Identification of key tumor cell-released factors that induce cachexia

描述(申请人提供)：恶病质是一种衰减性疾病，以肌肉进行性丧失为特征，伴有或不伴有脂肪质量丧失，经常与癌症有关，估计是20%至40%癌症患者的直接死亡原因。恶病质的显著临床特征是体重减轻，伴随着厌食、炎症、胰岛素抵抗和肌肉蛋白质分解增加。然而，由于对其病因的了解很少，目前还没有FDA批准的癌症诱发恶病质的治疗方法。根据现有的数据，我们假设快速生长的肿瘤通过释放因子来维持高水平的蛋白质合成，从而通过刺激蛋白质分解从骨骼肌中提取氨基酸，这是 由控制细胞蛋白质降解的系统调节。然而，诱导分解代谢作用的关键肿瘤细胞释放因子的特性仍然不清楚。在初步研究中，我们发现许多恶病质肿瘤细胞结构性地释放特异性热休克蛋白(HSPs)，这似乎是肿瘤诱导恶病质的关键因素。传统上，热休克蛋白主要作为细胞内的分子伴侣，负责蛋白质的折叠、组装和转位，从而使其具有细胞保护作用。最近，包括肿瘤细胞在内的某些细胞将热休克蛋白释放到细胞外空间，在细胞间串扰中发挥重要作用。研究表明，肿瘤细胞释放的热休克蛋白可通过免疫细胞激发炎症反应，促进肿瘤转移。重要的是，高水平的血清HSP水平与结直肠癌和肺癌患者的高死亡率有关，而恶病质往往是死亡的直接原因。然而，细胞外热休克蛋白对肌肉细胞的影响尚不清楚。初步数据表明，肿瘤细胞释放的热休克蛋白直接作用于肌肉细胞，激活细胞蛋白降解系统，对肿瘤诱导的肌肉分解代谢至关重要。我们建议在细胞培养和癌症恶病质小鼠模型中，利用细胞和分子方法评估肿瘤释放的热休克蛋白在恶病质发展中的作用。本研究的目的有三个：1)评价肿瘤细胞释放的热休克蛋白在恶病质中的作用；2)阐明细胞外热休克蛋白诱导肌肉分解代谢的信号机制；3)确定肿瘤细胞结构性释放热休克蛋白的机制。当前项目的成功将为癌症恶病质的病因和治疗建立一个新的范例。尽管恶病质影响了大约50%的癌症患者，但它基本上没有得到治疗。通过以上拟议的研究了解细胞外HSPs在癌症恶病质中的作用，可以在短期内利用FDA已批准用于人类的试剂或临床试验来测试对癌症恶病质的治疗，这些试剂可以抑制HSPs、其膜受体和细胞内信号通路，或它们从肿瘤细胞中的释放。

DESCRIPTION (provided by applicant): Cachexia, a wasting disease characterized by progressive loss of muscle with or without loss of fat mass, is frequently associated with cancer and is estimated to be the immediate cause of death in 20% to 40% of cancer patients. The prominent clinical feature of cachexia is weight loss, along with anorexia, inflammation, insulin resistance, and increased muscle protein breakdown. However, due to the poor understanding of its etiology there is currently no FDA-approved treatment for cancer-induced cachexia. Based on existing data, we postulate that fast growing tumors sustain high-level protein synthesis by releasing factors to extract amino acids from skeletal muscle via stimulating proteolysis, which is mediated by the systems that govern cellular protein degradation. However, the identities of the key tumor cell-release factors that induce the catabolic actions remain elusive. In preliminary studies, we found that a number of cachectic tumor cells constitutively release specific heat shock proteins (HSPs), which appear to be critical agents in tumor-induced cachexia. Traditionally, HSPs are primarily known as intracellular molecular chaperones for protein folding, assembly, and translocation, thus making them cytoprotective. Recently, HSPs have been shown being released by certain cells, including tumor cells, into the extracellular space where they play a major role in intercellular crosstalk. Tumor cell-released HSPs have been shown to elicit inflammatory responses via immune cells and promote metastasis. Importantly, high serum level of HSP associates with the high mortality in patients with colorectal and lung cancer, of which cachexia is often the immediate cause of death. However, the effects of extracellular HSPs on muscle cells are unknown. Preliminary data suggest that tumor cell- released HSPs are crucial for tumor-induced muscle catabolism by acting directly on muscle cells to activate the cellular protein degradation systems. We propose to evaluate the role of tumor-released HSPs in the development of cachexia, utilizing cellular and molecular approaches, in cell culture and mouse models of cancer cachexia. Three specific aims will be pursued: 1) to evaluate the contribution of tumor cell-released HSPs to cachexia; 2) to elucidate the signaling mechanism through which extracellular HSPs induce muscle catabolism; and 3) to determine the mechanism of constitutive release of HSPs by tumor cells. Success of the current project would establish a new paradigm for the etiology and treatment of cancer cachexia. Despite the fact that cachexia affects about 50% of cancer patients, it is essentially left untreated. By understanding the role of extracellular HSPs in cancer cachexia through the proposed studies above, treatment of cancer cachexia in humans could be tested in the short-term by utilizing reagents that have already been approved by the FDA for human use or clinical trials that inhibit HSPs, their membrane receptors and intracellular signaling pathways, or their release from tumor cells.