FGF21-IGFBP1 axis mediates musculoskeletal deficits in colorectal cancer cachexia

项目摘要 恶病质被定义为作为慢性炎症的副产品而发生的体重和肌肉质量的进行性损失。 疾病，包括癌症。据估计，高达80%的癌症患者发生肌肉骨骼萎缩， 包括结肠直肠癌，生活质量和生存率急剧下降。因此，迫切需要 为癌症引起的肌肉骨骼萎缩开发新的治疗方法。我们最近发表的观察 显示即使在没有直接转移到骨骼的情况下也会发生骨骼萎缩，这表明肿瘤- 衍生的可溶性因子可能在引发骨丢失中起关键作用。此外，我们发表的观察结果 表明结直肠癌肝转移的形成加剧了肌肉骨骼的消耗， 肝脏在调节骨骼肌和骨质流失中的可能作用。在这方面，我的初步研究 提示成纤维细胞生长因子21（FGF 21）和肝胰岛素样生长因子结合蛋白1（IGFBP 1） 导致结直肠癌的肌肉骨骼萎缩。在初步的研究中，我发现携带 皮下MC-38结直肠肿瘤表现为肌肉和骨丢失，沿着高FGF 21和鲁棒性。 IGFBP1.有趣的是，用重组FGF 21处理肝细胞诱导IGFBP 1产生。 首先，具有皮下C26结肠直肠肿瘤的小鼠，其特征在于低FGF 21表达， 与皮下MC-38宿主相比，肌肉损失而无骨损失和显著较低的IGFBP 1。但是，在这方面， 携带C26肝转移瘤的小鼠的肌肉骨骼消耗加重，IGFBP 1水平升高 与携带C26皮下肿瘤的小鼠相比。有趣的是，用重组体处理的鼠肌管 IGFBP 1经历萎缩，而抗IGFBP 1中和抗体在C2 C12中保留了肌管大小 暴露于来自携带C26肝转移瘤的小鼠的血浆的培养物，和感染了AAV-1的C26宿主。 shIGFBP 1维持肌肉质量和强度。因此，本提案的目的是询问 FGF 21-IGFBP 1轴与结直肠癌相关的肌肉和骨丢失根据初步数据和 我的中心假设是肿瘤源性FGF 21促进恶病质和肝脏产生 IGFBP 1，这反过来又介导了结肠直肠癌中的肌肉骨骼消耗。在目标1中，我将确定 肿瘤和宿主源性FGF 21对肝脏IGFBP 1产生和肌肉骨骼消耗的影响 结直肠癌无骨转移。我假设肿瘤源性FGF 21促进肝脏IGFBP 1 和肌肉骨骼萎缩在目标2中，我将确定IGFBP 1依赖性对肌肉骨骼消耗的影响。 在结肠直肠癌中。我推测IGFBP 1促进结直肠癌中的肌肉骨骼消耗。的 这些研究的结果将确定FGF 21-IGFBP 1轴作为治疗糖尿病的新靶点。 治疗结直肠癌的肌肉和骨骼萎缩，并将为恶病质研究开辟新途径。

PROJECT SUMMARY Cachexia is defined as progressive loss of body weight and muscle mass that occurs as a byproduct of chronic diseases, including cancer. It is estimated that musculoskeletal wasting occurs in up to 80% of cancer patients, including colorectal cancer, drastically worsening quality of life and survival. Thus, there is an urgent need to develop new treatments for cancer-induced musculoskeletal wasting. Our recent published observations showing that skeletal wasting occurs even in the absence of direct metastases to the bone, suggest that tumor- derived soluble factors may play a critical role in initiating bone loss. Additionally, our published observations showing that formation of liver metastases in colorectal cancer exacerbates musculoskeletal wasting, suggests a possible role of the liver in mediating skeletal muscle and bone loss. In this regard, my preliminary studies suggest that fibroblast growth factor 21 (FGF21) and liver-insulin-like growth factor binding protein 1 (IGFBP1) contribute to musculoskeletal wasting in colorectal cancer. In preliminary studies, I found that mice bearing subcutaneous MC-38 colorectal tumors present with muscle and bone loss, along with high FGF21 and robust IGFBP1. Interestingly, treatment of hepatocytes with recombinant FGF21 induced IGFBP1 production. Contrarily, mice bearing subcutaneous C26 colorectal tumors, characterized by low FGF21 expression, have muscle loss without bone loss and markedly lower IGFBP1 compared to subcutaneous MC-38 hosts. However, mice bearing C26 liver metastases have exacerbated musculoskeletal wasting and higher IGFBP1 levels compared to mice bearing C26 subcutaneous tumors. Intriguingly, murine myotubes treated with recombinant IGFBP1 undergo atrophy, whereas anti-IGFBP1 neutralizing antibodies preserved myotube size in C2C12 cultures exposed to plasma from mice bearing C26 liver metastases, and C26 hosts infected with AAV- shIGFBP1 maintained muscle mass and strength. Hence, the objective of this proposal is to interrogate the FGF21-IGFBP1 axis in colorectal cancer-associated muscle and bone loss. Based on preliminary data and published work my central hypothesis is that tumor-derived FGF21 promotes cachexia and hepatic production of IGFBP1, which in turn mediates musculoskeletal wasting in colorectal cancer. In Aim 1, I will determine the effects of tumor- and host-derived FGF21 on hepatic IGFBP1 production and musculoskeletal wasting in colorectal cancer without bone metastases. I hypothesize that tumor-derived FGF21 promotes hepatic IGFBP1 and musculoskeletal wasting. In Aim 2 I will determine the IGFBP1-depedent effects on musculoskeletal wasting in colorectal cancer. I hypothesize that IGFBP1 promotes musculoskeletal wasting in colorectal cancer. The findings from the proposed studies will identify the FGF21-IGFBP1 axis as a novel therapeutic target for the treatment of muscle and bone wasting in colorectal cancer and will open new avenues for cachexia research.