胰岛素样生长因子系统在癌症恶病质的病理生理学中起什么作用，以及它是如何被调节的？

What is the role of the insulin-like growth factor system in the pathophysiology of cancer cachexia, and how is it regulated?

作者信息

Crown A L, Cottle K, Lightman S L, Falk S, Mohamed-Ali V, Armstrong L, Millar A B, Holly J M P

机构信息

Department of Medicine, University of Bristol, UK.

出版信息

Clin Endocrinol (Oxf). 2002 Jun;56(6):723-33. doi: 10.1046/j.1365-2265.2002.01540.x.

DOI:10.1046/j.1365-2265.2002.01540.x

PMID:12072041

Abstract

OBJECTIVE AND BACKGROUND

The cancer cachexia syndrome is characterized by anorexia, weight loss with muscle wasting and increased energy expenditure. It is associated with increased morbidity and mortality, but its aetiology is poorly understood and no effective therapeutic intervention is available. It may result from an imbalance between the activity or effect of anabolic and catabolic hormones, mediated by the inflammatory cytokines. IGF-I is a potent anabolic agent, with therapeutic potential. Our objective was to investigate the role and regulation of the IGF system in cancer cachexia.

DESIGN AND PATIENTS

We set up a prospective study of 30 patients with newly diagnosed unresectable non-small cell lung cancer, together with a cross-sectional comparison group of healthy volunteers.

MEASUREMENTS

We examined the relationship between aspects of the IGF system, including IGFBP-3 proteolysis (using Western ligand and immunoblotting and an in vitro IGFBP-3 protease assay); the inflammatory cytokines and their soluble receptors; and food intake and nutritional status (including biochemical and anthropometric assessments).

RESULTS

Although we did not observe a marked reduction in food intake in the cancer patients, the majority lost weight and functionally important lean body mass. We observed GH resistance in the cancer patients, and intermittent proteolysis of IGFBP-3, which correlated with the circulating interleukin-6 (IL-6) concentration. The pattern of IGFBP-3 proteolysis was unusual, with a prominent 17-kDa fragment. Less IGFBP-3 proteolysis was associated with more weight loss, suggesting that this could be a protective counter-regulatory mechanism, increasing IGF-I bioavailability to the tissues.

CONCLUSIONS

Cancer cachexia in humans is a complex condition. Patients tend to be GH resistant. The significance of the intermittent increases in IGFBP-3 proteolysis, which may be regulated by IL-6, remains uncertain. A better understanding of the pathophysiology should enable the development of novel therapeutic approaches.

摘要

目的与背景

癌症恶病质综合征的特征为厌食、体重减轻伴肌肉消耗以及能量消耗增加。它与发病率和死亡率的升高相关，但其病因了解甚少，且尚无有效的治疗干预措施。它可能是由促合成代谢激素和分解代谢激素的活性或作用失衡所致，由炎性细胞因子介导。胰岛素样生长因子-I（IGF-I）是一种强效的促合成代谢剂，具有治疗潜力。我们的目的是研究IGF系统在癌症恶病质中的作用及调节机制。

设计与患者

我们对30例新诊断的不可切除非小细胞肺癌患者进行了一项前瞻性研究，并设立了一个健康志愿者的横断面比较组。

测量

我们研究了IGF系统各方面之间的关系，包括IGF结合蛋白-3（IGFBP-3）的蛋白水解作用（采用Western配体法、免疫印迹法以及体外IGFBP-3蛋白酶测定法）；炎性细胞因子及其可溶性受体；以及食物摄入量和营养状况（包括生化和人体测量评估）。

结果

尽管我们未观察到癌症患者食物摄入量有明显减少，但大多数患者体重减轻且功能性瘦体重减少。我们在癌症患者中观察到生长激素抵抗，以及IGFBP-3的间歇性蛋白水解，这与循环白细胞介素-6（IL-6）浓度相关。IGFBP-3蛋白水解模式异常，有一个突出的17 kDa片段。IGFBP-3蛋白水解较少与体重减轻较多相关，这表明这可能是一种保护性的反调节机制，可增加IGF-I对组织的生物利用度。