Mechanisms associated with systemic effects of cancer

注意到的问题：转移性环境中的功能受限、骨量减少、骨质性肥胖和恶病质。 在许多癌症中都很常见。功能限制在机械上伴随着旁分泌效应。 可能是由于骨骼肌功能障碍，包括异常的干细胞-祖细胞分化细胞 肌肉发生层级。尽管恶病质在乳腺癌中很少见，但癌症和/或治疗导致的骨骼 肌肉功能障碍和肌萎缩症在乳腺癌患者中很常见。然而，目前还不清楚 具有不同基因组异常的肿瘤亚型，因此具有不同的旁分泌信号特征， 不同地影响肌肉发生的层级。同样未知的是，癌症诱导的骨骼肌 缺陷是性别特有的，如果是这样的话，性别丰富的激素是如何影响肌肉生成的。 当前资助的相关发现：MMTV-PYMT小鼠的乳腺肿瘤，腔B模型 乳腺癌亚型，与MMTV-Neu中的乳腺肿瘤相比，对骨骼肌有明显影响 老鼠。与对照组动物相比，两种模型都显示骨骼肌干的表达减少。 细胞(MUSC)相关转录因子Hoxa9降低成肌微RNA miR-486水平 循环和骨骼肌中，细胞外基质沉积增加，握力和握力降低 旋转棒表演。然而，只有MMTV-PYMT模型显示Pax7的表达减少， 另一种MUSC转录因子，以及线粒体功能障碍。相比之下，只有MMTV-Neu的骨骼 肌肉表型与Duchenne肌营养不良症(DMD)模型相似。此外，与DMD一样， 模型，MMTV-Neu的骨骼肌缺陷可以通过肌肉特异性的过度表达来纠正 MIR-486这些骨骼肌表型的差异与循环细胞因子的差异有关 两个型号之间的配置文件。 为了进一步发展循环miR-486作为癌症相关骨骼肌缺陷的生物标志物，我们 分析了膀胱癌、肺癌和胰腺癌患者的血浆样本。耐人寻味的是， 在这些癌症中观察到男性而不是女性的血液循环miR-486。体外研究表明， 雌激素(E_2)或托瑞米芬(Toremifen)是一种临床上使用的选择性雌激素受体调节剂(SERM)，可增加miR- 486，E2和托瑞米芬都降低了miR-486靶点Smad2的水平。Smad2 是肌肉抑制素/激活素A/B诱导的信号中不可或缺的一部分，该信号介导癌症中的肌肉丢失。因此，E2或 SERM可能被用来减少骨骼肌缺陷并提高男性患者的生活质量 各种癌症。此外，乳腺癌患者停止抗雌激素芳香酶抑制剂治疗 继发于治疗引起的肌肉无力的患者可能是由于E2-MR-486信号受损。 假设：乳腺癌患者根据基因组的不同经历类似DMD的骨骼肌表型 癌症中的异常和性别对其他实体肿瘤的肌肉功能也有影响。因此， 为了理解癌症中的骨骼肌生物学，需要将癌症基因组学与性别相结合。 目的：1)证明癌症中的基因组异常决定了癌症中分子缺陷的类型 骨骼肌，2)确定循环肌肉和骨骼肌水平的性别差异 MIR-486存在于实体瘤中3)研究芳香酶抑制剂是否会改变肌原转录 通过解除对包括miR-486在内的E2调节的microRNAs的调控而形成的因子网络，以及4)以确定 雌二醇或托瑞米芬降低男性癌症模型功能缺陷的作用。 研究影响：这项研究将开发一种个性化的方法来评估癌症对骨骼的影响 肌肉，类似于目前在个体层面上描述肿瘤的努力。如果E2或托瑞米芬被证明是 在男性癌症模型中，通过干扰肌肉生长抑制素有效地减少癌症诱导的全身效应- Smad2/3信号，它们可以立即翻译到临床上，因为这两种药物已经在临床上使用。

Problems noted: Functional limitation, sarcopenia, sarcopenic obesity, and cachexia in the metastatic setting are common across many cancers. Functional limitation is mechanistically concomitant to the paracrine effects of cancer and is likely due to skeletal muscle dysfunction including aberrant stem-progenitor-differentiated cell myogenesis hierarchy. Although cachexia is rare in breast cancer, cancer- and/or treatment-induced skeletal muscle dysfunction and sarcopenia are common in breast cancer patients. However, it is unknown whether tumor subtypes with distinct genomic aberrations, and consequently different paracrine signaling features, differentially affect the myogenesis hierarchy. It is also unknown whether cancer-induced skeletal muscle defects are gender-specific, and, if so, how gender-enriched hormones influence myogenesis. Relevant findings from the current funding: Mammary tumors in MMTV-PyMT mice, a model for luminal B breast cancer subtype, had distinct effect on skeletal muscle compared to mammary tumors in MMTV-Neu mice. Compared to control animals, both models demonstrated reduced expression of skeletal muscle stem cell (MuSC)-associated transcription factor Hoxa9, reduced levels of myogenic microRNA miR-486 in circulation and in skeletal muscle, increased extracellular matrix deposition, and lower grip strength and rotarod performance. However, only the MMTV-PyMT model demonstrated reduced expression of Pax7, another MuSC transcription factor, and mitochondrial dysfunction. By contrast, only the MMTV-Neu's skeletal muscle phenotype resembled that of Duchenne muscular dystrophy (DMD) models. Furthermore, as with DMD models, skeletal muscle defects in MMTV-Neu could be rectified through muscle-specific overexpression of miR-486. These differences in skeletal muscle phenotype correlated with differences in circulating cytokine profiles between the two models. To further develop circulating miR-486 as a biomarker of cancer-associated skeletal muscle defects, we analyzed plasma samples of bladder, lung and pancreatic cancer patients. Intriguingly, striking reduction of circulating miR-486 in men but not women was observed in these cancers. In vitro studies showed that estradiol (E2) or toremifene, a clinically used selective estrogen receptor modulator (SERM), increased miR- 486 in myogenic cell lines and both E2 and toremifene reduced the levels of smad2, a miR-486 target. Smad2 is an integral part of myostatin/activin A/B-induced signaling that mediates muscle loss in cancer. Thus, E2 or SERMs can potentially be used to reduce skeletal muscle defect and improve quality of life for men with various cancers. Additionally, discontinuation of anti-estrogen aromatase inhibitor therapy by breast cancer patients secondary to treatment-induced muscle weakness could be due to impaired E2-mR-486 signaling. Hypothesis: Breast cancer patients experience DMD-like skeletal muscle phenotype depending on genomic aberrations in cancer, and gender also has an effect on muscle function in other solid tumors. Therefore, integrating cancer genomics with gender is required to understand skeletal muscle biology in cancer. Aims: 1) To demonstrate that genomic aberrations in cancer determine the types of molecular defects in skeletal muscle, 2) To establish that gender specific differences in circulating and skeletal muscle levels of miR-486 exist across solid tumors 3) To investigate whether aromatase inhibitors alter myogenic transcription factor network through deregulation of E2-regulated microRNAs including miR-486, and 4) To determine the effects of E2 or toremifene in reducing functional limitations in male cancer models. Study impact: This study will develop an individualized method to assess the effect of cancer on skeletal muscle, similar to current efforts of characterizing tumors at the individual level. If E2 or toremifene proves to be effective in reducing cancer-induced systemic effects in male models of cancer by disrupting myostatin- smad2/3 signaling, they can be translated immediately into clinic as both drugs are already in clinical use.