Translational research on cancer anorexia-cachexia syndrome

恶病质是癌症中最令人衰弱和危及生命的方面之一，与厌食、脂肪和肌肉组织消耗、心理困扰和生活质量降低有关。恶病质由简单饥饿中所见的适应性进食反应的失败引起，并且包括细胞因子产生。我们证明，细胞因子在长期抑制摄食中起着关键作用，通过模拟下丘脑对瘦素过度负反馈信号的作用，瘦素是脂肪组织分泌的一种激素，是体重调节的稳态循环的组成部分。细胞因子信号传导导致持续抑制摄食刺激电路，包括ghrelin-神经肽Y，如我们在colon 26或其他癌细胞携带小鼠中的研究所示。药物治疗的两个主要选择是促孕剂或皮质类固醇。然而，对癌症恶病质综合征机制的认识仍在继续 关于我们 从而为该综合征的几个方面提供有效的治疗干预。我们已经表明，生长素释放肽激动剂GHRP 2逆转由5 FU诱导的厌食症，并增加癌症恶病质模型中的累积食物摄入。GHRP 2增加抑郁症患者的食欲。与此相反，去酰基ghrelin和obestatin，另一种ghrelin基因产物是促消化和抗胃促动力的，与酰基ghrelin相反，并且过量产生的转基因小鼠表现出瘦的表型。因此，这三种生长素释放肽基因产物的相对丰度可以决定肽系统的总体输出。虽然我们不能成功地开发出与GHRP 2相比具有增加效力的新肽，但最近对厌食症患者施用生长激素释放肽表明其在改善厌食症方面的有用性。由于体重减轻缩短了癌症患者的生存时间并降低了体能状态，因此有效的治疗将延长患者的生存时间并提高生活质量。我们的动物实验部分支持了这一观点。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