Malignant cells exhibit elevated rates of protein synthesis and secretion to facilitate tumor growth, proliferation, and tumorigenesis. Upon malignant transformation, the endoplasmic reticulum (ER) experiences stress due to the accumulation of unfolded or misfolded proteins in the ER lumen, lack of nutrient availability and overall hostile tumor microenvironment conditions. The demand for regulated protein turnover and proteostasis reinstatement results in the activation of the unfolded protein response (UPR) pathway for cellular adaptation and survival. The UPR machinery utilizes the BiP chaperone and three ER-bound sensors, PERK, IRE1, and ATF6, to substantiate signal transduction and orchestrate gene expression associated with protein folding, degradation and recycling, inflammation, autophagy, and programmed cell death. The pleiotropic function of UPR emerges as a central mediator for tumor progression, especially in multiple myeloma and glioblastoma pathologies. Numerous studies have recently pointed out that communication of the extracellular matrix (ECM) with surrounding tumor cells dictates in part UPR activity and vice versa. In the context of this dynamic interplay, ER stress and UPR mechanisms have been proposed as potential targets to elicit novel and effective therapeutic approaches in clinical trials.
恶性细胞表现出较高的蛋白质合成与分泌速率，以促进肿瘤生长、增殖及肿瘤发生。在恶性转化过程中，由于未折叠或错误折叠蛋白在内质网腔内的积累、营养物质缺乏以及整体恶劣的肿瘤微环境条件，内质网承受应激压力。为满足对蛋白质周转调控及蛋白质稳态恢复的需求，细胞会激活未折叠蛋白反应通路以实现细胞适应与存活。该反应机制利用BiP分子伴侣及三种内质网膜结合传感器——PERK、IRE1和ATF6，完成信号转导并协调与蛋白质折叠、降解与循环、炎症反应、自噬及程序性细胞死亡相关的基因表达。未折叠蛋白反应的多效性功能已成为肿瘤进展的核心调控因素，在多发性骨髓瘤和胶质母细胞瘤病理过程中尤为显著。近期多项研究指出，细胞外基质与周围肿瘤细胞的交互作用部分决定了未折叠蛋白反应的活性，反之亦然。在这种动态相互作用背景下，内质网应激与未折叠蛋白反应机制已被提议作为临床试验中开发新型有效治疗策略的潜在靶点。
肿瘤(癌症)患者之家