Identification of key tumor cell-released factors that induce cachexia

描述（由申请人提供）：恶病质是一种消耗性疾病，其特征是肌肉进行性损失，伴有或不伴有脂肪量损失，通常与癌症相关，估计是20%至40%癌症患者死亡的直接原因。恶病质的突出临床特征是体重减轻，沿着厌食、炎症、胰岛素抵抗和增加的肌肉蛋白质分解。然而，由于对其病因学的认识不足，目前还没有FDA批准的用于癌症诱导的恶病质的治疗方法。基于现有的数据，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，以通过刺激蛋白质水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介导。然而，诱导分解代谢作用的关键肿瘤细胞释放因子的身份仍然难以捉摸。在初步研究中，我们发现一些恶病质肿瘤细胞组成性释放特定的热休克蛋白（HSP），这似乎是肿瘤诱导恶病质的关键因素。传统上，热休克蛋白主要被认为是细胞内的分子伴侣，用于蛋白质的折叠、组装和转位，从而使它们具有细胞保护作用。最近，热休克蛋白已被证明是由某些细胞，包括肿瘤细胞，释放到细胞外空间，在那里他们发挥了重要作用，在细胞间串扰。肿瘤细胞释放的热休克蛋白已被证明通过免疫细胞引发炎症反应并促进转移。重要的是，高血清HSP水平与结直肠癌和肺癌患者的高死亡率相关，其中恶病质通常是死亡的直接原因。然而，细胞外热休克蛋白对肌肉细胞的影响是未知的。初步数据表明，肿瘤细胞释放的热休克蛋白通过直接作用于肌肉细胞以激活细胞蛋白降解系统，对肿瘤诱导的肌肉紧张症至关重要。我们建议评估肿瘤释放的热休克蛋白在恶病质的发展中的作用，利用细胞和分子的方法，在细胞培养和癌症恶病质的小鼠模型。本研究的目的有三：1）评价肿瘤细胞释放的热休克蛋白对恶病质的作用; 2）阐明细胞外热休克蛋白诱导肌肉紧张症的信号传导机制; 3）确定肿瘤细胞组成性释放热休克蛋白的机制。本项目的成功将为癌症恶病质的病因学和治疗建立一个新的范式。尽管恶病质影响约50%的癌症患者，但它基本上未经治疗。通过上述提出的研究理解细胞外HSP在癌症恶病质中的作用，可以通过利用已经被FDA批准用于人类使用或临床试验的试剂在短期内测试人类癌症恶病质的治疗，所述试剂抑制HSP、其膜受体和细胞内信号传导途径或其从肿瘤细胞释放。

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.