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CANCER CELL:慢性炎症致癌机制揭开

2012-12-04 CANCER CELL CANCER CELL

  据EurekAlert!网站近日报道,虽然以往的科研证实,慢性炎症有可能导致癌症,但这是如何发生的,科学家并不知晓。而美国俄亥俄州立大学综合癌症中心进行的一项新研究显示,人体制造的一种类似于激素的炎症促进物质在处于高水平时,能够引发一种恶性血癌的产生。相关研究报告发表在近期出版的《癌细胞》杂志上。   这项研究表明,仅高水平的白细胞介素15(IL-15)一项就可在动物模型中导致大颗粒淋巴细胞

  据EurekAlert!网站近日报道,虽然以往的科研证实,慢性炎症有可能导致癌症,但这是如何发生的,科学家并不知晓。而美国俄亥俄州立大学综合癌症中心进行的一项新研究显示,人体制造的一种类似于激素的炎症促进物质在处于高水平时,能够引发一种恶性血癌的产生。相关研究报告发表在近期出版的《癌细胞》杂志上。

  这项研究表明,仅高水平的白细胞介素15(IL-15)一项就可在动物模型中导致大颗粒淋巴细胞白血病的发生,这是一种罕见却常常致命的癌症。科研人员发现,IL-15在患有大颗粒淋巴细胞白血病的患者体内处于过度表达状态,也是它导致了类似的细胞变化。通常,体内会释放IL-15来刺激天然杀手细胞,即可破坏癌细胞和被病毒感染细胞的免疫细胞的发育、生存和增殖。这一研究证实,当IL-15在体内长期以高量水平存在时,例如在病人患有慢性炎症期间,其可能导致名为大颗粒淋巴细胞的特定免疫细胞转变成为癌细胞。

  这种癌变开始于IL-15与正常的人类大颗粒淋巴细胞表面上的受体结合时,这一事件会提升细胞内部的致癌蛋白质Myc的水平。而高水平的Myc反过来也会带来相关变化,引起染色体的不稳定和额外的基因突变。同时,其还会激活DNA甲基化过程,这个过程将关闭各种各样的基因,其中就包括会抑制癌症生长的重要基因。

  研究负责人、综合癌症中心的主任迈克尔·卡利朱里博士谈到:“我们知道炎症可以导致癌症,但却不知道其准确的机制。这次的研究展示了恶性白血病可能发生的一种方式,当我们了解它的产生原因时,就可能开发出相应疗法,干扰这个过程,并最终治愈癌症。”

  该校药剂学和药物化学教授罗伯特·李就根据研究获取的信息,开发出了一种蛋白酶体抑制剂硼替佐米的脂质体剂型。它能关闭致癌路径,有可能治愈这种恶性疾病。




Highlights
A single pro-inflammatory cytokine, IL-15, can initiate malignant transformation
IL-15-mediated induction of Myc is central to the genesis of leukemia
Targeting miR-29b with a single therapeutic induces long-term remission of leukemia

Summary
How inflammation causes cancer is unclear. Interleukin-15 (IL-15) is a pro-inflammatory cytokine elevated in human large granular lymphocyte (LGL) leukemia. Mice overexpressing IL-15 develop LGL leukemia. Here, we show that prolonged in vitro exposure of wild-type (WT) LGL to IL-15 results in Myc-mediated upregulation of aurora kinases, centrosome aberrancies, and aneuploidy. Simultaneously, IL-15 represses miR-29b via induction of Myc/NF-κBp65/Hdac-1, resulting in Dnmt3b overexpression and DNA hypermethylation. All this is validated in human LGL leukemia. Adoptive transfer of WT LGL cultured with IL-15 led to malignant transformation in vivo. Drug targeting that reverses miR-29b repression cures otherwise fatal LGL leukemia. We show how excessive IL-15 initiates cancer and demonstrate effective drug targeting for potential therapy of human LGL leukemia.
    

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    2013-04-28 维他命
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    2012-12-06 jambiya

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