Translational research on cancer anorexia-cachexia syndrome

恶病质是癌症中最虚弱和最危及生命的方面之一，与厌食症、脂肪和肌肉组织浪费、心理痛苦和生活质量下降有关。恶病质是简单饥饿时适应性摄食反应失败的结果，包括细胞因子的产生。我们通过模拟下丘脑对瘦素的过度负反馈信号的影响，证明了细胞因子在长期抑制摄食中发挥关键作用。瘦素是一种由脂肪组织分泌的激素，是体重调节的动态平衡环路的组成部分。细胞因子信号导致包括Ghrelin-神经肽Y在内的摄食刺激回路的持续抑制，正如我们在结肠26或其他携带癌细胞的小鼠中的研究所显示的那样。药物治疗的两个主要选择是孕激素或皮质类固醇。然而，关于癌症厌食-恶病质综合征的机制的知识继续…多从S导致的几个方面对本病进行有效的治疗干预。我们已经证明，Ghrelin激动剂GHRP2逆转了5FU引起的厌食，并增加了癌症恶病质模型的累积食物摄入量。GHRP2可增加抑郁症患者的食欲。相反，另一种ghrelin基因产物去脂酰Ghrelin和Obestatin是厌食和抗胃促动力的，而不是酰基Ghrelin，过量生产的转基因小鼠表现出瘦削的表型。因此，这三种Ghrelin基因产物的相对丰度可能决定了多肽系统的总体产量。虽然我们不能成功地开发出与GHRP2相比效力更高的新多肽，但最近给厌食症患者服用Ghrelin表明了它在改善厌食症方面的有效性。由于减肥缩短了癌症患者的生存时间，降低了患者的运动状态，有效的治疗将延长患者的生存时间，提高生活质量。我们的动物实验部分支持了这一观点。较少

Cachexia is among the most debilitating and life-threatening aspects of cancer and is associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life. Cachexia results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production. We demonstrated that cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. The cytokine signaling leads to persistent inhibition of feeding-stimulatory circuitry including ghrelin-neuropeptide Y, as shown in our studies in colon26 or other cancer cell-bearing mice. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome continue … More s to lead to effective therapeutic interventions for several aspects of the syndrome. We have shown that ghrelin agonist GHRP2 reverses anorexia induced by 5FU and increases cumulative food intake in cancer cachexia models. GHRP2 increases appetite in patients with depression. In contrast, desacyl ghrelin and obestatin, the another ghrelin gene products are anorexigenic and anti-gastroprokinetic as opposed to acyl ghrelin, and overproduction of the transgenic mice showed lean phenotype. Therfore, the relative abundance of these three ghrelin gene products may determine the overall output of the peptide system. Although we could not succeed to develop new peptides with increased potency compared to GHRP2, recent administration of ghrelin to anorexic patiens suggests the usefulness in improving anorexia. Because weight loss shortens the survival time of cancer patients and decreases performance status, effective therapy would extend patient survival and improve quality of life. Our animal experiments partly supported the notion. Less