Mechanisms associated with systemic effects of cancer

与癌症全身效应相关的机制

基本信息

批准号：
10515659
负责人：
Harikrishna Nakshatri
金额：
--
依托单位：
RLR VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10515659
关键词：
Activin Receptor Affect Animal Model Aromatase Inhibitors Biological Biological Models Biology Breast Cancer Model Breast Cancer Patient Breast Cancer therapy Cachexia Cancer Model Cancer Patient Cell Differentiation process Cell Line Cells Circulation Clinic Clinical Colon Carcinoma Control Animal Data Defect Deposition Dimensions Duchenne muscular dystrophy Dystrophin ERBB2 gene Eotaxin Estradiol Estrogen Antagonists Extracellular Matrix Female Functional disorder Funding GDF8 gene Gender Genomics Hand Strength Hormones Human Impairment In Vitro Individual KAI1 gene Letrozole Link Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Mammary Neoplasms Mediating Metabolic Methods MicroRNAs Mitochondria Modeling Molecular Mouse Mammary Tumor Virus Mus Muscle Muscle Weakness Muscle function Muscle satellite cell Muscular Atrophy Musculoskeletal Outcome Study Paracrine Communication Patients Performance Pharmaceutical Preparations Phenotype Plasma Precision therapeutics Protein Isoforms Quality of life Regenerative capacity Sampling Secondary to Selective Estrogen Receptor Modulators Signal Induction Signal Transduction Skeletal Muscle Solid Neoplasm TNF gene Therapeutic Toremifene Transforming Growth Factor beta Transgenic Model Translating Tumor Subtype Woman Xenograft Model Xenograft procedure activin A c-myc Genes cancer biomarkers cancer genome cancer genomics cancer subtypes carcinogenesis chemotherapy comparison control cytokine estrogenic activity experience gender difference genomic aberrations improved in vitro Model individual patient induced pluripotent stem cell male malignant breast neoplasm men mitochondrial dysfunction myogenesis overexpression pancreatic cancer patients paracrine polyoma middle tumor antigen progenitor response restoration sarcopenia sarcopenic obesity senescence stem stem cells symptom science therapy design transcription factor tumor

项目摘要

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.

注意到的问题：转移环境中的功能限制、少肌症、少肌性肥胖和恶病质在许多癌症中都很常见。功能限制在机制上与旁分泌效应同时发生癌症的原因可能是骨骼肌功能障碍，包括异常的干祖细胞分化细胞肌生成层次结构。尽管恶病质在乳腺癌中很少见，但癌症和/或治疗引起的骨骼肌肉功能障碍和肌肉减少症在乳腺癌患者中很常见。不过，尚不清楚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传导特征，不同程度地影响肌生成层次。目前还不清楚癌症是否会诱发骨骼肌缺陷是性别特异性的，如果是的话，性别丰富的激素如何影响肌肉生成。当前资助的相关发现：MMTV-PyMT 小鼠乳腺肿瘤，Luminal 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。与对照动物相比，两种模型均表现出骨骼肌干表达减少细胞 (MuSC) 相关转录因子 Hoxa9，肌源性 microRNA miR-486 水平降低循环和骨骼肌中，增加细胞外基质沉积，并降低握力和旋转杆性能。然而，只有 MMTV-PyMT 模型表现出 Pax7 表达减少，另一种 MuSC 转录因子和线粒体功能障碍。相比之下，只有 MMTV-Neu 的骨架肌肉表型类似于杜氏肌营养不良症（DMD）模型。此外，与 DMD 一样模型中，MMTV-Neu 中的骨骼肌缺陷可以通过肌肉特异性过度表达来纠正 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配置文件。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本。有趣的是，显着减少在这些癌症中观察到男性而非女性中存在循环 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 在生肌细胞系中，E2 和托瑞米芬均降低了 smad2（miR-486 靶标）的水平。斯马德2 是肌肉生长抑制素/激活素 A/B 诱导的信号传导的一个组成部分，介导癌症中的肌肉损失。因此，E2 或 SERM 可用于减少骨骼肌缺陷并改善男性的生活质量各种癌症。此外，乳腺癌患者应停止抗雌激素芳香酶抑制剂治疗继发于治疗引起的肌无力的患者可能是由于 E2-mR-486 信号传导受损所致。假设：乳腺癌患者会经历类似 DMD 的骨骼肌表型，具体取决于基因组癌症中的畸变以及性别也会对其他实体瘤中的肌肉功能产生影响。所以，要了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畸变决定了癌症中分子缺陷的类型骨骼肌，2) 确定循环肌和骨骼肌水平的性别特异性差异 miR-486 存在于实体瘤中 3) 研究芳香酶抑制剂是否改变肌源性转录通过解除 E2 调节的 microRNA（包括 miR-486）的因子网络，以及 4) 确定 E2 或托瑞米芬在减少男性癌症模型功能限制方面的作用。研究影响：这项研究将开发一种个体化方法来评估癌症对骨骼的影响肌肉，类似于目前在个体水平上表征肿瘤的努力。如果 E2 或托瑞米芬被证明有效通过破坏肌肉生长抑制素，有效减少男性癌症模型中癌症引起的全身效应 smad2/3 信号传导，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。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle.

人类骨骼肌干/肌管模型揭示了骨骼肌中癌症分泌组的多个信号靶标。

DOI：
发表时间：
2023-04-21
期刊：
影响因子：
5.8
作者：
Wang, Ruizhong;Kumar, Brijesh;Bhat;Khatpe, Aditi S;Murphy, Michael P;Wanczyk, Kristen E;Simpson, Edward;Chen, Duojiao;Gao, Hongyu;Liu, Yunlong;Doud, Emma H;Mosley, Amber L;Nakshatri, Harikrishna
通讯作者：
Nakshatri, Harikrishna

Inflammation-associated microRNA changes in circulating exosomes of heart failure patients.

心力衰竭患者循环外泌体中炎症相关的 microRNA 变化。

DOI：
发表时间：
2017-12-19
期刊：
影响因子：
1.8
作者：
Beg, Faheemullah;Wang, Ruizhong;Saeed, Zeb;Devaraj, Srikant;Masoor, Kamalesh;Nakshatri, Harikrishna
通讯作者：
Nakshatri, Harikrishna

Pharmacological Dual Inhibition of Tumor and Tumor-Induced Functional Limitations in a Transgenic Model of Breast Cancer.

乳腺癌转基因模型中肿瘤的药理学双重抑制和肿瘤诱导的功能限制。

DOI：
发表时间：
2017-12
期刊：
影响因子：
5.7
作者：
Wang, Ruizhong;Bhat;Padua, Maria B;Prasad, Mayuri S;Anjanappa, Manjushree;Jacobson, Ma;Finnearty, Courtney;Sefcsik, Victoria;McElyea, Kyle;Redmond, Rachael;Sandusky, George;Penthala, Narsimha;Crooks, Peter A;Liu, Jianguo
通讯作者：
Liu, Jianguo

Hormonally Regulated Myogenic miR-486 Influences Sex-specific Differences in Cancer-induced Skeletal Muscle Defects.

激素调节的肌源性 miR-486 影响癌症引起的骨骼肌缺陷的性别特异性差异。