Schamhart D H, Kurth K H
Department of Urology, University of Amsterdam, The Netherlands.
Urol Res. 1997;25 Suppl 2:S89-96. doi: 10.1007/BF00941994.
Development and progression of prostate cancer is a multistep process of cumulative genetic damage, acquired during a life-time. However, the altered genotype acts against an appropriate background of epigenetic control mechanisms. Several mechanisms of mitotically heritable, epigenetic control of differential gene transcription have been noted, such as stromal-epithelial and cell-cell interactions. In prostate cancer, an important, supporting and/or inhibiting role of stromal-epithelial interaction has been implicated in tumor growth, angiogenesis and metastasis, which includes cell proliferation, adhesion and motility. Within these processes, data mainly obtained in systems other than the prostate have shown a crucial (regulatory) role of proteoglycans (PGs) acting at the level of cell-cell and cell-pericellular matrix interactions. Although little information has been recorded from normal, benign hyperplastic and malignant prostate tissue, PGs are components of both the cell surface and the extracellular matrix (ECM) that form associations with other molecules, such as fibronectin and laminin. On the basis of cell-ECM adhesion/interaction as a prerequisite for both cell proliferation and motility, and the involvement of PGs, the purpose of this study was to investigate the possible biological relevance of (free) glycosaminoglycans (GAGs), as major functional substructures of PGs, on cell adhesion of a series of human prostatic cell lines cultured in vitro. The effects of a series of exogenously applied GAGs on cell adhesion and proliferation were studied in the human cell lines LNCaP, DU 145 and PC-3, cultured on tissue culture plastic as substratum. The applied GAGs were the natural GAGs heparin, heparan, dermatan, chondroitin-4 and chondroitin-6 sulfate, and the semisynthetic, GAG-like pentosan polysulfate (PPS). Addition of GAGs (1-300 micrograms/ml) to cultures that were allowed to adhere for 24 h prior to GAG addition did not affect cell proliferation. In contrast, whereas the natural GAG added during cell adhesion had no effect. PPS strongly inhibited proliferation of LNCaP and DU145, but not the less anchorage-dependent PC-3 cells. Under the latter conditions, after 6 days of culturing the IC50 of proliferation were determined to be < 1 and 50 micrograms PPS/ml for LNCaP and DU145, respectively, corresponding with a profound effect on cell morphology. Direct measurements of cell adhesion confirmed that, in contrast to the natural GAGs, PPS inhibited cell adhesion. In conclusion, the interference of a nonnatural, GAG-like structure with cell adhesion may be interpreted as the involvement of PGs of the cell surface in cell adhesion, possibly affecting the various processes (proliferation, angiogenesis and metastasis) of prostate tumor progression. Although similar interferences of nonnatural GAGs with cell-adhesion-associated proliferation of anchorage-dependent cells remain to be established under in vivo conditions, this type of compounds deserves further attention as a tool with which to study the role of cell adhesion in the progression of prostate cancer and as a potential candidate for the development of a stromal-epithelial targeted therapy.
前列腺癌的发生和发展是一个在一生中累积遗传损伤的多步骤过程。然而,改变的基因型是在表观遗传控制机制的适当背景下起作用的。已经注意到几种有丝分裂可遗传的、对差异基因转录进行表观遗传控制的机制,如基质 - 上皮和细胞 - 细胞相互作用。在前列腺癌中,基质 - 上皮相互作用在肿瘤生长、血管生成和转移中所起的重要的支持和/或抑制作用,涉及细胞增殖、黏附和迁移。在这些过程中,主要在前列腺以外的系统中获得的数据表明蛋白聚糖(PGs)在细胞 - 细胞和细胞 - 周细胞基质相互作用水平上起着关键(调节)作用。尽管从正常、良性增生和恶性前列腺组织中记录的信息很少,但PGs是细胞表面和细胞外基质(ECM)的组成部分,它们与其他分子如纤连蛋白和层粘连蛋白形成关联。基于细胞 - ECM黏附/相互作用是细胞增殖和迁移的先决条件以及PGs的参与,本研究的目的是调查(游离)糖胺聚糖(GAGs)作为PGs的主要功能亚结构,对一系列体外培养的人前列腺细胞系的细胞黏附可能具有的生物学相关性。在以组织培养塑料为基质培养的人细胞系LNCaP、DU 145和PC - 3中,研究了一系列外源性应用的GAGs对细胞黏附和增殖的影响。应用的GAGs是天然GAGs肝素、硫酸乙酰肝素、硫酸皮肤素、硫酸软骨素 - 4和硫酸软骨素 - 6,以及半合成的、类似GAG的聚硫酸戊聚糖(PPS)。在添加GAGs之前允许细胞黏附24小时的培养物中添加GAGs(1 - 300微克/毫升)不影响细胞增殖。相反,在细胞黏附期间添加天然GAGs没有效果,而PPS强烈抑制LNCaP和DU145的增殖,但对锚定依赖性较小的PC - 3细胞没有抑制作用。在后一种条件下,培养6天后,LNCaP和DU145增殖的IC50分别测定为<1和50微克PPS/毫升,这对细胞形态有深远影响。细胞黏附的直接测量证实,与天然GAGs相反,PPS抑制细胞黏附。总之,一种非天然的、类似GAG的结构对细胞黏附的干扰可能被解释为细胞表面的PGs参与细胞黏附,这可能影响前列腺肿瘤进展的各种过程(增殖、血管生成和转移)。尽管在体内条件下非天然GAGs对锚定依赖性细胞与细胞黏附相关的增殖的类似干扰仍有待确定,但这类化合物作为研究细胞黏附在前列腺癌进展中的作用的工具以及作为基质 - 上皮靶向治疗开发的潜在候选物值得进一步关注。