Abstract：
BACKGROUND: Small intestinal neuroendocrine tumors (SI-NET) are highly differentiated and genetically stable malignant tumors, yet they often present with advanced metastatic spread at the time of diagnosis. In contrast to many other types of malignant tumors, primary SI-NET are often asymptomatic and typically smaller in size compared to adjacent lymph node metastases. This study explores the hypothesis that stimulating the chemosensing olfactory receptor 51E1 (OR51E1) decreases SI-NET proliferation suggesting a mechanism that explains a difference in proliferative rate based on tumor location.
METHODS: Clinical data was used to address difference in tumor size depending on location. A SI-NET tissue microarray was used to evaluate expression of OR51E1 and olfactory marker protein (OMP). Primary cultured tumor cells from 5 patients were utilized to determine the effect of OR51E1 agonist nonanoic acid on metabolic activity. The SI-NET cell line GOT1 was used to determine effects of nonanoic acid on the transcriptome as well as long-term effects of nonanoic acid exposure with regards to cell proliferation, serotonin secretion, alterations of the cell-cycle and morphology.
RESULTS: Tumor size differed significantly based on location. OR51E1 and OMP were generally expressed in SI-NET. Primary SI-NET cells responded to nonanoic acid with a dose dependent altered metabolic activity and this was replicated in the GOT1 cell line but not in the MCF10A control cell line. Nonanoic acid treatment in GOT1 cells upregulated transcripts related to neuroendocrine differentiation and hormone secretion. Long-term nonanoic acid treatment of GOT1 cells decreased proliferation, induced senescence, and altered cell morphology.
CONCLUSIONS: Our results raise the possibility that exposure of intraluminal metabolites could represent a mechanism determining aspects of the SI-NET tumor phenotype. However, we could not causally link the observed effects of nonanoic acid exposure to the OR51E1 receptor.
METHODS: Clinical data was used to address difference in tumor size depending on location. A SI-NET tissue microarray was used to evaluate expression of OR51E1 and olfactory marker protein (OMP). Primary cultured tumor cells from 5 patients were utilized to determine the effect of OR51E1 agonist nonanoic acid on metabolic activity. The SI-NET cell line GOT1 was used to determine effects of nonanoic acid on the transcriptome as well as long-term effects of nonanoic acid exposure with regards to cell proliferation, serotonin secretion, alterations of the cell-cycle and morphology.
RESULTS: Tumor size differed significantly based on location. OR51E1 and OMP were generally expressed in SI-NET. Primary SI-NET cells responded to nonanoic acid with a dose dependent altered metabolic activity and this was replicated in the GOT1 cell line but not in the MCF10A control cell line. Nonanoic acid treatment in GOT1 cells upregulated transcripts related to neuroendocrine differentiation and hormone secretion. Long-term nonanoic acid treatment of GOT1 cells decreased proliferation, induced senescence, and altered cell morphology.
CONCLUSIONS: Our results raise the possibility that exposure of intraluminal metabolites could represent a mechanism determining aspects of the SI-NET tumor phenotype. However, we could not causally link the observed effects of nonanoic acid exposure to the OR51E1 receptor.
摘要：
背景：小肠神经内分泌肿瘤（SI-NET）是高度分化且遗传稳定的恶性肿瘤，然而，他们往往在诊断时出现晚期转移扩散。与许多其他类型的恶性肿瘤相比，原发性SI-NET通常无症状,与邻近淋巴结转移相比,体积通常较小.这项研究探索了刺激化学传感嗅觉受体51E1（OR51E1）降低SI-NET增殖的假设，这表明了一种解释基于肿瘤位置的增殖率差异的机制。
方法：临床数据用于解决肿瘤大小随位置的差异。SI-NET组织微阵列用于评估OR51E1和嗅觉标记蛋白(OMP)的表达。使用来自5名患者的原代培养的肿瘤细胞来确定OR51E1激动剂壬酸对代谢活性的影响。SI-NET细胞系GOT1用于确定壬酸对转录组的影响以及壬酸暴露对细胞增殖的长期影响，血清素分泌，细胞周期和形态学的改变。
结果：肿瘤大小因位置而异。OR51E1和OMP在SI-NET中普遍表达。原代SI-NET细胞对壬酸的反应具有剂量依赖性改变的代谢活性，这在GOT1细胞系中复制，但在MCF10A对照细胞系中未复制。GOT1细胞中壬酸处理上调与神经内分泌分化和激素分泌相关的转录本。长期壬酸处理GOT1细胞的增殖减少，诱导衰老，和改变细胞形态。
结论：我们的结果提出了管腔内代谢物的暴露可能代表决定SI-NET肿瘤表型的机制的可能性。然而,我们无法将观察到的壬酸暴露对OR51E1受体的影响因果关系联系起来.
方法：临床数据用于解决肿瘤大小随位置的差异。SI-NET组织微阵列用于评估OR51E1和嗅觉标记蛋白(OMP)的表达。使用来自5名患者的原代培养的肿瘤细胞来确定OR51E1激动剂壬酸对代谢活性的影响。SI-NET细胞系GOT1用于确定壬酸对转录组的影响以及壬酸暴露对细胞增殖的长期影响，血清素分泌，细胞周期和形态学的改变。
结果：肿瘤大小因位置而异。OR51E1和OMP在SI-NET中普遍表达。原代SI-NET细胞对壬酸的反应具有剂量依赖性改变的代谢活性，这在GOT1细胞系中复制，但在MCF10A对照细胞系中未复制。GOT1细胞中壬酸处理上调与神经内分泌分化和激素分泌相关的转录本。长期壬酸处理GOT1细胞的增殖减少，诱导衰老，和改变细胞形态。
结论：我们的结果提出了管腔内代谢物的暴露可能代表决定SI-NET肿瘤表型的机制的可能性。然而,我们无法将观察到的壬酸暴露对OR51E1受体的影响因果关系联系起来.
