Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
Adv Exp Med Biol. 2024;1460:727-766. doi: 10.1007/978-3-031-63657-8_25.
Higher body fat content is related to a higher risk of mortality, and obesity-related cancer represents approximately 40% of all cancer patients diagnosed each year. Furthermore, epigenetic mechanisms are involved in cellular metabolic memory and can determine one's predisposition to being overweight. Low-grade chronic inflammation, a well-established characteristic of obesity, is a central component of tumor development and progression. Cancer-associated adipocytes (CAA), which enhance inflammation- and metastasis-related gene sets within the cancer microenvironment, have pro-tumoral effects. Adipose tissue is a major source of the exosomal micro ribonucleic acids (miRNAs), which modulate pathways involved in the development of obesity and obesity-related comorbidities. Owing to their composition of cargo, exosomes can activate receptors at the target cell or transfer molecules to the target cells and thereby change the phenotype of these cells. Exosomes that are released into the extracellular environment are internalized with their cargo by neighboring cells. The tumor-secreted exosomes promote organ-specific metastasis of tumor cells that normally lack the capacity to metastasize to a specific organ. Therefore, the communication between neighboring cells via exosomes is defined as the "next-cell hypothesis." The reciprocal interaction between the adipocyte and tumor cell is realized through the adipocyte-derived exosomal miRNAs and tumor cell-derived oncogenic miRNAs. The cargo molecules of adipocyte-derived exosomes are important messengers for intercellular communication involved in metabolic responses and have very specific signatures that direct the metabolic activity of target cells. RNA-induced silencing regulates gene expression through various mechanisms. Destabilization of DICER enzyme, which catalyzes the conversion of primary miRNA (pri-miRNA) to precursor miRNA (pre-miRNA), is an important checkpoint in cancer development and progression. Interestingly, adipose tissue in obesity and tumors share similar pathogenic features, and the local hypoxia progress in both. While hypoxia in obesity leads to the adipocyte dysfunction and metabolic abnormalities, in obesity-related cancer cases, it is associated with worsened prognosis, increased metastatic potential, and resistance to chemotherapy. Notch-interleukin-1 (IL-1)-Leptin crosstalk outcome is referred to as "NILCO effect." In this chapter, obesity-related cancer development is discussed in the context of "next-cell hypothesis," miRNA biogenesis, and "NILCO effect."
较高的体脂肪含量与更高的死亡率相关，而与肥胖相关的癌症约占每年诊断出的所有癌症患者的 40%。此外，表观遗传机制参与细胞代谢记忆，并能决定一个人超重的倾向。低度慢性炎症是肥胖的一个公认特征，是肿瘤发生和发展的一个核心组成部分。癌症相关脂肪细胞（CAA）增强了癌症微环境中与炎症和转移相关的基因集，具有促进肿瘤的作用。脂肪组织是外泌体微小核糖核酸（miRNA）的主要来源，这些 miRNA 调节与肥胖和肥胖相关合并症发展相关的途径。由于其货物组成，外泌体可以激活靶细胞上的受体或将分子转移到靶细胞，并由此改变这些细胞的表型。释放到细胞外环境中的外泌体被邻近细胞内化并携带其货物。肿瘤分泌的外泌体促进肿瘤细胞的器官特异性转移，而这些肿瘤细胞通常缺乏转移到特定器官的能力。因此，通过外泌体进行的邻近细胞之间的通讯被定义为“下一个细胞假说”。脂肪细胞和肿瘤细胞之间的相互作用是通过脂肪细胞衍生的外泌体 miRNA 和肿瘤细胞衍生的致癌 miRNA 实现的。脂肪细胞衍生的外泌体的货物分子是参与代谢反应的细胞间通讯的重要信使，并且具有非常特定的特征，指导靶细胞的代谢活性。RNA 诱导的沉默通过多种机制调节基因表达。DICER 酶的失稳，该酶催化初级 miRNA（pri-miRNA）转化为前体 miRNA（pre-miRNA），是癌症发展和进展中的一个重要检查点。有趣的是，肥胖和肿瘤中的脂肪组织具有相似的致病特征，并且两者都存在局部缺氧进展。虽然肥胖中的缺氧导致脂肪细胞功能障碍和代谢异常，但在肥胖相关的癌症病例中，它与预后恶化、转移潜力增加和化疗耐药性相关。Notch-白细胞介素-1（IL-1）-瘦素相互作用的结果被称为“NILCO 效应”。在这一章中，将根据“下一个细胞假说”、miRNA 生物发生和“NILCO 效应”讨论与肥胖相关的癌症发展。
