Singh Shailesh, Singh Udai P, Grizzle William E, Lillard James W
Morehouse School of Medicine, Atlanta, GA 30310, USA.
Lab Invest. 2004 Dec;84(12):1666-76. doi: 10.1038/labinvest.3700181.
The mechanisms responsible for prostate cancer metastasis are incompletely understood at both the cellular and molecular levels. In this regard, chemokines are a family of small, cytokine-like proteins that induce motility of neoplastic cells, leukocytes and cancer cells. The current study evaluates the molecular mechanisms of CXCL12 and CXCR4 in prostate cancer cell migration and invasion. We report that functional CXCR4 is significantly expressed by prostate cancer cell lines, LNCaP and PC3, when compared with normal prostatic epithelial cells (PrEC). As measured using motility and invasion chamber assays, prostate cancer cells migrated and invaded through extracellular matrix components in response to CXCL12, at rates that corresponded to CXCR4 expression. Anti-CXCR4 antibodies (Abs) significantly impaired the migration and invasive potential of PC3 and LNCaP cells. CXCL12 induction also enhanced collagenase-1 (metalloproteinase-1 (MMP-1)) expression by LNCaP and PC3 cells. Collagenase-3 (MMP-13) was expressed by prostate cancer cells, but it was not expressed by PrEC cells or modulated by CXCL12. CXCL12 increased MMP-2 expression by LNCaP and PC3; however, MMP-9 expression was elevated only in PC3 cells after CXCL12-CXCR4 ligation. PC3 cells also expressed high levels of stromelysin-1 (MMP-3) after CXCL12 stimulation. CXCL12 also significantly increased stromelysin-2 (MMP-10) expression by LNCaP cells. Stromelysin-3 (MMP-11) was expressed by LNCaP cells, but not by PC3 or PrEC cells and CXCL12 induced PC3 MMP-11 expression. Membrane type-1 MMP (MMP-14) was not expressed by PrEC or LNCaP cells, but CXCL12 significantly enhanced MMP-14 expression by PC3 cells. These studies reveal important cellular and molecular mechanisms of CXCR4/CXCL12-mediated prostate cancer cell migration and invasion.
在细胞和分子水平上，前列腺癌转移的机制尚未完全明确。在这方面，趋化因子是一类小分子、细胞因子样蛋白，可诱导肿瘤细胞、白细胞和癌细胞的运动。本研究评估了CXCL12和CXCR4在前列腺癌细胞迁移和侵袭中的分子机制。我们报告，与正常前列腺上皮细胞（PrEC）相比，前列腺癌细胞系LNCaP和PC3显著表达功能性CXCR4。使用运动和侵袭小室分析测定，前列腺癌细胞响应CXCL12迁移并穿过细胞外基质成分，其速率与CXCR4表达相对应。抗CXCR4抗体（Abs）显著损害PC3和LNCaP细胞的迁移和侵袭潜能。CXCL12诱导还增强了LNCaP和PC3细胞中胶原酶-1（金属蛋白酶-1（MMP-1））的表达。前列腺癌细胞表达胶原酶-3（MMP-13），但PrEC细胞不表达，且不受CXCL12调节。CXCL12增加了LNCaP和PC3中MMP-2的表达；然而，在CXCL12-CXCR4结合后，仅PC3细胞中的MMP-9表达升高。CXCL12刺激后，PC3细胞也高水平表达基质溶解素-1（MMP-3）。CXCL12还显著增加了LNCaP细胞中基质溶解素-2（MMP-10）的表达。LNCaP细胞表达基质溶解素-3（MMP-11），但PC3或PrEC细胞不表达，CXCL12诱导PC3表达MMP-11。膜型-1 MMP（MMP-14）在PrEC或LNCaP细胞中不表达，但CXCL12显著增强了PC3细胞中MMP-14的表达。这些研究揭示了CXCR4/CXCL12介导的前列腺癌细胞迁移和侵袭的重要细胞和分子机制。
