A new molecular link between inflammation and cancer, discovered through experiments with mice, has revealed how the body's natural repair response to tissue injury can actually spur tumor growth.
最近的一项利用小鼠进行的实验表明，人体对于组织损伤产生的自然的修复反应确实可以刺激肿瘤的生长，而这也为炎症反应与癌症之间提示了一个新的分子生物学上的关联。
Howard Hughes Medical Institute investigator Ruslan Medzhitov and colleague Seth Rakoff-Nahoum have found that a protein involved in repairing damaged tissue in the intestine also drives the growth of intestinal tumors. The scientists, both at the Yale University School of Medicine, reported their findings in the July 6, 2007, issue of the journal Science. They said the new study will help scientists understand, and perhaps ultimately control, the tissue repair pathway that feeds tumor growth.
Howard Hughes医学研究所（HHMI）的研究者Ruslan Medzhitov和他的同事Seth Rakoff-Nahoum发现，一个促使肠癌的生长的蛋白，正常情况下此蛋白参与肠组织的损伤修复。耶鲁大学医学院的科学家们在2007年七月六号的Science上发表了这个发现。他们说，这项新的研究将帮助科学家们理解并可能最终控制这条促进肿瘤生长的组织修复途径。
Medzhitov and Rakoff-Nahoum explored the function of a protein called Myd88, which participates in a molecular signaling pathway that launches tissue repair in the intestine. Myd88 receives its activating signal from a set of key immune-system regulators called Toll-like receptors.
Medzhitov和Rakoff-Nahoum研究了一个称为Myd88的蛋白的功能，这个蛋白参与了引起肠部组织修复的一个分子信号通路。它能够接受称为Toll样受体的关键免疫系统调节蛋白的激活信号。
“It has long been speculated that the tissue-repair response may be involved in tumorigenesis, because tumor growth can be viewed as an unregulated state of tissue repair,” said Medzhitov. “So we hypothesized that induction of the tissue repair response by Toll-like receptors may contribute to tumorigenesis.”
“很早，人们就认为组织修复反应可能与肿瘤发生过程有关系，因为肿瘤生长也可以被视为一种不受调节的组织修复，” Medzhitov说，“所以我们假设Toll样受体导致的组织修复反应可能在肿瘤发生过程中有作用。”
In their experiments, the researchers used mice that have a mutation in a gene called adenomatous polyposis coli (APC), which in humans is associated with the vast majority of both inherited and sporadic colorectal cancers. Like humans, mice with the mutant gene develop abnormal intestinal growths and tumors. To test the role of Myd88 in tumor development, the researchers engineered these mice to also lack a functioning gene for the Myd88 protein.
在他们的实验中，研究者们使用了adenomatous polyposis coli (APC)基因突变的小鼠，这个基因与大部分人类遗传性和自发性的结肠癌密切相关。而像人类一样，带有此变异基因的小鼠会有不正常的肠组织的生长并且发生肿瘤。为了检验Myd88在肿瘤发生中的作用，研究者们设计制作出了一些不能产生Myd88蛋白的小鼠。
The resulting double-mutant mice developed fewer intestinal growths and tumors than mice who were missing only APC. Detailed comparisons of the two mouse strains revealed that both strains formed about the same number of pre-cancerous structures called microadenomas, but without Myd88, many of those microadenomas never progressed to tumors. This told the researchers that Myd88 contributes to tumor growth and progression, rather than the early initiation of cancer. This idea was further supported by genetic studies of the intestinal tumors, which showed that Myd88 activates a number of genes known to be involved in both tissue repair and tumor development, including some key modifier genes known to be critical for tumorigenesis in both humans and mice.
这些Myd88和APC基因都发生了突变的小鼠比那些只缺失了APC的小鼠的不正常肠组织生长和肿瘤发生都要少。而在仔细比较了两个品系的小鼠后发现，它们发生称为微腺瘤的癌前结构的数目是一样的，但是如果缺失了Myd88，那么很多的这些微腺瘤都不会进一步发生成为肿瘤。而这也告诉研究者们，Myd88对肿瘤的生长和发展有影响，但是对于癌症的早期发生则不然。
“These findings suggest to us that perhaps the Myd88 pathway controls tumorigenesis by controlling the induction of the tissue repair response,” said Medzhitov. “In normal tissues, once the tissue repair response is induced it replenishes the damaged tissue and then stops. But in the case of oncogenic mutations, the tissue-repair response is induced because initial tumor growth is sensed as damage to tissue. This turns into a vicious cycle, in which tissue repair generates cells that contribute to tumor mass, but that is perceived as even greater tissue damage, which provides even more cell mass to the growing tumor.”
“这项发现提示我们也许Myd88涉及的途经能够通过控制组织修复反应的起始来控制肿瘤的发生。” Medzhitov说，“在正常的组织中，一旦组织修复反应被诱导发生，它就能补充好损伤的组织，然后就停下来了。但是在有致癌性的突变的情况下，最初的肿瘤生长被认为是对组织的损害而激发组织修复反应的发生。这就导致了一个恶性循环：组织修复产生的细胞会被用于肿瘤团的生长，而更大的肿瘤团将被认为是更大的组织损害，从而导致组织修复反应提供更多的细胞用于肿瘤的生长。”
The researchers further confirmed the role of Myd88 in cancer growth with an entirely different model of intestinal tumor formation. They found that when mice were given the cancer-causing chemical azoxymethane, fewer tumors formed when Myd88 was missing. 研究者们利用一个完全不同的肠瘤形成模型进一步证实了Myd88在癌症生长中的作用。他们发现如果对这些小鼠施以一种称为azoxymethane的化学致癌物的时候，它们生长的肿瘤要比正常的小鼠少。
While they have identified Myd88 as an important trigger of the tissue-repair response, Medzhitov said that future studies in his laboratory will seek to identify the molecular signal that switches off that response once tissue is repaired. “If we could identify this negative signal, it might lead to a therapeutic application in which tumor growth could be inhibited by providing that signal,” said Medzhitov. Future studies will also search for the signal the tumor uses to trigger the tissue-repair response. “If we knew what that signal was, we could attempt to neutralize it, and that could also potentially help to inhibit or block tumor growth, by blocking this tumor tissue-repair program,” he said.
Medzhitov说，在已经确认Myd88是组织修复反应的重要启动因子以后，他的实验室下一步的研究方向将是寻找能够在组织修复完毕后来关掉这个反应的分子信号。“如果我们能够鉴定出这个负控制信号，也许可以通过提供这样一个信号来治疗肿瘤，”Medzhitov说。寻找肿瘤所利用的触发组织修复反应的信号也是将来的研究方向之一。“如果我们知道那个信号是什么，我们就能试着去中和它，从而阻止肿瘤组织修复程序，而这也能帮助来抑制或阻止肿瘤的生长。” |
发表于 2007-9-20 01:03:35