研究人员阐明一种肿瘤抑制物的机制

    德国卡尔斯鲁厄大学彼得·赫里奇博士领导的研究小组最近发现了肿瘤抑制物牟林(merlin)在细胞生长过程中的具体作用。牟林发生突变会引起II型多发性神经纤维瘤，这是一种常见的遗传病，发病特征是出现中枢神经系统的多发性良性肿瘤。该研究报告发表在《基因与发展》杂志上，里面细致描述了肿瘤抑制物牟林发生突变而致癌的途径。

    细胞密度是限制细胞生长的因素之一，正常细胞在特定的空间内增殖，一旦接触到其它细胞或密集的细胞外环境，增殖就自动停止。这种生长接触抑制机制被破坏是导致肿瘤出现的一个主要原因。郝里奇博士和同事们发现牟林在细胞对接触抑制作出反应的过程中起了关键作用。

    以前的研究已经确定了牟林在细胞生长中的负向调控作用。这篇文章则首次阐明了牟林在生长接触抑制中的具体特殊作用。在高细胞密度的情况下，细胞膜形成蛋白CD44的细胞外膜会与包围在邻近增殖细胞周围的细胞基质中的特殊成份相结合。一旦这种情况发生，牟林即脱磷酸化，进而形成CD44的细胞内部份的紧密联接。牟林这种具有活性的形式可以有效地阻止细胞进一步增殖。

    文章提供的数据可以有效地说明缺乏牟林易致癌。II型多发性神经纤维瘤的患者体内的肿瘤都起源于神经胶质细胞，因为这些神经胶质细胞缺乏牟林/CD44的生长调控转换机制，故而细胞的生长接触抑制会被打破。

    尽管这种接触抑制机制只是细胞生长调节的其中一种形式，但研究人员的这一发现无疑将更有助于我们进一步了解肿瘤的生长过程。

    Merlin Tells When To Grow And When To Stop
    An international team of scientists lead by Dr. Peter Herrlich at the University of Karlsruhe in Germany has discovered how the tumor suppressor, merlin, functions. Mutations in merlin cause Neurofibromatosis type 2 (NF2), a common inherited disorder that features the predisposition to develop multiple benign tumors of the central nervous system. Published in Genes & Development, this work delineates the pathway by which cells that are mutant in merlin become tumorigenic.

    Cell density is one of several growth-limiting parameters. Normal cells proliferate until they occupy the space allotted to them, and stop proliferating once they contact other cells or a dense extracellular environment. Overcoming this contact growth inhibition is an integral aspect of cancer induction. Dr. Herrlich and colleagues have found that merlin is a key component of the mechanism by which a cell responds to contact inhibition.

    Although previous studies have identified merlin as a negative regulator of cell growth, this paper is the first documentation of merlin‘s specific role in the contact inhibition of growth. Under high cell density conditions, the extracellular portion of the cell membrane-spanning protein, CD44, binds to a specific component of the matrix that surrounds adjacent proliferating cells. Dr. Herrlich and colleagues have shown that once this occurs, merlin becomes desphosphorylated, and forms a tight bond with the intracellular portion of CD44. This activated form of merlin effectively blocks further cell proliferation.

    The data presented in this paper has significant implications for the understanding of how merlin deficiency contributes to tumorigenesis. NF2 patients display multiple tumors derived from glial cells. This work suggests that because these glial cells lacked the merlin/CD44 growth regulatory switch, they were able to overcome contact growth inhibition.

    Although contact inhibition is only one form of cell growth regulation, the insight that Dr. Herrlich and colleagues have provided into the mechanism of contact growth inhibition will undoubtedly improve our understanding of cancer development.

    Source: Cold Spring Harbor Laboratory