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PNAS:阻断癌细胞与正常细胞的交流

  1. 癌细胞
  2. 硫酸乙酰肝素蛋白多糖
  3. 胞吐小体

来源:生物谷 2013-10-18 14:29

2013年10月18日讯 /生物谷BIOON/--发表在PNAS杂志上的文章称,瑞典隆德大学科学家发现癌细胞采用胞吐小体(exosomes)与周围细胞进行交流,并在模型动物中成功阻断该过程抑制癌症恶化。 胞吐小体是一种小型类似病毒样的颗粒,能够在细胞间进行遗传物质,蛋白质的转运。近些年胞吐小体在肿瘤研究领域的重要性慢慢突显,之前研究显示阻断癌细胞内的胞吐小体的产生能够延缓癌症发育。

2013年10月18日讯 /生物谷BIOON/--发表在PNAS杂志上的文章称,瑞典隆德大学科学家发现癌细胞采用胞吐小体(exosomes)与周围细胞进行交流,并在模型动物中成功阻断该过程抑制癌症恶化。

胞吐小体是一种小型类似病毒样的颗粒,能够在细胞间进行遗传物质,蛋白质的转运。近些年胞吐小体在肿瘤研究领域的重要性慢慢突显,之前研究显示阻断癌细胞内的胞吐小体的产生能够延缓癌症发育。

在本次研究中,隆德大学科学家揭示了胞吐小体从释放细胞到接收细胞的整个旅程,并找到了阻断细胞接收胞吐小体的方法。Mattias Belting博士称,我们阻断了胞吐小体进入细胞之路,该方法对未来癌症治疗有重要意义。

科学家发现硫酸乙酰肝素蛋白多糖(heparan sulfate proteoglycans)能够作为胞吐小体的受体,协助它们进入细胞内。进一步发现正是蛋白聚糖的糖链,硫酸乙酰肝素能够捕获细胞表面的胞吐小体。

该文章的第一作者Helena Christianson博士称,之前研究发现硫酸乙酰肝素在细胞摄取不同病毒中起作用,如HIV病毒,疱疹病毒等。而我们发现胞吐小体进入细胞的机制与病毒侵染的方式类型。

Mattias Belting博士称,胞吐小体的研究非常鼓舞人心,我们认为胞吐小体可以作为不同癌症的生物标记物,并可以作为治疗癌症的靶点。(生物谷Bioon.com)

Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity

Christianson HC, Svensson KJ, van Kuppevelt TH, Li JP, Belting M.

Extracellular vesicle (EV)-mediated intercellular transfer of signaling proteins and nucleic acids has recently been implicated in the development of cancer and other pathological conditions; however, the mechanism of EV uptake and how this may be targeted remain as important questions. Here, we provide evidence that heparan sulfate (HS) proteoglycans (PGs; HSPGs) function as internalizing receptors of cancer cell-derived EVs with exosome-like characteristics. Internalized exosomes colocalized with cell-surface HSPGs of the syndecan and glypican type, and exosome uptake was specifically inhibited by free HS chains, whereas closely related chondroitin sulfate had no effect. By using several cell mutants, we provide genetic evidence of a receptor function of HSPG in exosome uptake, which was dependent on intact HS, specifically on the 2-O and N-sulfation groups. Further, enzymatic depletion of cell-surface HSPG or pharmacological inhibition of endogenous PG biosynthesis by xyloside significantly attenuated exosome uptake. We provide biochemical evidence that HSPGs are sorted to and associate with exosomes; however, exosome-associated HSPGs appear to have no direct role in exosome internalization. On a functional level, exosome-induced ERK1/2 signaling activation was attenuated in PG-deficient mutant cells as well as in WT cells treated with xyloside. Importantly, exosome-mediated stimulation of cancer cell migration was significantly reduced in PG-deficient mutant cells, or by treatment of WT cells with heparin or xyloside. We conclude that cancer cell-derived exosomes use HSPGs for their internalization and functional activity, which significantly extends the emerging role of HSPGs as key receptors of macromolecular cargo.

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