NF-kB Regulation of the Muscle Microenvironment in Cancer Cachexia

摘要 恶病质是一种使人衰弱的综合征，其导致严重的、非自愿的体重减轻，这是由于 骨骼肌质量这种综合征发生在大多数癌症中，约占三分之一。 占所有癌症死亡人数的三分之一。目前，还没有有效的治疗方法来对抗这种恶性疾病。胰腺 有效的恶病质疗法的潜在益处可能甚至大于其他恶病质疗法。 相关的恶性肿瘤，因为90%的这些患者平均减轻了14%的患病前体重， 恶病质极大地限制了他们耐受手术、化疗或放疗的能力。新的治疗方法可能会 从增强对导致肌肉萎缩的机制的理解演变而来。我们最近的努力 专注于肌肉微环境中肌纤维外发生的事件。我们发现， 肿瘤因子诱导骨骼肌损伤，导致肌肉祖细胞中NF-κ B的活化， 与接合的再生程序相关联。然而，再生受到抑制，导致肌肉 萎缩我们现在发现肌肉干细胞中的NF-kB激活也会促进局部肌肉炎症， 其特征在于产生细胞因子和趋化因子。这些信号促进了 表达M1炎性和M2抗炎标记物的巨噬细胞。此应用程序的目标是 测试肌肉祖细胞中的NF-kB调节局部炎症环境的假设， 会导致肌肉萎缩为了实现这一目标，我们力求实现以下两个具体目标：1） 确定NF-kB如何调节癌症恶病质中的局部肌肉炎症; 2）阐明表型 和巨噬细胞在癌症引起的肌肉萎缩中的相关性。实现这一目标，不仅可以 深入了解癌症中肌肉萎缩的机制和治疗靶点，但也将拓宽一个领域， 恶病质研究的一个新领域。

ABSTRACT Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle mass. This syndrome occurs in a majority of cancers and contributes to approximately a third of all cancer deaths. Currently, no effective therapy exists to combat this malignant disorder. For pancreatic cancer the potential benefit for effective cachexia therapies may be even greater than for other cachexia associated malignancies, since 90% of these patients lose on average 14% of their pre-illness weight, and cachexia dramatically limits their ability to tolerate surgery, chemo- or radiotherapy. New therapies will likely evolve from an enhanced understanding of the mechanisms leading to muscle wasting. Our recent efforts have focused on events that occur outside the myofiber in the muscle microenvironment. We showed that circulating tumor factors induce skeletal muscle damage leading to the activation of NF-kB in muscle progenitor cells that associated with an engaged regeneration program. However, regeneration is inhibited leading to muscle atrophy. We now find that NF-kB activation in muscle stem cells also promotes a local muscle inflammation, characterized by the production of cytokines and chemokines. These signals promote the recruitment of macrophages expressing M1 inflammatory and M2 anti-inflammatory makers. The goal of this application is to test the hypothesis that NF-kB in muscle progenitor cells regulates this local inflammatory environment that contributes to muscle atrophy. Towards this goal we seek to perform the following two specific aims: 1) Determine how NF-kB regulates local muscle inflammation in cancer cachexia; and 2) Elucidate the phenotype and relevance of macrophages in cancer-induced muscle wasting. Achieving this goal will not only provide insight into the mechanisms and therapeutic targets of muscle wasting in cancer, but will also broaden an area of cachexia research that is currently underexplored.