Mechanisms associated with systemic effects of cancer

与癌症全身效应相关的机制

• 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
• 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

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：在转移环境中的功能限制，肌肉减少症，肌肉减少肥胖和恶病质 在许多癌症中很常见。功能限制在机械上与旁分泌效应有关 癌症，可能是由于骨骼肌功能障碍，包括异常差异细胞 肌发生层次结构。尽管恶病质在乳腺癌，癌症和/或治疗诱导的骨骼中很少见 肌肉功能障碍和肌肉减少症在乳腺癌患者中很常见。但是，未知是否 具有不同基因组畸变的肿瘤亚型，因此不同的旁分泌信号传导特征， 差异影响肌发生层次结构。癌症引起的骨骼肌是否也尚不清楚 缺陷是特定性别的，如果是性别，则富含性别的激素如何影响肌发生。 当前资金的相关发现：MMTV-PYMT小鼠中的乳腺肿瘤，腔B的模型 与MMTV-NEU中的乳腺肿瘤相比，乳腺癌亚型对骨骼肌具有明显的影响 老鼠。与对照动物相比，这两个模型均显示骨骼肌茎的表达降低 细胞（MUSC）相关的转录因子HOXA9，肌源性microRNA miR-486的水平降低 循环和骨骼肌，细胞外基质沉积增加，握力强度降低， Rotarod性能。但是，只有MMTV-PYMT模型显示PAX7的表达降低， 另一个MUSC转录因子和线粒体功能障碍。相比之下，只有mmtv-neu的骨骼 肌肉表型类似于Duchenne肌肉营养不良（DMD）模型的表型。此外，与DMD一样 模型，MMTV-NEU中的骨骼肌缺陷可以通过肌肉特异性的过表达来纠正 mir-486。骨骼肌表型的这些差异与循环细胞因子的差异相关 两个模型之间的剖面。 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，肺和胰腺癌患者的血浆样品。有趣的是，显着减少了 在这些癌症中观察到男性但未观察到女性的miR-486。体外研究表明 雌二醇（E2）或Toremifene，一种临床使用的选择性雌激素受体调节剂（SERM），增加了mir-- 486在肌源性细胞系，E2和Toremifene均降低了miR-486靶标Smad2的水平。 Smad2 是肌抑素/激活素A/B诱导的信号的组成部分，介导癌症的肌肉损失。因此，E2或 SERMS有可能用于减少骨骼肌缺陷，并改善患有男性的男性的生活质量 各种癌症。另外，通过乳腺癌停止抗雌激素芳香酶抑制剂治疗 以治疗引起的肌肉无力的患者可能是由于E2-MR-486信号传导受损。 假设：乳腺癌患者经历了DMD样骨骼肌表型，具体取决于基因组 癌症的像差和性别对其他实体瘤的肌肉功能也有影响。所以， 需要将癌症基因组与性别相结合以了解癌症中的骨骼肌生物学。 目的：1）证明癌症中的基因组畸变决定了分子缺陷的类型 骨骼肌，2）确定循环和骨骼肌水平的性别特定差异 MiR-486在实体瘤中存在3）研究芳香酶抑制剂是否改变了肌源性转录 通过放松E2调节的microRNA（包括miR-486）和4）的因素网络，以确定 E2或心形芬在降低男性癌症模型功能局限性中的影响。 研究影响：本研究将开发一种个性化方法来评估癌症对骨骼的影响 肌肉，类似于当前表征个体肿瘤的努力。如果E2或Toremifene被证明 通过破坏Myostatin- SMAD2/3信号传导，它们可以立即转化为诊所，因为两种药物都已经在临床中。

项目成果

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

• DOI: 10.1186/s13104-017-3090-y
• 发表时间: 2017-12-19
• 期刊: BMC research notes
• 影响因子: 1.8
• 作者: Beg F;Wang R;Saeed Z;Devaraj S;Masoor K;Nakshatri H
• 通讯作者: Nakshatri H

Modeling Preclinical Cancer Studies under Physioxia to Enhance Clinical Translation.

• DOI: 10.1158/0008-5472.can-22-2311
• 发表时间: 2022-12-02
• 期刊: Cancer research
• 影响因子: 11.2

Aging-associated skeletal muscle defects in HER2/Neu transgenic mammary tumor model.

• DOI: 10.1002/rco2.23
• 发表时间: 2021-01
• 期刊: JCSM rapid communications
• 作者: Wang R;Kumar B;Bhat-Nakshatri P;Prasad MS;Jacobsen MH;Ovalle G;Maguire C;Sandusky G;Trivedi T;Mohammad KS;Guise T;Penthala NR;Crooks PA;Liu J;Zimmers T;Nakshatri H
• 通讯作者: Nakshatri H

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

• DOI: 10.1210/endocr/bqab142
• 发表时间: 2021-10-01
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Wang R;Bhat-Nakshatri P;Zhong X;Zimmers T;Nakshatri H
• 通讯作者: Nakshatri H

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

• DOI: 10.1158/1535-7163.mct-17-0717
• 发表时间: 2017-12
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Wang R;Bhat-Nakshatri P;Padua MB;Prasad MS;Anjanappa M;Jacobson M;Finnearty C;Sefcsik V;McElyea K;Redmond R;Sandusky G;Penthala N;Crooks PA;Liu J;Zimmers T;Nakshatri H
• 通讯作者: Nakshatri H