Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Department of Surgery, Creighton University School of Medicine, Omaha, NE 68178, USA.
Int J Mol Sci. 2020 Nov 12;21(22):8502. doi: 10.3390/ijms21228502.
Pancreatic ductal adenocarcinoma (PDAC), an extremely aggressive invasive cancer, is the fourth most common cause of cancer-related death in the United States. The higher mortality in PDAC is often attributed to the inability to detect it until it has reached advanced stages. The major challenge in tackling PDAC is due to its elusive pathology, minimal effectiveness, and resistance to existing therapeutics. The aggressiveness of PDAC is due to the capacity of tumor cells to alter their metabolism, utilize the diverse available fuel sources to adapt and grow in a hypoxic and harsh environment. Therapeutic resistance is due to the presence of thick stroma with poor angiogenesis, thus making drug delivery to tumor cells difficult. Investigating the metabolic mediators and enzymes involved in metabolic reprogramming may lead to the identification of novel therapeutic targets. The metabolic mediators of glucose, glutamine, lipids, nucleotides, amino acids and mitochondrial metabolism have emerged as novel therapeutic targets. Additionally, the role of autophagy, macropinocytosis, lysosomal transport, recycling, amino acid transport, lipid transport, and the role of reactive oxygen species has also been discussed. The role of various pro-inflammatory cytokines and immune cells in the pathogenesis of PDAC and the metabolites involved in the signaling pathways as therapeutic targets have been previously discussed. This review focuses on the therapeutic potential of metabolic mediators in PDAC along with stemness due to metabolic alterations and their therapeutic importance.
胰腺导管腺癌（PDAC）是一种极具侵袭性的癌症，是美国第四大常见的癌症相关死亡原因。PDAC 死亡率较高的原因通常是因为在其发展到晚期之前无法检测到。治疗 PDAC 的主要挑战是由于其难以捉摸的病理、效果不佳以及对现有治疗方法的耐药性。PDAC 的侵袭性是由于肿瘤细胞改变其代谢、利用各种可用燃料来源在缺氧和恶劣的环境中适应和生长的能力。治疗耐药性是由于存在厚的基质，血管生成不良，因此难以将药物输送到肿瘤细胞。研究参与代谢重编程的代谢介质和酶可能会导致新的治疗靶点的确定。葡萄糖、谷氨酰胺、脂质、核苷酸、氨基酸和线粒体代谢的代谢介质已成为新的治疗靶点。此外，自噬、巨胞饮作用、溶酶体转运、再循环、氨基酸转运、脂质转运以及活性氧的作用也已被讨论。各种促炎细胞因子和免疫细胞在 PDAC 发病机制中的作用以及参与信号通路的代谢物作为治疗靶点之前已经讨论过。本综述重点讨论了代谢介质在 PDAC 中的治疗潜力以及代谢改变引起的干性及其治疗重要性。
