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Abstract：
Introduction Pituitary neuroendocrine tumors (PitNETs) are rare skull base tumors which can impart significant disability owing to their locally invasive potential. To date, the gamut of PitNET subtypes remains ill-understood at the ligand-receptor (LR) interactome level, potentially limiting therapeutic options. Here, we present findings from in silico analysis of LR complexes formed by PitNETs with clinical presentations of acromegaly, Cushing\'s disease, high prolactin production, and without symptoms of hormone hypersecretion. Methods Previously published PitNET gene expression data was acquired from ArrayExpress. These data represented all secretion types. LR interactions were analyzed via a crosstalk score approach. Results Cortisol (CORT) ligand was significantly involved in tumor-to-tumor signaling across all PitNET subtypes but prolactinomas, which evidenced active CORT depletion. Likewise, CCL25 ligand was implicated in 20% of the top LR complex interactions along the tumor-to-stroma signaling axis, but silent PitNETs reported unique depletion of the CCL25 ligand. Along the stroma-to-tumor signaling axis, all clinical PitNET subtypes enriched stromal vasoactive intestinal polypeptide ligand interactions with tumor secretin receptor. All clinical PitNET subtypes enriched stromal DEFB103B (human β-defensin 103B) ligand interactions with stromal chemokine receptors along the stroma-to-stroma signaling axis. In PitNETs causing Cushing\'s disease, immune checkpoint ligand CD274 reported high stromal expression, and prolactinomas reported low stromal expression. Moreover, prolactinomas evidenced distinctly high stromal expression of immune-exhausted T cell response marker IL10RA compared with other clinical subtypes. Conclusion Relative crosstalk score analysis revealed a great diversity of LR complex interactions across clinical PitNET subtypes and between solid tumor compartments. More data are needed to validate these findings and exact clinical importance.
摘要：
背景技术垂体神经内分泌肿瘤(PitNETs)是罕见的颅底肿瘤,其由于其局部侵入潜力而可赋予显著的残疾。迄今为止,PitNET亚型的色域在配体-受体（LR）相互作用组水平上仍然不清楚，可能限制治疗选择。这里,我们提出了由PitNETs形成的LR复合物的计算机分析结果，这些复合物具有肢端肥大症的临床表现，库欣病,高催乳素产量，没有激素分泌过多的症状.方法先前发表的PitNET基因表达数据来自ArrayExpress。这些数据表示所有分泌类型。通过串扰评分方法分析LR相互作用。结果皮质醇（CORT）配体显著参与所有PitNET亚型的肿瘤到肿瘤信号传导，但催乳素瘤，这证明了活性CORT的消耗。同样，CCL25配体涉及沿肿瘤到基质信号轴的20％的顶部LR复合物相互作用，但沉默的PitNETs报告了CCL25配体的独特消耗。沿着间质到肿瘤信号轴，所有临床PitNET亚型都丰富了基质血管活性肠多肽配体与肿瘤促胰液素受体的相互作用。所有临床PitNET亚型都沿着基质到基质信号轴富集了基质DEFB103B（人β-防御素103B）配体与基质趋化因子受体的相互作用。在导致库欣病的PitNETs中，免疫检查点配体CD274报道了高基质表达，催乳素瘤报告基质表达低。此外，与其他临床亚型相比，泌乳素腺瘤证明了免疫耗竭T细胞反应标志物IL10RA的基质表达明显较高。结论相对串扰评分分析揭示了跨临床PitNET亚型和实体瘤区室之间的LR复合物相互作用的巨大多样性。需要更多的数据来验证这些发现和确切的临床重要性。
