DNA靶向抗肿瘤药物对肿瘤细胞核变形能力的影响

The interaction of cell organelles with topographically patterned materials has recently emerged as a new topic in the field of biomaterials. In particular, micrometer-sized surface features are of an appropriate scale for the interaction with organelles. Our group observed that the nuclei of rat bone marrow stromal cells (BMSCs) cultured on poly D,L-lactide-co-glycolide (PLGA) micropillars were deformed severely. Despite severe deformation of cell nuclei, BMSCs were able to proliferate and differentiate. The nuclear deformation behavior of other cell types was further investigated. My preliminary research revealed that the nuclear deformation extent of Hela cells was increased when treated with an anticancer drug doxorubicin. We were inspired by the nuclear deformation phenomenon to further consider its application in the field of biomedicine, and hypothesized that anticancer drugs targeting the DNA molecules of cell nucleus might affect the nuclear deformation degree of cancer cells. My recent experiments using doxorubicin as a model drug confirmed this hypothesis preliminarily, and extensive investigations are thus much desired. The change of nuclear morphological and mechanical plasticity during neoplastic transformation may represent a central determination of cell mobility during pathologic invasion and recirculation. Metastasis, as the culprit behind most cancer-related deaths, is the ultimate challenge in our effort to fight cancer as a life-threatening disease. Thus it is necessary to study the influence of anticancer drugs on the nuclear deformation and metastasis of cancer cells, which is the aim of this project. The correlation between the cell nuclear deformability and metastasis potential will be revealed. We were activated to further examine the interactions between the cancer cell nuclei and the polymeric materials. New strategy to screen anticancer drugs to treat the metastatic migration of cancer cells will be generated by exploring the actions of anticancer drugs on the cancer cell nuclear deformation and metastatic behaviors.

细胞器与材料的相互作用是近年来生物材料领域逐渐兴起的研究课题。我们课题组在实验过程中意外发现细胞核在聚合物微柱阵列上发生了严重的自我变形。在此基础上，申请人发现Hela细胞在药物阿霉素作用下细胞核变形程度增加，促使我们进一步思考细胞核变形现象在生物医学研究中的意义。由于细胞核形状及机械力学塑性的改变是肿瘤细胞转移通过致密3D组织的一个关键因素，而转移是多数肿瘤治疗失败的原因，因而有必要关注药物对肿瘤细胞核变形及转移过程的影响。本课题拟研究肿瘤细胞在DNA靶向抗肿瘤药物作用下的细胞核变形行为，探索药物对肿瘤细胞核变形及细胞转移能力的影响，获得药物和聚合物材料与细胞核之间相互作用的规律，构建用于筛选适用于转移阶段抗肿瘤药物的新方法。

细胞能够对所接触的材料表面做出响应，包括细胞黏附、迁移、增殖和分化等。微柱阵列提供了细胞与材料相互作用的独特界面。我们课题组在实验过程中意外发现细胞核在聚合物微柱阵列上发生了严重的自我变形，这一现象引起了我们的兴趣，并在课题执行期间，我们探究了细胞核变形的有关规律，发现如下：.1）细胞核在微柱阵列上能够发生细胞核变形，细胞核变形程度与微柱高度之间符合一级转变关系。使细胞核发生变形的微柱关键高度为3.12 m。细胞核在微柱阵列上，其形状处于动态变化中，通过长时间的观察分析，可以将该形变过程大致分为两个阶段：早期受细胞黏附物理因素介导的过冲形变，以及晚期受细胞分裂增殖以及可能由细胞内在信号传导导致的部分回复的形变。.2）细胞核变形及细胞增殖均呈现细胞种类依赖性。上皮样细胞比成纤维样的细胞核变形程度更为严重。Hela和MC3T3-E1细胞在微柱上的增殖受到一定程度的抑制，而HepG2和 NIH3T3细胞在微柱上的增殖不受影响。进一步分析表明细胞在微柱上的增殖受到抑制与细胞核尺寸减小有关。.3）在微柱阵列表面上骨髓基质干细胞更利于向成骨方向分化。.4）细胞加DNA 靶向抗肿瘤药物阿霉素处理后，其细胞核变形能力有所增强；药物处理引起细胞增殖受到抑制，但其在微柱阵列和光滑表面上的增殖速率没有差异。. 以上结果对于聚合物微柱材料在组织工程和肿瘤治疗领域具有指导作用。