Delineating the contribution of muscle wasting to tumor progression

摘要 高达80%的晚期癌症患者骨骼肌萎缩，并直接影响手术 预后、化疗反应、发病率、死亡率和生活质量。虽然已经付出了相当大的努力 深入了解肿瘤(以及宿主对肿瘤的反应)如何对癌症的病因做出贡献 恶病质，人们对恶病质状态如何反过来影响肿瘤动力学知之甚少。我们的长- 学期目标是更好地了解肿瘤与宿主之间的相互作用，以接近治疗方法。 癌症患者的发育更全面。我们提出的初步数据强调了肌肉的作用 与肿瘤进展有关的消瘦。首先，我们展示了转基因小鼠抵抗肌肉的能力 与对照组相比，衰弱的小鼠存活率提高，肿瘤生长缓慢。 相同的肿瘤移植方案。其次，对从这些小鼠身上分离出的肿瘤的初步分析表明 由于肌肉萎缩，细胞类型组成和基因表达存在显著差异。第三，我们 观察与持续肌纤维萎缩相关的发散/独特分泌体。这项建议建立在这些基础上 令人振奋的发现，并将解决中心假说，骨骼肌消耗积极促进肿瘤 进步。在这项提案中，我们将1)详细描述在存在/不存在肌肉萎缩和 确定浪费预防和干预是否足以促进肿瘤生长，以及2)询问 骨骼肌分泌组更好地了解分解代谢肌的命运、组成和功能 细分产品。我们共同期待这项工作是朝着更好的方向迈出的重要和创新的一步 了解肿瘤和宿主组织(如骨骼肌)之间的动态和复杂关系。

ABSTRACT Skeletal muscle wasting affects up to 80% of patients with advanced cancer and directly impacts surgical prognosis, chemotherapeutic response, morbidity, mortality, and quality of life. While considerable effort has gone into understanding how tumors (and the host response to tumors) contribute to the etiology of cancer cachexia, relatively little is known about how the cachectic state in turn influences tumor dynamics. Our long- term goal is to develop a better understanding of reciprocal tumor-host interactions to approach therapeutic development more holistically in cancer patients. We present preliminary data highlighting the role of muscle wasting with respect to tumor progression. First, we show that mice genetically engineered to resist muscle wasting exhibit enhanced survival and slower tumor growth compared to matched control mice subjected to the same tumor transplantation protocol. Second, preliminary analyses of tumors isolated from these mice point to significant differences in cell type composition and gene expression as a function of muscle wasting. Third, we observe a divergent/unique secretome associated with ongoing myofiber atrophy. This proposal builds on these exciting findings and will address the central hypothesis that skeletal muscle wasting actively promotes tumor progression. In this proposal we will 1) detail tumor progression in the presence/absence of muscle wasting and determine if wasting prevention and intervention is sufficient to augment tumor growth, and 2) interrogate the skeletal muscle secretome to better understand the fate, composition, and function of catabolic muscle breakdown products. Together, we anticipate this work being a significant and innovative step towards better understanding the dynamic and complex relationship between tumors and host tissues, such as skeletal muscle.