讨厌的(不期而至的)肿瘤复发

讨厌的(不期而至的)肿瘤复发
By Michael Price
ScienceNOW Daily News
28 August 2008

Why do some cancers relapse years after treatment? The question has frustrated scientists and doctors for decades, but a new study of lab mice suggests an answer: Cells may break off from a tumor even before they become cancerous, seeding the body with cells that evade detection and lie dormant for years before turning into tumors of their own.
为什么有些肿瘤在治疗多年后还会复发？这个问题困扰了科学家和医生很多年，不过最近一个小鼠实验室研究结果对这个问题提供了一个新的答案，那就是一些细胞在癌变前可能就和肿瘤分开了，它们在体内播种，且无法被探测到，这样静止许多年后才生成肿瘤。

Researchers already know that cells can break off from a malignant tumor and cause cancer elsewhere in the body, a process known as metastasis. Breast cancer, for example, often metastasizes to the lungs. But conventional thinking holds that metastasis happens fairly late in the tumor's growth. In theory, removing tumors should prevent metastases from forming, but it often doesn't. Recently, researchers have suggested that cells from small cancers might spread early in their development and lay dormant; Katrina Podsypanina, a cancer researcher at the Memorial Sloan-Kettering Cancer Center in New York City, has wondered whether this seeding can happen even before the tumor becomes cancerous.
研究人员已经知道，细胞可以从恶性肿瘤中分离并在身体的其他部位导致肿瘤，这个过程就是转移。比如乳癌，经常会转移到肺。不过传统认为转移一般发生在肿瘤生长的晚期。理论上说，切除肿瘤可以避免形成转移，不过通常事实并非如此。最近，研究人员发现，小肿瘤的细胞可能在肿瘤发生的早期就发生了传播，只是处于静止状态；纽约的纪念斯隆－凯特琳癌症中心的一位肿瘤研究人员－Katrina Podsypanina，提出这样的疑问：这种播种是否可能在肿瘤癌变之前就已经发生了？

Podsypanina and colleagues tested the theory using an experimental strain of mice that simulates metastasis. The mice had been genetically engineered with genes that trigger cell growth: When exposed to the antibiotic doxycycline, these genes switch on and lead to unchecked cell growth and division. The researchers took mammary cells from these mice and injected them intravenously into the tails of normal mice on a doxycycline diet. Mice's tail veins lead directly to lung capillaries. Six weeks later, the team found metastatic cancer cells in the lungs--even though the mammary cells weren't cancerous when first injected. Another experiment showed that the mammary cells can even become cancerous after lying dormant in the lungs for up to 16 weeks, the team reports online today in Science.
Podsypanina和她的同事一起利用试验小鼠模拟转移检测了这个疑问。小鼠被引入含有刺激细胞生长的基因：当它们暴露在四环素类抗生素下时，基因会被启动，然后导致不可控制的细胞增殖和分化。研究人员提取这些小鼠的乳腺细胞，然后把它们静脉注入服用四环素的正常小鼠的尾巴。小鼠的尾静脉直接通向肺的毛细血管。六周后，研究小组在肺部发现了转移的癌症细胞，尽管此时在最初注射部位的乳腺细胞还没有发生癌变。另外一个试验的结果是－乳腺细胞甚至在肺部静止了超过16周后才发生癌变。今天这个研究小组在网上Science汇报了这一结果。

The same process might partly explain why breast cancer can relapse. If mammary cells in humans break off from a nascent tumor in the mammary glands and circulate in the bloodstream, they wouldn't be detected--or killed by chemotherapy, as chemotherapy targets cells that are already dividing rapidly--after the primary tumor turns malignant and is removed. Later, they too could become tumors of their own, Podsypanina explains. She cautions, however, that it's unclear whether--in human cancer--premalignant mammary cells are capable of breaking off from tumors and entering the bloodstream, but she hopes her study will provoke researchers to find out.
相同的过程可能部分的解释了为什么乳癌会复发。Podsypanina解释说，如果人类的乳腺细胞与正在形成肿瘤过程的乳腺中脱离，在血液中循环，是没法被检测到的，也是不能被化疗药物杀死的，因为原始肿瘤变成恶性被切除后，化疗药物所针对的是已经快速分裂的细胞。后来它们也发展成了肿瘤。不过她也提醒大家，这在人类肿瘤转移方面尚未确认，比如恶变前的乳腺细胞是否能从肿瘤细胞中分离，是否可以进入血流等，不过她希望她的研究可以推动研究人员去找到答案。

Leif Ellisen, a cancer researcher at Massachusetts General Hospital Cancer Center in Boston, echoes those concerns. "A skeptic might say that we're not sure if this chain of events can actually happen [naturally in humans]," he says. "But it opens the door for looking more carefully at how frequent this type of seeding might be."
波士顿玛萨诸塞总医院癌症中心的癌症研究人员Leif Ellisen也持同样观点。他说，“质疑的人可能会说目前我们还不能确认是否这种转移发生的方式会在人类重现，不过不管怎样，这为我们打开了一扇门，使得我们更仔细的去找寻这种类型的播种可能的发生频率”。

http://www.sciencemag.org/cgi/content/abstract/1161621

Published Online August 28, 2008
Science DOI: 10.1126/science.1161621
Science Express Index

Reports
Submitted on June 10, 2008
Accepted on August 11, 2008

Seeding and Propagation of Untransformed Mouse Mammary Cells in the Lung
Katrina Podsypanina 1*, Yi-Chieh Nancy Du 1, Martin Jechlinger 1, Levi J. Beverly 1, Dolores Hambardzumyan 1, Harold Varmus 1
1 Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

* To whom correspondence should be addressed.
联系方式
Katrina Podsypanina , E-mail: podsypak@mskcc.org

Acquisition of metastatic ability by tumor cells is considered a late event in the evolution of malignant tumors. Here we report that untransformed mouse mammary cells, engineered to express inducible oncogenic transgenes: MYC and KrasD12, or polyoma middle T, and introduced into the systemic circulation of a mouse, can bypass transformation at the primary site and develop into metastatic pulmonary lesions upon immediate or delayed oncogene induction. Therefore, previously untransformed mammary cells may establish residence in the lung once they have entered the bloodstream, and may assume malignant growth upon oncogene activation. Mammary cells lacking oncogenic transgenes displayed a similar capacity for long-term residence in the lungs but did not form ectopic tumors.
肿瘤细胞转移能力的获得被认为是恶性肿瘤发展过程晚期才出现的。我们这里汇报了尚未转化的小鼠乳腺细胞通过基因转导表达可诱导的肿瘤转化基因：MYC和KrasD12，或多瘤病毒T，将它们引入小鼠的循环系统，这样可以在引入肿瘤基因后不出现原始引入部位的肿瘤，而是很快或稍后即出现肺部转移病灶。因此，先前未分化的乳腺细胞可能在它们一进入血流后就有部分贮留在肺部，可能在肿瘤基因启动后开始恶性增长。未经肿瘤基因转导的乳腺细胞也同样具有长期在肺部生存的能力，却并未发生异位肿瘤。

编译：
讨厌的（不期而至的）肿瘤复发
By Michael Price
ScienceNOW Daily News
28 August 2008

为什么有些肿瘤在治疗多年后还会复发？这个问题困扰了科学家和医生很多年，不过最近一个小鼠实验室研究结果对这个问题提供了一个新的答案，那就是一些细胞在癌变前可能就离开了肿瘤并在体内播种，此时它们无法被探测到，这样静止许多年后才生成肿瘤。

细胞可以从恶性肿瘤中分离并在身体的其他部位导致肿瘤，这个过程就是转移。比如乳癌，经常会转移到肺。不过传统认为转移一般发生在肿瘤生长的晚期。理论上说，切除肿瘤可以避免形成转移，不过通常事实并非如此。最近，研究人员发现，小肿瘤的细胞可能在肿瘤发生的早期就发生了传播，只是处于静止状态；纽约的纪念斯隆－凯特琳癌症中心的一位肿瘤研究人员－Katrina Podsypanina，提出这样的疑问：这种播种是否可能在肿瘤癌变之前就已经发生了呢？

Podsypanina和她的同事一起利用试验小鼠模拟转移检测了这个疑问。小鼠被引入含有刺激细胞生长的基因：当它们暴露在四环素类抗生素下时，基因会被启动，然后导致不可控制的细胞增殖和分化。研究人员提取这些小鼠的乳腺细胞，然后把它们静脉注入服用四环素的正常小鼠的尾巴。小鼠的尾静脉直接通向肺的毛细血管。六周后，研究小组在肺部发现了转移的癌症细胞，尽管此时在最初注射部位的乳腺细胞还没有发生癌变。另外一个试验的结果是－乳腺细胞甚至在肺部静止了超过16周后才发生癌变。今天这个研究小组在网上Science汇报了这一结果。

相同的过程可能部分的解释了为什么乳癌会复发。Podsypanina解释说，如果人类的乳腺细胞与正在形成肿瘤过程的乳腺中脱离，在血液中循环，是没法被检测到的，也是不能被化疗药物杀死的，因为原始肿瘤变成恶性被切除后，化疗药物所针对的是已经快速分裂的细胞。后来它们也发展成了肿瘤。不过她也提醒大家，这在人类肿瘤转移方面尚未确认，比如恶变前的乳腺细胞是否能从肿瘤细胞中分离，是否可以进入血流等，不过她希望她的研究可以推动研究人员去找到答案。

波士顿玛萨诸塞总医院癌症中心的癌症研究人员Leif Ellisen也持同样观点。他说，“质疑的人可能会说目前我们还不能确认是否这种转移发生的方式会在人类重现，不过不管怎样，这为我们打开了一扇门，使得我们更仔细的去找寻这种类型的播种可能的发生频率”。

http://www.sciencemag.org/cgi/content/abstract/1161621

Published Online August 28, 2008
Science DOI: 10.1126/science.1161621
Science Express Index

Reports
Submitted on June 10, 2008
Accepted on August 11, 2008

Seeding and Propagation of Untransformed Mouse Mammary Cells in the Lung
Katrina Podsypanina 1*, Yi-Chieh Nancy Du 1, Martin Jechlinger 1, Levi J. Beverly 1, Dolores Hambardzumyan 1, Harold Varmus 1
1 Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

联系方式
Katrina Podsypanina , E-mail: podsypak@mskcc.org

肿瘤细胞转移能力的获得被认为是恶性肿瘤发展过程晚期才出现的。我们这里汇报了尚未转化的小鼠乳腺细胞通过基因转导表达可诱导的肿瘤转化基因：MYC和KrasD12，或多瘤病毒T，将它们引入小鼠的循环系统，这样可以在引入肿瘤基因后不出现原始引入部位的肿瘤，而是很快或稍后即出现肺部转移病灶。因此，先前未分化的乳腺细胞可能在它们一进入血流后就有部分贮留在肺部，可能在肿瘤基因启动后开始恶性增长。未经肿瘤基因转导的乳腺细胞也同样具有长期在肺部生存的能力，却并未发生异位肿瘤。