Distinct Osteomimetic Response of Androgen-Dependent and Independent Human Prostate Cancer Cells to Mechanical Action of Fluid Flow: Prometastatic Implications
Distinct Osteomimetic Response of Androgen-Dependent and Independent Human Prostate Cancer Cells to Mechanical Action of Fluid Flow: Prometastatic Implications
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DOI：
10.1002/pros.23270
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发表时间：
2017-02-15
期刊：
影响因子：
2.8
通讯作者：
Vidal-Vanaclocha, Fernando
中科院分区：
文献类型：
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作者：
Gonzalez, Alvaro;Garcia de Durango, Cira;Vidal-Vanaclocha, Fernando
背景和方法。前列腺癌经常表达拟骨表型，但尚不清楚它是如何调节的以及它具有什么生物学和临床意义。由于机械力在生理上调节骨细胞中的骨重塑活动，因此我们假设癌症微环境中流体流动（MAFF）的机械作用可能类似地促进前列腺癌细胞拟骨。结果。我们发现，体外 MAFF 对雄激素依赖性 (LNCap) 和雄激素非依赖性 (PC3) 前列腺癌细胞显着增加了两种细胞系中 OPG、VEGF、RunX2、PTH1R 和 PTHrP 基因的表达，无论其雄激素依赖性如何。 MAFF 还改变了前列腺癌细胞的细胞因子分泌模式，包括两种细胞系上清液中 Ang2、SCF 和 TNF α 的增加以及 TRAIL 的减少； LnCap 中的瘦素和 PDGF-BB 以及 PC3 中的 VEGF、IL-8 和 G-CSF 优先增加； LnCap 中 FGFb、MIF 和 PECAM-1 独家增加，而 HGF 减少；PC3 中，TGBb1、HGF、M-CSF、CXCL1 和 CCL7 独家增加，NGF 减少。鼠MLO-Y4骨细胞条件培养基(CM)消除了机械刺激对PC3细胞的M-CSF、G-CSG、IL-8、TNFa和FGFb分泌刺激活性，并对LnCap细胞产生相反的作用。然而，MAFF 促进了 PC3 细胞而非 LnCap 细胞对机械刺激的骨细胞-CM 的拟骨基因表达反应。此外，它消除了骨细胞-CM对机械刺激的PC3细胞的TNFa和IL-8分泌抑制作用以及对机械刺激的LnCap细胞的G-CSF、TNFα和FGFb刺激作用。结论。 MAFF 激活前列腺癌细胞的成骨细胞样表型，并改变它们对骨细胞可溶性因子的反应。它还诱导骨细胞产生前列腺癌细胞的拟骨基因表达和细胞因子分泌刺激因子，特别是当它们受到机械刺激时。重要的是，MAFF 在雄激素非依赖性前列腺癌细胞中诱导了促转移反应，这表明机械刺激依赖性转录和分泌模式作为诊断生物标志物的兴趣，以及作为筛选在癌症微环境中前列腺癌细胞对 MAFF 反应期间上调的骨转移表型抑制剂的治疗靶标。 (C) 2016 年 Wiley 期刊公司。
BACKGROUND AND METHODS. Prostate cancer frequently expresses an osteomimetic phenotype, but it is unclear how it is regulated and what biological and clinical implications it confers. Because mechanical forces physiologically regulate bone-remodeling activity in osteocytes, we hypothesized that mechanical action of fluid flow (MAFF) at the cancer microenvironment may similarly foster prostate cancer cell osteomimicry.RESULTS. We showed that in vitro MAFF on androgen-dependent (LNCap) and androgen-independent (PC3) prostate cancer cells remarkably increased OPG, VEGF, RunX2, PTH1R, and PTHrP gene expression in both cell lines irrespective of their androgen dependency. MAFF also altered the cytokine secretion pattern of prostate cancer cells, including Ang2, SCF, and TNF alpha increase with TRAIL decrease in the supernatant of both cell lines; preferential increase of Leptin and PDGF-BB in LnCap and of VEGF, IL-8, and G-CSF in PC3; and exclusive increase of FGFb, MIF, and PECAM-1 with HGF decrease in LnCap, and of TGBb1, HGF, M-CSF, CXCL1, and CCL7 with NGF decrease in PC3. Murine MLO-Y4 osteocyte-conditioned medium (CM) abrogated M-CSF, G-CSG, IL-8, TNFa, and FGFb secretion-stimulating activity of mechanical stimulation on PC3 cells, and did the opposite effect on LnCap cells. However, MAFF fostered osteomimetic gene expression response of PC3 cells, but not of LnCap cells, to mechanically stimulated osteocyte-CM. Moreover, it abrogated TNFa and IL-8 secretion inhibitory effect of osteocyte-CM on mechanically stimulated PC3 cells and G-CSF, TNF alpha, and FGFb-stimulating effect on mechanically stimulated LnCap cells.CONCLUSIONS. MAFF activated osteoblast-like phenotype of prostate cancer cells and altered their responses to osteocyte soluble factors. It also induced osteocyte production of osteomimetic gene expression-and cytokine secretion-stimulating factors for prostate cancer cells, particularly, when they were mechanically stimulated. Importantly, MAFF induced a prometastatic response in androgen-independent prostate cancer cells, suggesting the interest of mechanical stimulation-dependent transcription and secretion patterns as diagnostic biomarkers, and as therapeutic targets for the screening of bone-metastasizing phenotype inhibitors upregulated during prostate cancer cell response to MAFF at the cancer microenvironment. (C) 2016 Wiley Periodicals, Inc.