Qian Xiaozhe, Zhang Donglei, Cao Ziang, Ma Haitao
Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Front Oncol. 2021 Apr 8;11:655861. doi: 10.3389/fonc.2021.655861. eCollection 2021.
Esophageal cancer (EC) is among the most malignant cancers globally due to its aggressiveness and poor survival. To set off from the inflammatory tumor immune microenvironment, we analyzed tumor tissues of EC patients with or without lymphatic metastasis to explore the importance of cancer cell derived neurotransmitters. Results have emphasized that the accumulation of dopamine but not other neurotransmitters could be observed in EC tumor tissue of patients, especially those who are bearing lymphatic metastasis. Transcriptional analysis of mentioned tissues was also performed to filter out key enzymes involved in dopamine pathway including tyrosine hydroxylase (TH), DOPA decarboxylase (DCC), monoamine oxidase (MAO), Further analysis on tumor tissues of patients indicated that dopamine receptor D5 was aberrantly upregulated and co-located with TH. Both and tests have demonstrated that dopamine could stimulate the proliferation and outgrowth of EC tumor cells the DRD5 mediated pathway. The exploration of mechanism has unveiled that activation of the dopamine pathway significantly enhanced the uptake of glucose and production of lactate of EC tumor cells. It can also facilitate the extracellular acid rate (ECAR), dedicating that DRD5-mediated activated dopamine pathway could effectively form and trigger Warburg effect, which is modulated by the cross-talk of mTOR and AKT pathway. Our results would unveil the relationship between cancer derived neurotransmitters and inflammatory tumor immune microenvironment, thus provide potential therapeutic targets and novel clinical strategy towards metastatic EC.
食管癌（EC）因其侵袭性和低生存率，是全球最恶性的癌症之一。从炎性肿瘤免疫微环境出发，我们分析了有或无淋巴转移的EC患者的肿瘤组织，以探究癌细胞衍生神经递质的重要性。结果强调，在患者的EC肿瘤组织中，尤其是那些有淋巴转移的患者中，可以观察到多巴胺的积累，而非其他神经递质。我们还对上述组织进行了转录分析，以筛选出多巴胺途径中涉及的关键酶，包括酪氨酸羟化酶（TH）、多巴脱羧酶（DCC）、单胺氧化酶（MAO）。对患者肿瘤组织的进一步分析表明，多巴胺受体D5异常上调，并与TH共定位。实验和测试均表明，多巴胺可通过DRD5介导的途径刺激EC肿瘤细胞的增殖和生长。机制探索揭示，多巴胺途径的激活显著增强了EC肿瘤细胞对葡萄糖的摄取和乳酸的产生。它还可以促进细胞外酸化率（ECAR），表明DRD5介导的激活多巴胺途径可以有效地形成并触发瓦伯格效应，这是由mTOR和AKT途径的相互作用调节的。我们的结果将揭示癌症衍生神经递质与炎性肿瘤免疫微环境之间的关系，从而为转移性EC提供潜在的治疗靶点和新的临床策略。
