Mechanisms associated with systemic effects of cancer

注意到的问题：转移性疾病中的功能受限、肌肉减少症、肌肉减少性肥胖和恶病质 在许多癌症中很常见。功能限制是机械伴随的旁分泌效应 可能是由于骨骼肌功能障碍，包括异常的干祖细胞分化细胞， 肌生成层次虽然恶病质在乳腺癌中很少见，但癌症和/或治疗引起的骨骼肌损伤在乳腺癌中很少见。 肌肉功能障碍和肌肉减少症在乳腺癌患者中是常见的。然而，不知道是否 具有不同基因组畸变的肿瘤亚型，因此具有不同的旁分泌信号特征， 差异性地影响肌生成层级。同样未知的是，癌症诱发的骨骼肌 缺陷是性别特异性的，如果是这样的话，性别富集激素如何影响肌生成。 当前资助的相关发现：MMTV-PyMT小鼠中的乳腺肿瘤，管腔B模型 乳腺癌亚型，在MMTV-Neu中与乳腺肿瘤相比，对骨骼肌有明显的影响。 小鼠与对照动物相比，两种模型均显示骨骼肌干细胞表达减少， 细胞（MuSC）相关转录因子Hoxa 9，降低了心肌细胞中肌源性microRNA miR-486的水平。 循环和骨骼肌中，细胞外基质沉积增加，握力降低， 旋转棒性能。然而，只有MMTV-PyMT模型显示Pax 7表达降低， 另一种MuSC转录因子和线粒体功能障碍。相比之下，只有MMTV-Neu的骨骼 肌肉表型与Duchenne型肌营养不良（DMD）模型相似。与DMD一样， 模型中，MMTV-Neu的骨骼肌缺陷可以通过肌肉特异性过表达 miR-486骨骼肌表型的这些差异与循环细胞因子的差异相关。 两个模型之间的关系。 为了进一步开发循环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品。有趣的是， 在这些癌症中观察到男性而非女性的循环miR-486。体外研究表明， 雌二醇（E2）或托瑞米芬（一种临床使用的选择性雌激素受体调节剂（SERM））可增加miR- 486在肌原性细胞系中的表达，并且E2和托瑞米芬都降低了smad 2（miR-486靶标）的水平。Smad2 是肌肉生长抑制素/激活素A/B诱导的信号传导的组成部分，其介导癌症中的肌肉损失。因此，E2或 SERM可能用于减少骨骼肌缺陷，改善男性的生活质量， 各种癌症。此外，乳腺癌患者停止抗雌激素芳香化酶抑制剂治疗 继发于治疗诱导的肌无力的患者可能是由于受损的E2-mR-486信号传导。 假设：乳腺癌患者经历DMD样骨骼肌表型取决于基因组 在癌症中，性别也对肌肉功能有影响。因此，我们认为， 将癌症基因组学与性别相结合是理解癌症中骨骼肌生物学所必需的。 目的：1）证明癌症中的基因组畸变决定了癌症中的分子缺陷类型， 2）确定循环和骨骼肌中 miR-486存在于实体瘤中3）研究芳香酶抑制剂是否改变肌原性转录 通过E2调节的microRNA（包括miR-486）的去调节来调节因子网络，以及4）为了确定E2调节的microRNA（包括miR-486）的表达， E2或托瑞米芬在男性癌症模型中减少功能限制的作用。 研究影响：本研究将开发一种个体化方法来评估癌症对骨骼肌的影响。 肌肉，类似于目前在个体水平上表征肿瘤的努力。如果证明E2或托瑞米芬 通过破坏肌肉生长抑制素，有效降低男性癌症模型中癌症诱导的全身效应， smad 2/3信号，它们可以立即转化为临床，因为这两种药物已经在临床使用。

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.