The knowledge of the molecular landscape of ileal neuroendocrine tumors (NETs) is affected by the lack of systematic studies investigating intra-tumoral heterogeneity. In this study, intra-tumoral heterogeneity was investigated in 27 primary ileal G1-NETs and their matched nodal and liver metastases in order to assess the tumor grading, the expression status of two somatostatin receptor isoforms (i.e. SSTR2A and SSTR5) and mTOR signaling dysregulation (ph-mTOR, ph-p70S6K, ph-4EBP1, PTEN and miR-21). Among the 27 G1 primary tumors, 4 shifted to G2 in the matched liver metastasis. Although mTOR activation was pretty consistent between primary and secondary malignancies, mTOR effectors (ph-p70S6K and ph-4EBP1) were overexpressed in matched liver metastases, whereas PTEN expression profile changed in only two cases. MiR-21 was significantly up-regulated in the metastatic setting. Although SSTRs expression was present in most of the primary tumors and matched metastasis, we found SSTR5 expression to be significantly increased in liver metastases. Notably, SSTRs expression was heterogeneous within the same lesions in most of the lesions. Overall, despite primary and metastatic ileal NETs show a similar molecular landscape, tumor grading and mTOR signaling pathway may diverge in the metastatic setting, thus affecting prognosis and treatment.

中文翻译：

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mTOR 通路和生长抑素受体在回肠 NETs 中表达瘤内异质性。

由于缺乏调查肿瘤内异质性的系统研究，回肠神经内分泌肿瘤 (NETs) 的分子景观知识受到影响。在这项研究中，研究了 27 个原发性回肠 G1-NET 及其匹配的淋巴结和肝转移瘤的肿瘤内异质性，以评估肿瘤分级、两种生长抑素受体亚型（即 SSTR2A 和 SSTR5）的表达状态和 mTOR 信号传导失调(ph-mTOR、ph-p70S6K、ph-4EBP1、PTEN 和 miR-21)。在 27 个 G1 原发肿瘤中，4 个在匹配的肝转移中转移到 G2。尽管 mTOR 激活在原发性和继发性恶性肿瘤之间非常一致，但 mTOR 效应子（ph-p70S6K 和 ph-4EBP1）在匹配的肝转移灶中过表达，而 PTEN 表达谱仅在两种情况下发生变化。MiR-21 在转移环境中显着上调。尽管 SSTRs 表达存在于大多数原发性肿瘤和匹配的转移灶中，但我们发现 SSTR5 表达在肝转移灶中显着增加。值得注意的是，在大多数病灶中，同一病灶内的 SSTR 表达是异质的。总体而言，尽管原发性和转移性回肠 NET 显示出相似的分子结构，但肿瘤分级和 mTOR 信号通路在转移性环境中可能存在差异，从而影响预后和治疗。