Kosaki R, Watanabe K, Yamaguchi Y
The Burnham Institute, La Jolla, California 92037, USA.
Cancer Res. 1999 Mar 1;59(5):1141-5.
Hyaluronan (HA) has long been implicated in malignant transformation and tumor progression. However, due to the lack of molecular tools to directly manipulate production of HA, which does not require a core protein for its synthesis, our understanding of the role of HA in tumor cells has been largely circumstantial. In this study, we genetically manipulated the production of HA by transfection of a mammalian HA synthase Has2 into human HT1080 cells and examined the malignant phenotype of transfected cells. We found that increased production of HA promotes anchorage-independent growth and tumorigenicity of the cells. Has2-transfected cells formed greater numbers of colonies in semisolid medium. Tumors in nude mice derived from Has2-transfected cells grew more rapidly and were 2-4 times larger than those derived from control cells at termination of experiments. Histological and biochemical analyses of tumors revealed no significant differences in cell density and tissue structures between them, indicating that the larger size of the tumors was due to enhanced cell proliferation, not to increased accumulation of tumor stroma or increased angiogenesis. These results demonstrate that HA production by tumor cells per se promotes proliferation of these cells in tissues and provides direct evidence for the role of HA in tumorigenicity.
长期以来，透明质酸（HA）一直被认为与恶性转化和肿瘤进展有关。然而，由于缺乏直接操纵HA产生的分子工具（HA的合成不需要核心蛋白），我们对HA在肿瘤细胞中作用的理解大多是间接的。在本研究中，我们通过将哺乳动物透明质酸合酶Has2转染到人HT1080细胞中，对HA的产生进行基因操作，并检测转染细胞的恶性表型。我们发现，HA产生的增加促进了细胞的非锚定依赖性生长和致瘤性。Has2转染的细胞在半固体培养基中形成了更多的集落。在实验结束时，源自Has2转染细胞的裸鼠肿瘤生长更快，比源自对照细胞的肿瘤大2至4倍。对肿瘤的组织学和生化分析表明，它们之间的细胞密度和组织结构没有显著差异，这表明肿瘤较大是由于细胞增殖增强，而不是肿瘤基质积累增加或血管生成增加。这些结果表明，肿瘤细胞自身产生的HA促进了这些细胞在组织中的增殖，并为HA在致瘤性中的作用提供了直接证据。
