恶性肿瘤细胞转移的开关

新发现的癌细胞行为预示危险的转移

一项在小鼠上进行的新的研究显示：最具攻击性的恶性肿瘤细胞具有一个“开关”，使其能够在形态上变成高移动性的细胞，从而入侵其他组织并随后在新环境中轻松的形成癌巢。

“该研究描绘出癌细胞如何在两种交互的状态下转变—迁移态和成巢态。这表明对于癌细胞是如何转移或扩散到人体其他部位的机制有了新的认识。”实施该项研究的杜克综合肿瘤中心的研究人员说。

“对这个开关的了解可能最终会使科学家们能够找到阻止细胞转移的方法，而转移是癌细胞最致命的特征。“研究的首席研究员Mariano Garcia-Blanco说（分子遗传学和微生物学博士）。

研究人员将要把他们的发现发表在2006年9月19日出版的国家科学院学报上，现在已经可以在网上看到。该项研究由国立癌症研究所提供经费。

目前为止，科学家普遍认为癌细胞必须永久性的由静止性的上皮细胞转变成迁移性的间充质细胞后才能够转移。

杜克大学的研究团队发现高度恶性的癌细胞中上皮性和间充质性细胞是相等的，可以相互转变以适应环境的需要。而细胞产生的蛋白质可以促使细胞向哪个方向转变。

在经典的适者生存的例子中，癌细胞在上皮性和间充质性之间变换的能力使得最恶性的细胞具有极强的侵袭性并能够顺利地适应不熟悉的地方，科学家们说。

“普遍的想法是癌细胞中间充质性细胞越多，癌细胞的移动性和转移性越强”Garcia-Blanco说，“实际上，侵袭性的癌细胞是不同源的，但他们都具有各种各样的适应生存环境变化的能力”

科学家们通过在观察选择剪切时发现的一个错误，在癌细胞中发现了这种转变。选择剪切是遗传复制过程中的一个重要组成部分。选择剪切决定了DNA怎样被切成片段然后重新组合的。DNA重组的顺序决定了该基因产生何种蛋白

在癌细胞中，剪切机制改变——就像细胞内其他功能的改变一样。当剪切向着一个方向进行，癌细胞变成间充质性；向着另一个方向进行，变成上皮性。

为了判断癌细胞的转变方向，科学家们建立了一个荧光指针——一种在细胞转向上皮态时会发出荧光，但是当细胞转向间充质态时保持静止的蛋白。

通过跟踪小鼠癌细胞中的指针光度，该团队观察到了这一选择性剪切的过程。研究人员可以将DNA特定部分显影--即所谓的外显子--来判断当细胞转变时，其是否包含在剪切过程中。

“我们在对间充质性细胞与上皮性细胞的比较中发现，选择剪切的规律是不一样的。”Garcia-Blanco说，“有一个特殊的外显子--FGFR2 IIIc--在间充质性细胞中是沉默的但在上皮性细胞中是活化的。”

“当基因发生改变时我们可以使其显影，”他说。“我们可以通过观察他们的剪切型式来判断细胞类型”

依照Garcia-Blanco所说，被认为能够引导剪切规律的细胞开关是一种称为Fox的蛋白。上皮性和间充质性细胞都合成Fox，但是Fox只在上皮性细胞中有活性，Garcia-Blanco说。

研究人员说，Fox也可能有一个协同因子或辅助因子存在于上皮性细胞内或周边，该因子能够将其迅速激活。他们推测这个辅助因子可能在接触基质后被激活--基质是肿瘤的结构支持细胞--因为观察到的多数上皮性癌细胞存在于基质。它们的高度存在意味着基质可能在癌细胞到达新的目的地后诱导其向上皮性转变，所以它们能够使一个新的癌灶稳定生长。

“我们的发现验证了肿瘤的行为是高度复杂的并且不单单需要一个基因的突变来改变其行为，”Sebastian Oltean说，M.D., Ph.D.,研究员，文章的第一作者。

“基因剪切的改变在自然界是微乎其微的，但是对癌细胞仍然是一个主要的影响并能够作为治疗的靶点。”

该小组的下一步是进一步确定癌细胞中控制开关机制的因素，Garcia-Blanco说，对肿瘤的自然演进中发生的多种步骤进行鉴别能够引导阻止转移的治疗方法的发现。


Newly discovered behavior in cancer cells signals dangerous metastasis

The most aggressively malignant cancer cells have a "toggle switch" that enables them to morph into highly mobile cells that invade other tissues and then nest comfortably in their new surroundings, a new study in rats suggests.

This picture of how cancer cells shift between two alternating states -- travelers and nesters -- represents a new understanding of how cancer metastasizes, or spreads to other parts of the body, said the Duke Comprehensive Cancer Center researchers who conducted the study.

"Understanding this toggle switch might ultimately enable scientists to find ways to stop cells from metastasizing, which is the most deadly trait of cancer," said the study's lead investigator, Mariano Garcia-Blanco, M.D., Ph.D., professor of molecular genetics and microbiology.

The researchers will publish their findings in the Sept. 19, 2006, issue of the journal Proceedings of the National Academy of Sciences, now available on line. The research was funded by the National Cancer Institute.

Until now, scientists have believed that cancer cells must transform permanently from stationary epithelial cells into migratory mesenchymal cells in order to metastasize.

The Duke team discovered that highly malignant cells are equal parts epithelial and mesenchymal, transitioning between the two as their surroundings necessitate. The proteins that the cell produces dictate which way the cell shifts.

In a classic example of survival of the fittest, a cancer cell's ability to toggle between epithelial and mesenchymal enables the most malignant cells to aggressively invade and then peacefully adapt in unfamiliar territory, the scientists said.

"The prevailing notion has been that the more mesenchymal the cancer cells, the more mobile and metastatic they would be," Garcia-Blanco said. "In reality, aggressive cancer cells are not homogenous, but are extremely versatile in their ability to adapt as their survival needs shift."

The researchers discovered this transition in cancer cells when they observed an error in "alternative splicing," a key element of the genetic copying program inside cells. Alternative splicing determines how the DNA is chopped into pieces and then reassembled. The order in which DNA is reassembled determines which proteins the gene produces.

In cancer cells, the splicing machinery goes awry -- as do myriad functions within the cells. When the splicing process proceeds one way, the cells become mesenchymal. Spliced another way, the cells turn epithelial.

To determine which way a cancer cell would turn, the scientists constructed a fluorescent "reporter" -- a protein that illuminates if the cell turns epithelial but lies dormant if the cell reverts to mesenchymal state.

By following the reporter's illumination within cancer cells in rats, the team viewed the very process of alternative splicing as it occurred in the tumors. The researchers were able to visualize specific portions of DNA, called exons, to see if they were included or excluded in the splicing process as the cell transformed.

"We found that the regulation of alternative splicing is different in mesenchymal versus epithelial cells," Garcia-Blanco said. "A particular exon, FGFR2 IIIc, is silenced in mesenchymal cells but is active in epithelial cells.

"We can visualize the genes as they are dynamically changing," he said. "We can define the cell types by observing their splicing patterns."

According to Garcia-Blanco, the cellular switch that is believed to guide the regulation of splicing is a protein called Fox. Both mesenchymal and epithelial cells produce Fox, but the protein is active only in epithelial cells, Garcia-Blanco said.

Fox also may have an accomplice or "co-factor" in or around epithelial cells that prompts it to activate, the researchers said. They speculate that this co-factor could be activated by contact with stroma --the supporting structural cells of a tumor -- because the stroma is where the majority of epithelial-type cancer cells were observed. Their heavy presence implies that the stroma may have induced the cancer cells to revert to epithelial when they reached a new destination, so they could stabilize to populate a new tumor site.

"Our findings validate that tumors are highly complex in their behavior and don't necessarily need a gene mutation to alter their behavior," said Sebastian Oltean, M.D., Ph.D., research associate and first author of the journal article.

"Alterations in gene splicing can be much more subtle in nature but still have a major impact on the cancer cell and can be targets of therapy."

The team's next step is to determine precisely what controls the toggle mechanism in cancer cells, Garcia-Blanco said. Identifying the various steps that occur during the natural progression of tumors could lead to therapies for blocking metastasis, he said.



编辑：bluelove