Neuroendocrine lung carcinogenesis in hamsters is inhibited by green tea or theophylline while the development of adenocarcinomas is promoted: implications for chemoprevention in smokers.
Neuroendocrine lung carcinogenesis in hamsters is inhibited by green tea or theophylline while the development of adenocarcinomas is promoted: implications for chemoprevention in smokers.
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绿茶或茶碱可抑制仓鼠神经内分泌肺癌的发生，同时促进腺癌的发展：对吸烟者化学预防的影响。
DOI：
10.1016/j.lungcan.2003.12.007
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Schmoyer,R
中科院分区：
文献类型：
--
作者：
Schuller,HildegardM;Porter,B;Riechert,A;Walker,K;Schmoyer,R
肺癌仍然是发达国家癌症死亡的主要原因。由于吸烟是肺癌的主要病因，因此非常需要开发化学预防治疗，以抑制戒烟者的初始细胞和癌前病变向显性肺癌的进展。虽然化学预防研究的主要重点一直放在抑制烟草制品中所含遗传毒性化学物质代谢激活的药物上，但其中一些药物可能额外调节生长调节信号转导。反过来，这些信号通路的功能是高度细胞类型特异性的，给定的信号通路抑制一种细胞类型的生长，同时刺激其他细胞类型的生长。本实验验证了绿茶和茶中所含的甲基黄嘌呤茶碱抑制高氧肺损伤仓鼠神经内分泌性肺癌的进展，并由烟草致癌物4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）启动，同时促进由NNK启动的健康仓鼠Clara细胞源性肺腺癌的发展。这一假设是基于已发表的证据，即人类小细胞肺癌和神经内分泌仓鼠肿瘤是通过激活Raf-1和有丝分裂原活化（MAP）激酶途径的自分泌信号通路调节的，而Clara细胞谱系的人类肺腺癌和这种癌症类型的仓鼠模型是由β-肾上腺素能通路调节的，包括激活环腺苷3′，5′-单磷酸（cAMP）和花生四烯酸（AA）级联反应。反过来，假设茶碱会抑制raf -1依赖的肿瘤进展，同时促进camp依赖的肿瘤进展，因为它有文献记载的抑制camp -磷酸二酯酶的能力。实验设计模拟前吸烟者的化学预防，在用NNK完成10周的肿瘤诱导期后开始用茶或茶碱治疗。我们的数据显示，绿茶和茶碱在神经内分泌癌模型中显著抑制肺肿瘤的多样性，而相同的化学预防治疗在腺癌模型中显著促进肺肿瘤的多样性。这些发现表明，绿茶和茶碱以及其他调节信号转导的化学预防剂可能对不同组织病理和细胞谱系的癌症具有相反的作用。在目前的知识水平下，这种化学预防治疗只能作为在病理和分子水平上已经充分表征的癌症的辅助治疗。
Lung cancer continues to be the leading cause of cancer death in developed countries. With smoking the major etiological factor for lung cancer, there is a great need for the development of chemopreventive treatments that inhibit the progression of initiated cells and premalignant lesions into overt lung cancer in smokers who quit. Although the major focus of chemoprevention research has been on agents that inhibit the metabolic activation of genotoxic chemicals contained in tobacco products, some of these agents may additionally modulate growth-regulating signal transduction. In turn, the function of such signaling pathways is highly cell type-specific, with a given pathway inhibiting the growth of one cell type while stimulating the growth of others. The current experiment has tested the hypothesis that green tea and the methylxanthine theophylline contained in tea inhibit the progression of neuroendocrine lung carcinogenesis in hamsters with hyperoxic lung injury and initiated with the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) while promoting the development of Clara cell-derived pulmonary adenocarcinomas initiated by NNK in healthy hamsters. This hypothesis is based on published evidence that human small cell lung cancer as well as the neuroendocrine hamster tumors are regulated via autocrine signaling pathways that activate Raf-1 and the mitogen-activated (MAP) kinase pathway whereas human pulmonary adenocarcinomas of Clara cell lineage and the hamster model of this cancer type are regulated by a β-adrenergic pathway involving the activation of cyclic adenosine 3′,5′-monophosphate (cAMP) and the arachidonic acid (AA) cascade. In turn, it was hypothesized that theophylline would inhibit Raf-1-dependent tumor progression while promoting cAMP-dependent tumor progression due to its documented ability to inhibit the enzyme cAMP-phophodiesterase. The experimental design simulated chemoprevention in former smokers in that treatments with tea or theophylline started after completion of a 10-week tumor induction period with NNK. Our data show that green tea as well as theophylline significantly inhibited lung tumor multiplicity in the neuroendocrine cancer model whereas identical chemopreventive treatments significantly promoted the lung tumor multiplicity in the adenocarcinoma model. These findings indicate that green tea and theophylline as well as other chemopreventive agents that modulate signal transduction may have opposite effects on cancers of different histolopathology and cell lineage. At the current state of knowledge such chemopreventive treatments should only be used as adjuvant to cancer therapy of cancers that have been fully characterized at the pathology and molecular level.