Department of Physiology, The Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, MD, 21205, USA.
Department of Neurological Surgery, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Cancer Metastasis Rev. 2020 Jun;39(2):519-534. doi: 10.1007/s10555-020-09870-1.
Extracellular acidification is a well-known driver of tumorigenesis that has been extensively studied. In contrast, the role of endosomal pH is novel and relatively unexplored. There is emerging evidence from a growing number of studies showing that the pH of endosomal compartments controls proliferation, migration, stemness, and sensitivity to chemoradiation therapy in a variety of tumors. Endosomes are a crucial hub, mediating cellular communication with the external environment. By finely regulating the sorting and trafficking of vesicular cargo for degradation or recycling, endosomal pH determines the fate of plasma membrane proteins, lipids, and extracellular signals including growth factor receptors and their ligands. Several critical regulators of endosomal pH have been identified, including multiple isoforms of the family of electroneutral Na/H exchangers (NHE) such as NHE6 and NHE9. Recent studies have shed light on molecular mechanisms linking endosomal pH to cancer malignancy. Manipulating endosomal pH by epigenetic reprogramming, small molecules, or nanoparticles may offer promising new options in cancer therapy. In this review, we summarize evidence linking endosomal pH to cancer, with a focus on the role of endosomal Na/H exchangers and how they affect the prognosis of cancer patients, and also suggest how regulation of endosomal pH may be exploited to develop new cancer therapies.
细胞外酸化是众所周知的肿瘤发生驱动因素，已得到广泛研究。相比之下，内体 pH 的作用是新颖的，相对未被探索的。越来越多的研究提供了新的证据，表明内体隔室的 pH 控制着多种肿瘤中的增殖、迁移、干性和对放化疗的敏感性。内体是一个至关重要的枢纽，介导细胞与外部环境的通讯。通过精细调节囊泡货物的分拣和运输以进行降解或回收，内体 pH 决定了质膜蛋白、脂质和包括生长因子受体及其配体在内的细胞外信号的命运。已经确定了几个内体 pH 的关键调节剂，包括多种电中性 Na/H 交换器（NHE）家族的同工型，如 NHE6 和 NHE9。最近的研究揭示了将内体 pH 与癌症恶性联系起来的分子机制。通过表观遗传重编程、小分子或纳米颗粒来操纵内体 pH，可能为癌症治疗提供有前途的新选择。在这篇综述中，我们总结了将内体 pH 与癌症联系起来的证据，重点介绍了内体 Na/H 交换器的作用以及它们如何影响癌症患者的预后，并提出了如何调节内体 pH 以开发新的癌症治疗方法的建议。
