Molecular Mechanisms of Muscle and Fat Wasting in Pancreatic Cancer Cachexia

胰腺癌恶病质中肌肉和脂肪消耗的分子机制

• 批准号: 10159842
• 负责人: Teresa A Zimmers
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159842
• 关键词: Acute-Phase Reaction; Adipose tissue; Anemia; Anorexia; Binding; Biological; Body Weight decreased; CTF1 gene; Cachexia; Cancer Model; Cellular Stress; Cessation of life; Chronic; Ciliary Neurotrophic Factor; Clinical; Data; Diabetes Mellitus; Eating; Family; Family member; Fatty acid glycerol esters; Female; Heart failure; IL6ST gene; Immunologic Surveillance; Incidence; Inflammation; Interleukin-6; LIF gene; Life; Limb structure; Link; Lipolysis; Literature; Liver; Longevity; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Metabolic; Metabolic dysfunction; Molecular; Mus; Muscle; Muscle Cells; Muscular Atrophy; Myocardium; Operative Surgical Procedures; Organ; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Patients; Performance Status; Pre-Clinical Model; Quality of life; Regulation; Respiratory Tract Infections; Role; Sampling; Severities; Signal Transduction; Skeletal Muscle; Source; Specimen; Survival Rate; System; Testing; Tissues; Treatment Protocols; Tumor Tissue; Tumor-Derived; Veterans; Withdrawal; aggressive therapy; biobank; cancer cachexia; cancer survival; cancer therapy; chemotherapy; clinically relevant; cytokine; early experience; effective therapy; experience; fat wasting; improved; improved functioning; inhibitor/antagonist; male; men; mortality; mouse model; muscle form; novel; pancreatic cancer model; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; preclinical study; preservation; prevent; response; sex; skeletal muscle wasting; therapy development; tumor; tumor growth; wasting

Cancer cachexia, or muscle wasting with chronic inflammation and dysmetabolism, causes roughly 1/3 of cancer deaths. Cachexia is most prevalent in pancreatic ductal adenocarcinoma (PDAC), afflicting >85% of patients. Loss of muscle mass in patients reduces performance status, predisposes to illness, including respiratory infections and heart failure, and reduces response to and tolerance of anti-cancer therapies. Moreover, presence of cachexia or low performance status due to wasting is a contraindication for aggressive treatment protocols and can trigger treatment withdrawal. Pre-clinical studies from our group and others prove that targeting circulating cachexia factors can preserve muscle, improve function and lengthen survival even without effects on tumor growth. Thus preventing muscle loss could promote quality and length of life and potential for cure. Considerable evidence implicates Interleukin-6 (IL-6) in PDAC and PDAC cachexia. IL-6 is well known to mediate both cachexia as well as PDAC progression and escape from immune surveillance. However, IL-6 is merely one of a family of related factors that all bind to GP130 to elicit common signaling and overlapping biological effects. Analyses of patients and mice demonstrate that adipose is lost first and preferentially in PDAC. Precedent in diabetes and other cancer models suggests that adipose is not a passive victim, but rather could be source of toxic metabolites that injure oxidative tissues like heart and muscle, ultimately causing their wasting. Thus, GP130 signaling combined with lipotoxicity could mediate heart and skeletal muscle wasting in PDAC. Hypothesis: IL-6 family cytokines are secreted by PDAC cells and also by the host in response to cancer. These cytokines elicit adipose lipolysis, cardiac and skeletal muscle wasting directly by signaling in those tissues through GP130. Cardiac and muscle wasting are also triggered indirectly when products of lipolysis accumulate in myocytes, enhancing cellular stress and metabolic dysfunction, leading to lipotoxicity and wasting. Blocking GP130 family cytokines should reduce wasting of fat, heart and skeletal muscle, promote response to therapy, and prolong life in PDAC. This project will leverage well-characterized pre-clinical models of pancreatic cancer, a PDAC cachexia biobank, and substantial experience in circulating mediators of cachexia to identify novel mediators, mechanisms and organ cross talk in PDAC cachexia. We will accomplish this in two Aims. AIM 1: Determine the contribution of tumor-derived and host-derived IL- 6 family/GP130 cytokines in clinically relevant mouse models and clinical specimens in PDAC cachexia. AIM 2. Determine the contribution of GP130 signaling in adipose tissue versus skeletal muscle in PDAC cachexia, using clinically relevant mouse models and patient samples.

癌症恶病质或肌肉萎缩伴慢性炎症和代谢异常， 癌症死亡恶病质在胰腺导管腺癌（PDAC）中最常见， 患者患者肌肉质量的损失降低了性能状态，易患疾病，包括 呼吸道感染和心力衰竭，并降低对抗癌疗法的反应和耐受性。 此外，由于消瘦而出现恶病质或低体力状态是攻击性治疗的禁忌症， 治疗方案，并可能引发治疗退出。我们小组和其他人的临床前研究 证明靶向循环恶病质因子可以保护肌肉，改善功能，延长生存期 即使对肿瘤生长没有影响。因此，防止肌肉损失可以提高生活质量和寿命 和治愈的潜力 大量证据表明白细胞介素-6（IL-6）与PDAC和PDAC恶病质有关。众所周知，IL-6 介导恶病质以及PDAC进展和逃避免疫监视。然而，IL-6是 仅仅是一个家族的相关因子，都结合到GP 130，引发共同的信号和重叠 生物效应。对患者和小鼠的分析表明，脂肪首先丢失，并且优先丢失， PDAC。糖尿病和其他癌症模型的先例表明，脂肪不是一个被动的受害者， 可能是有毒代谢物的来源，这些代谢物会损伤心脏和肌肉等氧化组织，最终导致心脏和肌肉的坏死。 浪费因此，GP 130信号传导与脂毒性结合可以介导心脏和骨骼肌的消耗。 PDAC。假设：IL-6家族细胞因子由PDAC细胞分泌，也由宿主响应于IL-6家族细胞因子分泌。 癌这些细胞因子直接通过在心肌细胞中的信号传导引起脂肪分解、心肌和骨骼肌的消耗。 这些组织通过GP 130。心脏和肌肉萎缩也间接触发时，产品 脂肪分解在肌细胞中积累，增强细胞应激和代谢功能障碍，导致 脂毒性和消耗。阻断GP 130家族细胞因子应减少脂肪、心脏和骨骼的消耗 肌肉，促进对治疗的反应，并延长PDAC的寿命。该项目将利用具有良好特征的 胰腺癌的临床前模型，PDAC恶病质生物库，以及循环 介质的恶病质，以确定新的介质，机制和器官串扰PDAC恶病质。我们 我们将通过两个目标来实现这一目标。目的1：确定肿瘤源性和宿主源性IL-2的贡献。 6家族/GP 130细胞因子在PDAC恶病质中的临床相关小鼠模型和临床标本中的表达。 AIM 2.确定GP 130信号传导在PDAC中脂肪组织与骨骼肌中的贡献 恶病质，使用临床相关的小鼠模型和患者样品。

项目成果

Tumours block protective muscle and nerve signals to cause cachexia.

肿瘤阻断保护性肌肉和神经信号，导致恶病质。

• DOI: 10.1038/d41586-021-02492-9
• 发表时间: 2021
• 期刊: Nature
• 影响因子: 64.8
• 作者: Zimmers,TeresaA

Dynamic Alterations to Hepatic MicroRNA-29a in Response to Long-Term High-Fat Diet and EtOH Feeding.

• DOI: 10.3390/ijms241914564
• 发表时间: 2023-09-26
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Liang T;Kota J;Williams KE;Saxena R;Gawrieh S;Zhong X;Zimmers TA;Chalasani N
• 通讯作者: Chalasani N