Inhibition of prostate tumor cell hyaluronan synthesis impairs subcutaneous growth and vascularization in immunocompromised mice
Inhibition of prostate tumor cell hyaluronan synthesis impairs subcutaneous growth and vascularization in immunocompromised mice
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DOI：
10.1016/s0002-9440(10)64245-9
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发表时间：
2002-09-01
影响因子：
6
通讯作者：
McCarthy, JB
中科院分区：
文献类型：
--
作者：
Simpson, MA;Wilson, CM;McCarthy, JB
透明质酸（HA）是细胞外基质的一种分泌型糖胺聚糖组分，在发育过程中对细胞增殖和运动至关重要。然而，升高的循环和细胞相关水平与各种类型的癌症相关，包括前列腺癌。我们先前已经表明，相对于侵袭性较低的细胞，侵袭性PC 3 M-LN 4前列腺肿瘤细胞合成过量的HA，并相应地表达更高水平的HA生物合成酶HAS 1和HAS 3。通过用反义HAS'或HAS 3表达构建体稳定转染PC 3 M-LN 4细胞来抑制这些酶减少了HA合成和表面保留。在这份报告中，我们使用这些HA缺陷的细胞系来研究HA在致瘤性中的作用。皮下注射透明质酸合成酶（HAS）反义转染细胞的SCID小鼠产生的肿瘤比对照转染子小三倍至四倍。相对于对照，来自HAS反义转染子的肿瘤在组织学上是HA缺陷的。HA缺乏对应于每个肿瘤的细胞数量减少三倍，但凋亡和增殖细胞的数量相当。转染后的细胞凋亡率与对照组相同，但反义抑制HA的合成使细胞生长速度减慢。肿瘤切片内血管密度的定量显示HAS反义肿瘤的血管减少了70 - 80%。总的来说，结果表明，前列腺肿瘤细胞的HAS过表达可能通过增强内在细胞生长速率和促进血管生成来促进其在复杂环境中的生长和增殖。此外，这是第一次报道抑制HA合成在降低肿瘤生长动力学中的作用。
Hyaluronan (HA), a secreted glycosaminoglycan component of extracellular matrices, is critical for cellular proliferation and motility during development. However, elevated circulating and cell-associated levels correlate with various types of cancer, including prostate. We have previously shown that aggressive PC3M-LN4 prostate tumor cells synthesize excessive HA relative to less aggressive cells, and express correspondingly higher levels of the HA biosynthetic enzymes HAS' and HAS3. Inhibition of these enzymes by stable transfection of PC3M-LN4 cells with antisense HAS' or HAS3 expression constructs diminishes HA synthesis and surface retention. In this report, we used these HA-deficient cell lines to examine the role of HA in tumorigenicity. Subcutaneous injection of SCID mice with hyaluronan synthase (HAS) antisense-transfected cells produced tumors threefold to fourfold smaller than control transfectants. Tumors from HAS antisense transfectants were histologically HA-deficient relative to controls. HA deficiency corresponded to threefold reduced cell numbers per tumor, but comparable numbers of apoptotic and proliferative cells. Percentages of apoptotic cells in cultured transfectants were identical to those of control cells, but antisense inhibition of HA synthesis effected slower growth rate of cells in culture. Quantification of blood vessel density within tumor sections revealed 70 to 80% diminished vascularity of HAS antisense tumors. Collectively, the results suggest HAS overexpression by prostate tumor cells may facilitate their growth and proliferation in a complex environment by enhancing intrinsic cell growth rates and promoting angiogenesis. Furthermore, this is the first report of a role for inhibition of HA synthesis in reducing tumor growth kinetics.