Adenosine is a signaling molecule that exerts dual effects on tumor growth: while it inhibits immune cell function and thereby prevents surveillance by the immune system, it influences tumorigenesis directly via activation of adenosine receptors on tumor cells at the same time. However, the adenosine-mediated mechanisms affecting oncogenic processes particularly in head and neck squamous cell carcinomas (HNSCC) are not fully understood. Here, we investigated the role of adenosine receptor activity on HNSCC-derived cell lines. Targeting the adenosine receptor A2B (ADORA2B) on these cells with the inverse agonist/antagonist PSB-603 leads to inhibition of cell proliferation, transmigration as well as VEGFA secretion in vitro. At the molecular level, these effects were associated with cell cycle arrest as well as the induction of the apoptotic pathway. In addition, shRNA-mediated downmodulation of ADORA2B expression caused decreased proliferation. Moreover, in in vivo xenograft experiments, chemical and genetic abrogation of ADORA2B activity impaired tumor growth associated with decreased tumor vascularization. Together, our findings characterize ADORA2B as a crucial player in the maintenance of HNSCC and, therefore, as a potential therapeutic target for HNSCC treatment.

中文翻译：

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腺苷受体2B的活性促进头颈部鳞状细胞癌细胞的自主生长，迁移以及血管形成。

腺苷是一种信号分子，对肿瘤的生长具有双重作用：虽然它抑制免疫细胞功能，从而阻止免疫系统的监视，但它同时通过激活肿瘤细胞上的腺苷受体直接影响肿瘤发生。然而，腺苷介导的影响致癌过程的机制，特别是在头颈部鳞状细胞癌（HNSCC）中，尚不完全清楚。在这里，我们调查了腺苷受体活性对HNSCC衍生细胞系的作用。用反向激动剂/拮抗剂PSB-603将腺苷受体A2B（ADORA2B）靶向这些细胞可抑制细胞增殖，迁移和体外VEGFA分泌。在分子水平上，这些作用与细胞周期停滞以及凋亡途径的诱导有关。此外，shRNA介导的ADORA2B表达下调导致增殖减少。此外，在体内异种移植实验中，ADORA2B活性的化学和遗传废除损害了与肿瘤血管生成减少有关的肿瘤生长。总之，我们的发现将ADORA2B表征为HNSCC维持中的关键角色，因此成为HNSCC治疗的潜在治疗靶标。