Recent evidence suggests a high-sodium microenvironment in breast tumors. However, the exact role of this high-sodium microenvironment on tumorigenesis is unknown. Salt (sodium chloride, NaCl) is a well-known inflammatory molecule playing a significant role in various chronic ailments like cardiovascular and autoimmune diseases. Importantly, chronic inflammation is recognized as one of the major hallmarks of carcinogenesis. Breast cancer cell culture-based studies demonstrated that high-salt (HS) treatment (Δ35–50 mM NaCl) induced cancer cell proliferation. However, preclinical murine research showed reduced tumor progression kinetics in mice fed a short-term HS diet (4% NaCl diet, 0–2 weeks prior to the injection of tumor cells). Molecular studies demonstrated that the short-term HS diet induced the inflammatory activation of naïve CD4+ T cells to the Th17/Th1 anti-tumor phenotype. As human health-related adverse outcomes from HS diets usually occur as a consequence of prolonged HS intake over a period of several years, we have developed a novel chronic HS dietary murine tumor model. In this model, tumor cells are sequentially passaged (four cycles) in vivo under high-salt conditions, and tumor kinetics were analyzed in the passage-4 mice. These studies demonstrated enhanced tumor progression (pro-tumor) under chronic HS dietary conditions through the activation of tumor-initiating stem cells, along with the exhaustion of immune cells. Based on the, apparently paradoxical, evidence, we propose a comprehensive unifying hypothesis to elucidate the complex role of a high-sodium microenvironment towards tumor immune sculpting. This understanding will enable novel drug repositioning strategies, the development of unique ion channel-based anti-cancer therapeutics and promote low-salt diet intake in breast cancer patients on immunotherapy.
最新研究表明，乳腺肿瘤中存在高钠微环境，但该环境对肿瘤发生的具体作用尚不明确。食盐（氯化钠，NaCl）作为一种公认的炎症诱导分子，在心血管疾病和自身免疫性疾病等多种慢性疾病中发挥重要作用。值得注意的是，慢性炎症已被确认为致癌过程的主要特征之一。基于乳腺癌细胞培养的研究显示，高盐处理（Δ35–50 mM NaCl）可诱导癌细胞增殖。然而，临床前小鼠实验表明，短期高盐饮食（4% NaCl饲料，肿瘤细胞注射前0–2周）会减缓肿瘤进展速度。分子机制研究揭示，短期高盐饮食可诱导初始CD4+ T细胞向具有抗肿瘤特性的Th17/Th1表型发生炎症激活。鉴于人类因高盐饮食引发的健康损害通常需要数年长期累积，我们构建了一种新型慢性高盐饮食小鼠肿瘤模型。该模型通过在高盐条件下对肿瘤细胞进行连续体内传代（四个周期），并对第四代传代小鼠的肿瘤动力学进行分析。研究发现，慢性高盐饮食条件可通过激活肿瘤起始干细胞并耗竭免疫细胞，从而加速肿瘤进展（促肿瘤作用）。基于这些看似矛盾的证据，我们提出一个综合性统一假说，以阐明高钠微环境在肿瘤免疫重塑中的复杂作用。这一认识将有助于开发新型药物重定位策略，推动基于离子通道的抗癌疗法创新，并促进接受免疫治疗的乳腺癌患者实施低盐饮食干预。
High-Salt Tumor Microenvironment: Not as Bad as It Sounds, Not as Good as It Seems
肿瘤(癌症)患者之家