Progression to steroid autonomy is a major clinical problem in the treatment of steroid-sensitive tumours. Molecular mechanisms remain unknown but recent hypotheses imply a role for growth factors in this progression. Since S115 + A androgen-responsive mouse mammary tumour cells provide a model system to study this phenomenon in vitro, we have used this model to investigate growth factor gene expression and sensitivity during progression from a steroid sensitive to insensitive state. S115 + A androgen-responsive cells showed a positive proliferative response, morphological response and increased saturation density to various forms of fibroblast growth factor (FGF) and transforming growth factor beta (TGF beta) in both monolayer and suspension culture. A marked synergy was noted, however, between FGF and TGF beta in promoting growth in suspension culture. S115 + A cells possessed mRNA for both acidic FGF (aFGF) and TGF beta 1, both of which were increased by testosterone. Progression to androgen insensitivity was associated with a reversal of growth factor response such that all growth factor responses became generally inhibitory on growth of the unresponsive cells but with a particularly striking synergistic action between FGF and TGF beta 1 on inhibition of both monolayer and suspension growth. Levels of aFGF and TGF beta 1 mRNAs remained low in steroid-insensitive S115-A cells, indicating that loss of response was not associated with any constitutive upregulation of endogenous production of one of these growth factors. The scientific and clinical implications are discussed.

译文

进展到类固醇自主性是治疗类固醇敏感性肿瘤的主要临床问题。分子机制仍然未知,但最近的假设暗示生长因子在这一进程中的作用。由于S115 + 雄激素反应性小鼠乳腺肿瘤细胞提供了一个模型系统来在体外研究这种现象,我们已经使用该模型来研究生长因子基因表达和从类固醇敏感到不敏感状态的过程中的敏感性。在单层和悬浮培养中,S115 A雄激素反应细胞对各种形式的成纤维细胞生长因子 (FGF) 和转化生长因子 β (TGF β) 均显示出阳性的增殖反应,形态反应和饱和密度增加。然而,在促进悬浮培养的生长方面,FGF和TGF β 之间存在明显的协同作用。S115 A细胞同时具有酸性FGF (aFGF) 和tgfβ1的mRNA,两者均被睾丸激素增加。对雄激素不敏感的进展与生长因子反应的逆转有关,因此所有生长因子反应通常都抑制无反应细胞的生长,但在FGF和tgfβ1之间具有特别显着的协同作用,抑制单层和悬浮液的生长。在类固醇不敏感的S115-A细胞中,aFGF和tgfβ1 mrna的水平仍然很低,这表明反应的丧失与这些生长因子之一的内源性产生的任何组成性上调无关。讨论了科学和临床意义。

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