Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, Gothenburg, 405 30, Sweden.
Department of Vascular Surgery, Sahlgrenska University Hospital, Gothenburg, 413 45, Sweden.
BMC Cancer. 2023 Mar 23;23(1):267. doi: 10.1186/s12885-023-10722-8.
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.
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.
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.
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.
小肠类癌（SI-NET）是高度分化且遗传稳定的恶性肿瘤，但它们在诊断时经常已经发生晚期转移扩散。与许多其他类型的恶性肿瘤不同，原发性 SI-NET 通常没有症状，而且与相邻的淋巴结转移相比，其肿瘤通常较小。本研究旨在探讨刺激嗅觉受体 51E1（OR51E1）是否能降低 SI-NET 增殖的假说，这一假说表明，基于肿瘤位置的不同，存在一种可解释增殖率差异的机制。
临床数据用于解决肿瘤大小与位置的差异。使用 SI-NET 组织微阵列评估 OR51E1 和嗅觉标记蛋白（OMP）的表达。从 5 名患者中分离出原代培养的肿瘤细胞，以确定 OR51E1 激动剂壬酸对代谢活性的影响。使用 SI-NET 细胞系 GOT1 来确定壬酸对转录组的影响，以及壬酸暴露对细胞增殖、血清素分泌、细胞周期改变和形态的长期影响。
肿瘤大小与位置显著相关。OR51E1 和 OMP 通常在 SI-NET 中表达。原代 SI-NET 细胞对壬酸呈剂量依赖性的代谢活性改变，这在 GOT1 细胞系中得到了复制，但在 MCF10A 对照细胞系中没有得到复制。壬酸处理 GOT1 细胞上调了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 细胞可降低增殖、诱导衰老，并改变细胞形态。
我们的结果提出了这样一种可能性，即腔内代谢物的暴露可能代表决定 SI-NET 肿瘤表型的一个方面的机制。然而，我们不能将观察到的壬酸暴露的效应与 OR51E1 受体因果联系起来。
