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.

项目概要 结直肠癌（CRC）经常伴有恶病质的发展，恶病质是一种多系统消耗 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 （LM）。肌肉和骨质流失是恶病质最有害的症状之一，并直接导致 发病率和死亡率增加。我们和其他人已经证明 CRC 还可以促进代谢和基因组 肝脏的干扰，此外，LM 的形成会加剧肌肉和骨质消耗。 不幸的是，目前尚无治疗恶病质的方法，并且关于肝脏对肌肉骨骼萎缩的影响的研究 一直缺乏癌症；因此，迫切需要开发针对恶病质相关的新疗法 肌肉骨骼症状。在这方面，我们的初步研究结果表明 IGFBP1（一种肝源性激素） 属于胰岛素样生长因子结合蛋白 (IGFBP) 家族，在癌症中发挥着致病作用- 相关的肌肉骨骼并发症。 在我们的初步研究中，发现 CRC 患者和 CRC 宿主体内的 IGFBP1 以及肌肉组织均升高。 和骨质流失。 IGFBP1 诱导肌管萎缩和破骨细胞分化。皮下携带 C26 的小鼠 CRC 显示肌肉萎缩，但没有骨质流失，而携带 C26 LM 的小鼠则显示出明显的肌肉萎缩和骨质流失。 骨质流失，以及 IGFBP1 显着升高。抗 IGFBP1 治疗可预防 CRC 诱发 在体外，肌纤维萎缩和破骨细胞生成，而肝脏 IGFBP1 的耗竭则消除了骨质流失和 改善 CRC 宿主的肌肉消耗。 IGFBP1 在混合肝细胞-CRC 培养物中也被发现升高 以及转移性结直肠癌宿主的肝脏中，表明 IGFBP1 在癌症传播中的作用。 该提案的目的是确定 IGFBP1 驱动骨质流失并促进骨质流失的机制 CRC 中的肌肉萎缩。我们的中心假设是，IGFBP1 升高会通过以下方式加剧 CRC 引起的恶病质： 触发与肌肉骨骼消耗一致的事件。在目标 1 中，我们将通过以下方式确定机制： IGFBP1 会引发 CRC 骨质流失。我们假设在 CRC 中 IGFBP1 信号通过 ITGB1 升高 并促进破骨细胞生成，从而导致骨质流失。在目标 2 中，我们将阐明其机制 IGFBP1 会导致 CRC 中的肌肉萎缩。我们假设高 IGFBP1 参与肌肉萎缩。在 目标 3，我们将探讨肝脏微环境在 CRC 恶病质恶化中的作用。我们 假设肿瘤扩散到肝脏决定了两个肝细胞中基因表达的变化 和癌细胞，与生长速度加快和 IGFBP1 及其他肝脏和细胞因子的表达改变一致。 肿瘤来源的可溶性因子。 我们的研究结果将定义 IGFBP1 在恶病质中的机制作用，并将 IGFBP1 确定为一种新的治疗方法 结直肠癌多器官并发症的治疗目标。这些结果也将为 恶病质研究。