Fiorentini Chiara, Facchetti Marco, Finardi Alessandra, Sigala Sandra, Páez-Pereda Marcelo, Sher Emanuele, Spano PierFranco, Missale Cristina
Division of Pharmacology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Via Valsabbina 19, 25124 Brescia, Italy.
Eur J Endocrinol. 2002 Sep;147(3):371-9. doi: 10.1530/eje.0.1470371.
Nerve growth factor (NGF) has antiproliferative and differentiating effects in neuroendocrine tumors. In cell lines derived from small cell lung cancer (SCLC), NGF treatment stimulates NGF receptor expression, activates NGF secretion, inhibits proliferation and abrogates invasion. Since these effects are lost upon NGF withdrawal, it is relevant to identify other differentiation factors that may co-operate with the NGF system to control SCLC growth and differentiation.
Retinoic acid (RA), which has been shown to inhibit cell transformation and proliferation, modulates the expression of NGF receptors and the sensitivity to NGF in different cell models. In the present study, we have investigated whether NGF and RA may interact to control the proliferation of SCLC cell lines.
SCLC cells were exposed to 50 ng/ml NGF or 1 microM all-trans RA for different times. Cell proliferation was measured by the [(3)H]thymidine incorporation test and NGF receptor expression was evaluated by immunofluorescence.
We found that RA increased the expression of both trkA and p75 NGF receptors in NCI-N-592 and GLC8 cell lines and prevented the loss of both NGF production and NGF receptor expression occurring when NGF treatment was discontinued. As a result, RA, which did not inhibit the proliferation of untreated cells, abolished NGF withdrawal-related increase in cell proliferation both in vitro and in vivo, thus making permanent the antiproliferative effects of NGF.
These data suggest that combined treatments with NGF and RA or mimicking drugs may represent a strategy to be further investigated for the treatment of SCLC.
神经生长因子（NGF）在神经内分泌肿瘤中具有抗增殖和分化作用。在源自小细胞肺癌（SCLC）的细胞系中，NGF处理可刺激NGF受体表达、激活NGF分泌、抑制增殖并消除侵袭。由于这些作用在撤除NGF后会消失，因此识别其他可能与NGF系统协同控制SCLC生长和分化的分化因子具有重要意义。
视黄酸（RA）已被证明可抑制细胞转化和增殖，在不同细胞模型中调节NGF受体的表达以及对NGF的敏感性。在本研究中，我们调查了NGF和RA是否可能相互作用以控制SCLC细胞系的增殖。
将SCLC细胞暴露于50 ng/ml NGF或1 μM全反式视黄酸不同时间。通过[³H]胸腺嘧啶核苷掺入试验测量细胞增殖，并通过免疫荧光评估NGF受体表达。
我们发现RA增加了NCI-N-592和GLC8细胞系中trkA和p75 NGF受体的表达，并防止了停止NGF处理时发生的NGF产生和NGF受体表达的丧失。结果，未抑制未处理细胞增殖的RA在体外和体内消除了与NGF撤除相关的细胞增殖增加，从而使NGF的抗增殖作用持久。
这些数据表明，联合使用NGF和RA或模拟药物治疗可能是一种有待进一步研究用于治疗SCLC的策略。
