Associated changes of lipid peroxidation and transforming growth factor β1 levels in human colon cancer during tumour progression
Associated changes of lipid peroxidation and transforming growth factor β1 levels in human colon cancer during tumour progression
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作者：
Biasi, F;Tessitore, L;Poli, G
背景资料：在肿瘤进展过程中，转化生长因子β 1（TGF-β 1）依赖性细胞生长控制的改变可能是转化细胞克隆选择性增殖的重要机制。据报道，TGF-β 1受体的调节缺陷发生在许多人类恶性肿瘤中，而对这种生长抑制细胞因子在癌症中的实际水平知之甚少。基于已证实的主要脂质过氧化产物如4-羟基壬烯醛调节TGF-β 1表达和合成的能力，我们推测，如在肿瘤组织中经常观察到的，脂质氧化减少将有助于通过降低肿瘤块内细胞因子的表达来选择性促进肿瘤生长。为了寻求在不同生长阶段的人结肠癌中脂质过氧化的主要代谢终产物的稳态水平与TGF-β 1含量之间的可能关联。对15例不同TNM和G分期的结肠腺癌成人患者的组织活检进行了脂质过氧化、醛类和净TGF-β 1水平的比较。为了进行更全面的分析，在肿瘤活检中测量了细胞因子I型和II型受体。在一组实验中，为了支持上述结论，在人结肠癌细胞系CaCo-2中评估了TGF-β 1的凋亡作用，保留了与在癌症患者中观察到的受体变化一致的受体变化。除了两个非常晚期的病例（T4/G3），其中组织脂质过氧化水平在正常范围内，4-羟基壬烯醛在所有其他癌症标本中显著降低。与脂质过氧化水平一致，与所有测试活检中肿瘤周围的相应正常组织相比，TGF-β 1蛋白显著降低甚至可以忽略不计，除了两个T4/G3结肠癌，其中细胞因子含量再次在正常范围内。至于TGF-β 1受体，无论是在肿瘤切片和CaCo-2细胞，下调TGF-β 1受体I大于受体II。值得注意的是，在CaCo-2细胞，孵育适当剂量的TGF-β 1导致显着的核碎裂和apoptosis.Conclusions：逃避人类结肠癌细胞从TGF-β 1介导的生长抑制似乎是由于不仅下调TGF-β 1受体，这是不一致的，无关的癌症的发展，但也是恒定的低浓度的这种细胞因子在肿瘤块。相关的脂质过氧化醛类的水平，远低于对照组织，可能代表了一个较低的刺激TGF-β 1的生产在肿瘤领域，从而为肿瘤进展的有利条件。
Background: During neoplastic progression, alterations in transforming growth factor beta1 (TGF-beta1) dependent control of cell growth may be an important mechanism of selective proliferation of transformed cellular clones. Defective regulation of TGF-beta1 receptors has been reported to occur in a number of human malignant tumours while little is known of the actual levels of this growth inhibitory cytokine in cancer. On the basis of the demonstrated ability of major lipid peroxidation products such as 4-hydroxynonenal to modulate TGF-beta1 expression and synthesis, we speculated that decreased lipid oxidation, as frequently observed in neoplastic tissues, would contribute to the selective promotion of tumour growth through decreased expression of the cytokine within the tumour mass.Aims: To seek a possible association between steady state levels of major aldehydic end products of lipid peroxidation and TGF-beta1 content in human colon cancer at different stages of growth.Patients and methods: Tissue biopsies from 15 adult patients with colon adenocarcinoma of different TNM and G stagings were compared with regard to lipid peroxidation aldehydes and net TGF-beta1 levels. For a more comprehensive analysis, cytokine type I and II receptors were measured in tumour biopsies. In one set of experiments, to support the conclusions, the apoptotic effect of TGF-beta1 was evaluated in a human colon cancer cell line, CaCo-2, retaining receptor changes consistent with those observed in cancer patients.Results: With the exception of two extremely advanced cases (T4/G3) in which tissue levels of lipid peroxidation were within the normal range, 4-hydroxynonenal was significantly decreased in all other cancer specimens. Consistent with lipid peroxidation levels, TGF-beta1 protein was markedly decreased or even negligible compared with the corresponding normal tissue surrounding the tumour in all tested biopsies except for the two T4/G3 colon cancers in which cytokine content was again within the normal range. As regards TGF-beta1 receptors, both in tumour sections and CaCo-2 cells, downregulation was greater for TGF-beta1 receptor I than for receptor II. Of note, in CaCo-2 cells, incubation with appropriate doses of TGF-beta1 led to marked nuclear fragmentation and apoptosis.Conclusions: Evasion of human colon cancer cells from TGF-beta1 mediated growth inhibition appears to be due not only to downregulation of TGF-beta1 receptors, which is inconsistent and unrelated to cancer development, but also to the constant low concentration of this cytokine in the tumour mass. The associated levels of lipid peroxidation aldehydes, much lower than in control tissue, probably represent a lower stimulus for TGF-beta1 production in the neoplastic area and thus a favourable condition for neoplastic progression.