Gene expression of angiogenic factors correlates with metastatic potential of prostate cancer cells
Gene expression of angiogenic factors correlates with metastatic potential of prostate cancer cells
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DOI：
10.1158/0008-5472.can-2506-2
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发表时间：
2004-08-01
期刊：
影响因子：
11.2
通讯作者：
Schwartz, SA
中科院分区：
文献类型：
--
作者：
Aalinkeel, R;Nair, MPN;Schwartz, SA
我们推测促血管生成基因的表达与前列腺癌细胞的转移潜能相关。LNCaP、DU-145和PC-3分别是具有低、中和高转移潜力的前列腺癌细胞系，正如我们通过其侵入细胞外基质的能力（一种已建立的肿瘤侵入测定法）所证明的。与LNCaP细胞相比，在更具转移性的DU-145和PC-3细胞中，促血管生成因子、血管内皮生长因子、细胞间粘附分子-1、白细胞介素-8和转化生长因子-β 2的组成性基因表达显著更高。基质金属蛋白酶（MMP）-9被认为有助于肿瘤细胞的侵袭表型。与LNCaP和DU-145相比，PC-3细胞显示MMP-9和膜型4-MMP的表达增加。DU-145和PC-3细胞中金属蛋白酶组织抑制剂1和4基因表达升高，但矛盾的是，LNCaP细胞中这些基因的水平检测不到。我们转染和过度表达MMP-9在转移性差的LNCaP细胞，并测量其侵袭活性。人MMP-9在LNCaP细胞中的瞬时表达产生MMP-9活性的3-5倍增加，侵袭性相当地增加。反义消融DU-145和PC-3细胞中MMP-9的表达产生伴随的促血管生成因子、血管内皮生长因子和细胞间粘附分子-1（ICAM-1）的基因表达抑制。用MMP-9蛋白酶活性的选择性化学抑制剂处理DU-145和PC-3细胞也抑制其侵袭活性。这些结果支持了我们的假设，前列腺癌细胞的转移潜能与促血管生成因子的表达相关。
We hypothesize that expression of proangiogenic genes correlates with the metastatic potential of prostate cancer cells. LNCaP, DU-145, and PC-3 are prostate cancer cell lines with low, moderate, and high metastatic potential, respectively, as we demonstrated by their capacity to invade an extracellular matrix, an established tumor invasion assay. The constitutive gene expression of the proangiogenic factors, vascular endothelial growth factor, intercellular adhesion molecule-1, interleukin-8, and transforming growth factor-beta2, was significantly greater in the more metastatic DU-145 and PC-3 cells as compared with LNCaP cells. Matrix metalloproteinase (MMP)-9 is thought to contribute to the invasive phenotype of tumor cells. PC-3 cells showed increased expression of MMP-9 and membrane type 4-MMP as compared with LNCaP and DU-145. Tissue inhibitors of metalloproteinase 1 and 4 gene expression were elevated in DU-145 and PC-3 cells, but paradoxically, LNCaP cells had undetectable levels of these genes. We transfected and overexpressed MMP-9 in poorly metastatic LNCaP cells and measured their invasive activity. Transient expression of human MMP-9 in LNCaP cells produced a 3-5-fold increase in MMP-9 activity with a comparable increase in invasiveness. Antisense ablation of the expression of MMP-9 in DU-145 and PC-3 cells produced concomitant inhibition of the gene expression of the proangiogenic factors, vascular endothelial growth factor, and intercellular adhesion molecule-1 (ICAM-1). Treatment of DU-145 and PC-3 cells with a selective chemical inhibitor of MMP-9 proteinase activity also inhibited their invasive activity. These results support our hypothesis that metastatic potential of prostate cancer cells correlates with expression of proangiogenic factors.