文章：

胰岛素样生长因子与肿瘤

Insulin-like growth factors and neoplasia

原文发布日期：2004-07-01

DOI: 10.1038/nrc1387

类型: Review Article

开放获取: 否

要点：

1. Insulin-like growth factor 1 (IGF1) has characteristics of both a circulating hormone and a tissue growth factor.
2. Circulating IGF1 levels vary considerably between normal individuals and there is evidence from epidemiological studies that individuals with levels at the higher end of the normal range have increased cancer risk. As this risk could apply to ∼ 25% of the population, the attributable disease burden might be substantial, even though the relative risk associated with higher IGF1 levels is modest.
3. Laboratory carcinogenesis models have provided data consistent with the population studies.
4. Higher IGF1 levels might be associated with higher risk of a cancer diagnosis because of subtle influences on renewal dynamics of epithelial-cell populations: somatic cells of individuals with higher levels of IGF1 might show slightly higher proliferation rates and have a slightly increased chance of survival in the presence of genetic damage, because of the anti-apoptotic effects of IGF1. This would facilitate stepwise carcinogenesis. Higher IGF1 levels might also reduce the time interval between emergence of a transformed clone of cells and a clinically significant cancer.
5. The syndrome of insulin resistance, characterized by increased insulin levels and obesity, is also associated with increased cancer risk and might involve similar mechanisms.
6. In experimental models, the growth of many established cancers can be inhibited by pharmacological strategies that reduce IGF1-receptor (IGF1R) signalling; this observation will lead to clinical trials of new drug candidates, such as anti-IGF1R antibodies and IGF1R tyrosine kinase inhibitors.
7. Dietary restriction confers protection against carcinogens and extends life expectancy in experimental models; there is evidence that both of these actions involve IGF signalling. Whereas higher levels of IGF signalling are associated with a shorter lifespan in model organisms, at the cellular level IGF1R activation activates anti-apoptotic pathways. A 'rate of living' model reconciles these observations.

要点翻译：

1. 胰岛素样生长因子1（IGF1）兼具循环激素和组织生长因子的特性。
2. 正常个体间的循环IGF1水平存在显著差异，流行病学研究表明，水平处于正常范围上限的个体癌症风险增加。由于这种风险可能涉及约25%的人群，即使较高IGF1水平的相对风险值不高，其相关的疾病负担可能相当重大。
3. 实验室致癌模型提供的数据与人群研究结果一致。
4. 较高IGF1水平可能通过以下机制增加癌症诊断风险：对上皮细胞群更新动态的微妙影响——IGF1水平较高者的体细胞可能呈现略高的增殖速率，且因IGF1的抗凋亡作用，在存在遗传损伤时存活几率略有增加。这将促进渐进性致癌过程。较高IGF1水平还可能缩短转化细胞克隆出现与临床显著癌症形成的时间间隔。
5. 以胰岛素水平升高和肥胖为特征的胰岛素抵抗综合征同样与癌症风险增加相关，可能涉及类似机制。
6. 实验模型中，通过药物策略降低IGF1受体（IGF1R）信号传导可抑制多种已形成癌症的生长；这一发现将推动新候选药物（如抗IGF1R抗体和IGF1R酪氨酸激酶抑制剂）的临床试验。
7. 在实验模型中，饮食限制能增强对致癌物的抵抗并延长预期寿命；有证据表明这两种作用均与IGF信号通路相关。虽然较高水平的IGF信号传导与模式生物寿命缩短相关，但在细胞层面IGF1R激活会启动抗凋亡通路。"生命速率"模型可协调这些观察结果。

英文摘要：

The insulin-like growth factor 1 (IGF1) signalling pathway has important roles in regulating cellular proliferation and apoptosis. Converging results from epidemiological research and in vivo carcinogenesis models indicate that high levels of circulating IGF1 are associated with increased risk of several common cancers. Ongoing research seeks to clarify the mechanisms underlying these observations and to determine the extent to which IGF physiology influences patterns of cancer incidence. Various therapeutic strategies that target the IGF1 receptor have demonstrated impressive antineoplastic activity in laboratory models, and clinical trials of several novel drug candidates are planned.

摘要翻译： 

胰岛素样生长因子1（IGF1）信号通路在调节细胞增殖和凋亡中发挥重要作用。流行病学研究和体内致癌模型的交叉结果表明，循环中高IGF1水平与多种常见癌症风险增加相关。当前研究正致力于阐明这些观察背后的机制，并确定IGF生理对癌症发病模式的影响程度。多种靶向IGF1受体的治疗策略在实验室模型中展现出显著的抗肿瘤活性，几种新型候选药物的临床试验也在计划中。

原文链接：

Insulin-like growth factors and neoplasia