IGFBP1 mediates a liver-bone-muscle axis in colorectal cancer cachexia

IGFBP1 在结直肠癌恶病质中介导肝-骨-肌肉轴

• 批准号: 10338817
• 负责人: Andrea Bonetto
• 金额: $ 41.27万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338817
• 关键词: Affect; Animals; Antibodies; Atrophic; Automobile Driving; Binding; Binding Proteins; Bone Resorption; Cachexia; Cancer Survivor; Colorectal Cancer; Communication; Development; Diagnosis; Disease; Endocrine Glands; Event; Exhibits; Experimental Models; Family; Gene Expression; Genomics; Goals; Growth; Health; Hepatic; Hepatocyte; Homeostasis; Hormones; IGFBP1 gene; Implant; In Vitro; Integrins; Knock-out; Knockout Mice; Light; Liver; Liver neoplasms; MC38; Malignant Neoplasms; Mediating; Metabolic; Metastatic Neoplasm to the Liver; Morbidity - disease rate; Mus; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Musculoskeletal; Neoplasm Metastasis; Osteoclasts; Pathologic; Patients; Play; Quality of life; Recombinants; Reporting; Research; Resolution; Role; Signal Transduction; Skeletal Muscle; Somatomedins; Surface; Symptoms; Tissues; Transplantation; Tumor-Derived; Viral Vector; Wasting Syndrome; bone; bone loss; bone mass; cancer cachexia; cancer cell; colon cancer patients; colorectal cancer prevention; improved; in vivo; knock-down; metastatic colorectal; mortality; muscle form; new therapeutic target; novel; osteoclastogenesis; overexpression; prevent; receptor; reduced muscle mass; response; single-cell RNA sequencing; skeletal preservation; subcutaneous; therapeutic target; tumor; tumor growth; tumor initiation; wasting

PROJECT SUMMARY Colorectal cancer (CRC) is frequently accompanied by the development of cachexia, a multi-systemic wasting syndrome that affects the majority of patients, especially when the disease recurs by forming liver metastases (LMs). Muscle and bone loss are amongst the most detrimental symptoms of cachexia and directly cause increased morbidity and mortality. We and others have shown that CRC also promotes metabolic and genomic perturbations of the liver, and further, that formation of LMs exacerbates muscle and bone wasting. Unfortunately, no cure is available for cachexia, and research on liver contribution to musculoskeletal wasting in cancer has been lacking; hence, there is an urgent need to develop novel treatments for cachexia-related musculoskeletal symptoms. In this regard, our preliminary findings suggest that IGFBP1, a liver-derived hormone belonging to the insulin-like growth factor family of binding proteins (IGFBPs), plays a causative role in cancer- associated musculoskeletal complications. In our preliminary studies, IGFBP1 was found elevated in CRC patients and in CRC hosts, along with muscle and bone loss. IGFBP1 induced myotube atrophy and osteoclast differentiation. Mice bearing subcutaneous C26 CRC displayed muscle atrophy, but no bone loss, whereas mice bearing C26 LMs showed marked muscle and bone wasting, along with dramatically elevated IGFBP1. Anti-IGFBP1 treatments prevented CRC-induced myofiber atrophy and osteoclastogenesis in vitro, whereas depletion of liver IGFBP1 abolished bone loss and improved muscle wasting in CRC hosts. IGFBP1 was also found elevated in mixed hepatocyte-CRC cultures and in the liver of metastatic CRC hosts, suggesting a role of IGFBP1 in cancer dissemination. The objective of this proposal is to define the mechanisms by which IGFBP1 drives bone loss and contributes to muscle wasting in CRC. Our central hypothesis is that elevated IGFBP1 exacerbates CRC-induced cachexia by triggering events consistent with musculoskeletal wasting. In Aim 1, we will determine the mechanism(s) by which IGFBP1 triggers bone loss in CRC. We hypothesize that in CRC elevated IGFBP1 signals through ITGB1 and promotes osteoclastogenesis, hence bone loss. In Aim 2, we will elucidate the mechanism(s) by which IGFBP1 causes muscle wasting in CRC. We hypothesize that high IGFBP1 participates in muscle atrophy. In Aim 3, we will explore the role of the liver microenvironment in the exacerbation of CRC cachexia. We hypothesize that tumor dissemination to the liver determines changes in gene expression in both hepatocytes and cancer cells consistent with enhanced growth rates and altered expression of IGFBP1 and other liver- and tumor-derived soluble factors. Our findings will define the mechanistic effects of IGFBP1 in cachexia and identify IGFBP1 as a new therapeutic target for the treatment of multi-organ complications in CRC. These results will also open new avenues for cachexia research.

项目总结 结直肠癌(CRC)常伴有恶病质的发展，恶病质是一种多系统的消耗。 影响大多数患者的综合征，尤其是当疾病因形成肝转移而复发时 (LMS)。肌肉和骨骼丢失是恶病质最有害的症状之一，直接导致 发病率和死亡率增加。我们和其他人已经表明，CRC还促进新陈代谢和基因组 肝脏的紊乱，以及LMS的形成，会加剧肌肉和骨骼的损耗。 不幸的是，目前还没有治疗恶病质的方法，而且有研究表明肝脏对肌肉骨骼损耗的影响。 癌症一直缺乏；因此，迫切需要开发与恶病质相关的新疗法。 肌肉骨骼症状。在这方面，我们的初步发现表明IGFBP1，一种肝脏衍生的激素 属于胰岛素样生长因子结合蛋白家族(IGFBPs)，在癌症- 相关的肌肉骨骼并发症。 在我们的初步研究中，IGFBP1在结直肠癌患者和结直肠癌宿主中以及肌肉中都被发现升高 和骨质流失。IGFBP1诱导肌管萎缩和破骨细胞分化。皮下接种C26的小鼠 CRC显示肌肉萎缩，但没有骨丢失，而携带C26 LMS的小鼠显示明显的肌肉和 骨量减少，同时IGFBP1显著升高。抗IGFBP1治疗预防结直肠癌 在体外，肌纤维萎缩和破骨细胞生成，而肝脏IGFBP1的耗竭则消除了骨丢失和骨再生。 改善了CRC东道主的肌肉消耗。IGFBP1在肝细胞-结直肠癌混合培养中也被发现升高 在转移性结直肠癌宿主的肝脏中表达，提示IGFBP1在肿瘤扩散中起作用。 这项建议的目标是定义IGFBP1驱动骨丢失和促进骨丢失的机制 结直肠癌的肌肉萎缩。我们的中心假设是IGFBP1升高通过以下方式加重结直肠癌诱导的恶病质 引发与肌肉骨骼消耗相一致的事件。在目标1中，我们将通过以下方式确定机制(S) 哪种IGFBP1在结直肠癌中引发骨丢失。我们假设在CRC中，IGFBP1信号通过ITGB1升高 促进破骨细胞生成，从而导致骨质流失。在目标2中，我们将阐明(S) IGFBP1导致结直肠癌肌肉萎缩。我们假设高IGFBP1参与肌肉萎缩。在……里面 目的探讨肝脏微环境在结直肠癌恶病质加重中的作用。我们 假设肿瘤扩散到肝脏决定了两个肝细胞基因表达的变化 以及与IGFBP1和其他肝脏生长速度加快和表达改变相一致的癌细胞 肿瘤衍生的可溶性因子。 我们的发现将确定IGFBP1在恶病质中的作用机制，并确定IGFBP1是一种新的治疗方法 结直肠癌多器官并发症的治疗靶点。这些成果还将开辟新的途径 恶病质研究。