Spontaneous Metastasis of Prostate Cancer Is Promoted by Excess Hyaluronan Synthesis and Processing
Spontaneous Metastasis of Prostate Cancer Is Promoted by Excess Hyaluronan Synthesis and Processing
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DOI：
10.2353/ajpath.2009.080501
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发表时间：
2009-03-01
影响因子：
6
通讯作者：
Simpson, Melanie A.
中科院分区：
文献类型：
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作者：
Bharadwaj, Alamelu G.;Kovar, Joy L.;Simpson, Melanie A.
细胞外透明质酸 (HA) 及其加工酶透明质酸酶 Hyal1 的积累可预测人类前列腺癌的侵袭性、转移性进展。为了剖析透明质酸合酶 (HAS) 和 Hyal1 在肿瘤发生和转移中的作用，我们选择了单独过表达 HAS2、HAS3 或 Hyal1 的非转移性 22Rv1 前列腺肿瘤细胞，并将这些细胞与表达 Hyal1 + HAS2 或 Hyal1 + HAS3 的共转染子进行比较。原位注射到小鼠体内时，仅表达 HAS 的细胞比载体对照转染子的致瘤性更小。相比之下，共表达 Hyal1 + HAS2 或 Hyal1 + HAS3 的细胞的肿瘤发生率分别增加六倍和两倍以上。荧光和组织学定量显示，所有植入 Hyal1 转染子的小鼠均出现自发性淋巴结转移，并且当 Hyal1 和 HAS 共表达时，淋巴结负担额外增加两倍。仅表达HAS的细胞没有转移。因此，过量的HA合成和加工协同加速前列腺肿瘤细胞获得转移表型。肿瘤内血管分布与肿瘤大小或转移潜力均不相关。细胞周期进程分析显示 Hyal1 表达细胞的倍增时间缩短。在HA过量产生的细胞中，细胞外基质上的粘附和运动均减弱；然而，Hyal1 表达使运动能力增加两倍，Hyal1/HAS 共表达使运动能力增加四到六倍，这与观察到的转移潜力密切一致。这是在相关前列腺癌微环境中对这些酶的首次全面检查。 （Am J Pathol 2009，174：1027-1036；DOI：10.2353/ajpath.2009.080501）
Accumulation of extracellular hyaluronan (HA) and its processing enzyme, the hyaluronidase Hyal1, predicts invasive, metastatic progression of human prostate cancer. To dissect the roles of hyaluronan synthases (HAS) and Hyal1 in tumorigenesis and metastasis, we selected nonmetastatic 22Rv1 prostate tumor cells that overexpress HAS2, HAS3, or Hyal1 individually, and compared these cells with co-transfectants expressing Hyal1 + HAS2 or Hyal1 + HAS3. Cells expressing only HAS were less tumorigenic than vector control transfectants on orthotopic injection into mice. In contrast, cells co-expressing Hyal1 + HAS2 or Hyal1 + HAS3 showed greater than sixfold and twofold Increases in tumorigenesis, respectively. Fluorescence and histological quantification revealed spontaneous lymph node metastasis in all Hyal1 transfectant-implanted mice, and node burden increased an additional twofold when Hyal1 and HAS were co-expressed. Cells only expressing HAS were not metastatic. Thus, excess HA synthesis and processing in concert accelerate the acquisition of a met-static phenotype by prostate tumor cells. Intratumoral vascularity did not correlate with either tumor size or metastatic potential. Analysis of cell cycle progression revealed shortened doubling times of Hyal1-expressing cells. Both adhesion and motility on extracellular matrix were diminished in HA-overproducing cells; however, motility was increased twofold by Hyal1 expression and fourfold to sixfold by Hyal1/HAS co-expression, in close agreement with observed metastatic potential. This is the first comprehensive examination of these enzymes In a relevant prostate cancer microenvironment. (Am J Pathol 2009, 174:1027-1036; DOI: 10.2353/ajpath.2009.080501)