telomeres, leading to a premature cellular growth arrest."
供给了功能性WRN基因的细胞比没有被供给的细胞的DNA损伤有所减少。这个结论是可以预见的：WRN基因编码一个叫解螺旋酶的蛋白，它在细胞分裂时可以解开紧紧绕住的DNA双链。人WRN蛋白的丢失是Werner综合症的病因。现在是法国蒙特利尔人类基因研究所的博士后的Crabbe解释说：“单一蛋白(WRN)的缺乏可诱导端粒的丢失，导致细胞生长的过早停止。” However, the most interesting finding was what the scientists observed in cells supplied with added telomerase. "When we put telomerase into cells, we suppressed accumulation of mutations to the same degree as when we put the WRN protein back," reports Karlseder. "It fixed the defect by elongating short telomeres seen in Werner Syndrome cells."
然而，最令人感兴趣的发现是科学家们观察到的供给了端粒酶的细胞中的现象。Karlseder报道：“当我们把端粒酶加入细胞，我们看到了和加入WRN蛋白的细胞中相同程度的累积突变受抑现象。它通过延长短的端粒而弥补了Werner综合症患者细胞的缺陷。”
Crabbe, who is continuing to study DNA replication as a postdoc, concludes that these findings not only provide a mechanism underlying accelerated aging seen in Werner Syndrome but establish a link to cancer predisposition, saying, "These results indicate that the telomere dysfunction in Werner Syndrome cells is a major cause of genomic instability and could explain the high incidence of cancer seen in this disease."
还在做研究DNA复制方向的博士后的Crabbe总结说，这些发现不仅提供了存在于Werner综合症中的潜在加速衰老的机制，还和癌症易感建立了联系。他说：“这些结论表明Werner综合症患者细胞中的端粒酶功能障碍是基因组不稳定性的主要原因，还可以解释在这种病中见到的癌症的高发生率。”
Translating these findings into a treatment for Werner Syndrome will be extremely difficult. However, Karlseder feels optimistic about what these investigations show. "We study this disease because it is an excellent model for aging, and we show here a direct relation between aging, telomere loss, and cancer occurrence," he says. "I predict that cancer in older people has precisely the same basis as that seen in Werner Syndrome patients. That is why this was such a satisfying study."
把这些发现转化为治疗Werner综合症是相当困难的。但Karlseder对这些研究结果感到乐观，他说：“我们研究这个疾病是因为它是衰老的理想模型，我们在此发现衰老，端粒丢失和癌症发生有直接联系。我认为老人的癌症发生基础也是和在Werner综合症患者中所见是一样的。这就是我对这项研究满意的原因。”

wangyuankai

　　　　　　　寻找癌症与衰老之间的联系
　　　　　　　文章日期：2007年2月7日- 7:00 PST

　　Salk生物研究所的科学家们通过利用染色体彩涂板来观察Werner综合征（一种遗传性早衰疾病）患者细胞中的染色体，使我们对于衰老与癌症之间的关系有了进一步的认识。
Salk生物研究所调节生物学实验室助理教授Jan Karlseder博士领导的研究小组在本周的《美国国家科学院学报》网络版上发表的一项研究表明，端粒（每个染色体的末端都有的重建结构）可以阻断Werner综合征患者细胞中的这种基因损害。
Werner综合征患者会出现一些衰老的体征，比如在少年时出现皮肤皱纹，秃头，或灰发。大部分患者由于疾病（如癌症）的易感性在40多岁或50多岁是时死亡。Karlseder解释说：“癌症几乎总是和染色体不稳定联系，如果端粒在人的染色体中丢失，染色体就不会受保护，它可能与其它不受保护的染色体融合。当细胞分裂时，染色体随机分开，导致基因组的不稳定。”
　　Karlseder的最近相关研究发表于2004年（第一作者为当时在Karlseder实验室读研究生的Laure Crabbe博士） 在那项研究中，研究人员用叫做FISH（荧光素原位杂交）的技术使Werner综合症患者的端粒和染色体DNA在显微镜下可视。他们报道在患者的染色体中有些保护性的端粒实际上丢失了，Karlseder把这个发现描述为“细胞的灾难性事件”。
　　目前的研究，Salk的研究人员在组织培养皿中培养来自Werner综合症患者的细胞，并由德国爱得堡人类基因研究所的同事们帮助，用叫做染色体彩涂的高度彩色变化的FISH技术评估DNA损伤。这种技术用不同的彩色荧光染料“彩涂”或标记46条染色体的每一对，从而研究者在显微镜下很容易看到被损伤DNA特征性的染色体的断裂和融合。
　　然后他们人为地在培养细胞中供给下述两种基因的其中之一，一种是WRN基因的功能性拷贝，它在Werner综合症患者中是突变的或无功能的。在细胞分裂几次之后，再检查与衰老和癌症均有关的DNA损伤类型。
　　供给了功能性WRN基因的细胞比没有被供给的细胞的DNA损伤有所减少。这个结论是可以预见的：WRN基因编码一个叫解螺旋酶的蛋白，它在细胞分裂时可以解开紧紧绕住的DNA双链。人WRN蛋白的丢失是Werner综合症的病因。现在是法国蒙特利尔人类基因研究所的博士后的Crabbe解释说：“单一蛋白(WRN)的缺乏可诱导端粒的丢失，导致细胞生长的过早停止。”然而，最令人感兴趣的发现是科学家们观察到的供给了端粒酶的细胞中的现象。Karlseder报道：“当我们把端粒酶加入细胞，我们看到了和加入WRN蛋白的细胞中相同程度的累积突变受抑现象。它通过延长短的端粒而弥补了Werner综合症患者细胞的缺陷。”
　　还在做研究DNA复制方向的博士后的Crabbe总结说，这些发现不仅提供了存在于Werner综合症中的潜在加速衰老的机制，还和癌症易感建立了联系。他说：“这些结论表明Werner综合症患者细胞中的端粒酶功能障碍是基因组不稳定性的主要原因，还可以解释在这种病中见到的癌症的高发生率。”
　　把这些发现转化为治疗Werner综合症是相当困难的。但Karlseder对这些研究结果感到乐观，他说：“我们研究这个疾病是因为它是衰老的理想模型，我们在此发现衰老，端粒丢失和癌症发生有直接联系。我认为老人的癌症发生基础也是和在Werner综合症患者中所见是一样的。这就是我对这项研究满意的原因。”

wangyuankai

个人观点，仅供参考：

Wielding a palette of chromosome paints, scientists at the Salk Institute for Biological Studies have taken a step closer to understanding the relationship between aging and cancer by visualizing chromosomes of cells from patients with a heritable premature aging disease known as Werner Syndrome.
利用染色体彩涂板，Salk生物研究所的科学家们从患一种遗传性早衰疾病称为Werner综合症的患者的细胞中的染色体进行可视化，使我们对衰老和癌症的联系的理解又迈出了一步。
Salk生物研究所的科学家们通过利用染色体彩涂板来观察Werner综合征（一种遗传性早衰疾病）患者细胞中的染色体，使我们对于衰老与癌症之间的关系有了进一步的认识。

In a study to be published in this week's online edition of the Proceedings of the National Academy of Sciences researchers led by Jan Karlseder, Ph.D., assistant professor in Salk's Regulatory Biology Laboratory, showed that rebuilding structures called telomeres, which are found at the tips of each chromosome, significantly blocks the type of genetic damage seen in cells of patients with Werner Syndrome.
发表在本周《国家科学院学报》网络版由Salk研究所调节生物学实验室的博士后，助理教授Jan Karlseder 主持的一项研究表明，重建称为端粒的结构，这种结构出现在各个染色体的顶端，可以显著阻断见于Werner综合症患者细胞中的这种基因损害。
Salk生物研究所调节生物学实验室助理教授Jan Karlseder博士领导的研究小组在本周的《美国国家科学院学报》网络版上发表的一项研究表明，端粒（每个染色体的末端都有的重建结构）可以阻断Werner综合征患者细胞中的这种基因损害。

Patients with Werner Syndrome manifest signs of aging, such as skin wrinkling, baldness, or hair graying, in their teens.
患Werner综合症的患者会出现一些衰老的征象，如在少年时出现皮肤皱纹，秃头，或灰发。
Werner综合征患者会出现一些衰老的体征，比如在少年时出现皮肤皱纹，秃头，或灰发。

Most die in their 40's or 50's due to a predisposition to diseases like cancer.
大部分患者由于疾病（如癌症）的易感性在40多岁或50多岁是时死亡。
由于易患癌症等疾病，大部分Werner综合征患者会在40多岁或50多岁时死亡。

"Cancer is almost always related to chromosomal instability," explains Karlseder.
Karlseder解释说：“癌症几乎总是和染色体不稳定联系，
Karlseder解释说：“癌症几乎总是和染色体不稳定有关，

"If telomeres are lost on individual chromosomes, then chromosomes are not protected and can fuse with other nonprotected chromosomes.
如果端粒在人的染色体中丢失，染色体就不会受保护，它可能与其它不受保护的染色体融合。
如果人的染色体丢失了端粒，染色体就会由于失去保护而与其它失去保护的染色体融合。

The current study extended work published in 2004 by Karlseder and first author Laure Crabbe, Ph.D., who was a graduate student in the Karlseder lab at the time.
目前的研究是由Karlseder和第一作者，博士后Laure Crabbe在2004年发表的论著的延伸。Laure Crabbe当时是Karlseder实验室的一名研究生。
Karlseder的最近相关研究发表于2004年（第一作者为当时在Karlseder实验室读研究生的Laure Crabbe博士）