Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany.
Institute of Pathology, University Hospital Marburg, Philipps-University Marburg, Marburg, Germany.
J Neuroendocrinol. 2024 Feb;36(2):e13364. doi: 10.1111/jne.13364. Epub 2024 Jan 21.
Neuroendocrine tumors of the small intestine (SI-NETs) often develop lymph node metastasis (LNM)-induced mesenteric fibrosis (MF). MF can cause intestinal obstruction as well as ischemia and render surgical resection technically challenging. The underlying pathomechanisms of MF are still not well understood. We examined mesenteric LNM and the surrounding stroma compartment from 24 SI-NET patients, including 11 with in situ presentation of strong MF (MF+) and 13 without MF (MF-). Differential gene expression was assessed with the HTG EdgeSeq Oncology Biomarker Panel comparing MF+ with MF- within LNM and paired stromal samples, respectively. Most interesting differentially expressed genes were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in combination with validation of associated protein levels utilizing immunohistochemistry (IHC) staining of MF+ and MF- formalin-fixed, paraffin-embedded (FFPE) patient samples. Overall, 14 genes measured with a 2549-gene expression panel were differentially expressed in MF+ patients compared to MF-. Of those, nine were differentially expressed genes in LNM and five genes in the stromal tissue (>2-fold change, p < .05). The top hits included increased COMP and COL11A1 expression in the stroma of MF+ patients compared to MF-, as well as decreased HMGA2, COL6A6, and SLC22A3 expression in LNM of MF+ patients compared to LNM of MF- patients. RT-qPCR confirmed high levels of COMP and COL11A1 in stroma samples of MF+ compared to MF- patients. IHC staining confirmed the enrichment of α-smooth muscle actin-positive fibrosis in MF+ compared to MF- patients with corresponding increase of COMP-expressing stromal cells in MF+. Since COMP is associated with the known driver for fibrosis development transforming growth factor beta and with a cancer-associated fibroblasts enriched environment, it seems to be a promising new target for MF research.
小肠神经内分泌肿瘤（SI-NET）常发生淋巴结转移（LNM）诱导的肠系膜纤维化（MF）。MF 可导致肠梗阻、缺血，并使手术切除具有挑战性。MF 的潜在病理机制尚不清楚。我们检查了 24 例 SI-NET 患者的肠系膜 LNM 及其周围基质区室，其中 11 例为原位 MF 强阳性（MF+），13 例为 MF 阴性（MF-）。我们使用 HTG EdgeSeq Oncology Biomarker Panel 分别比较了 LNM 和配对的基质样本中 MF+和 MF-的差异基因表达。利用免疫组织化学（IHC）染色对 MF+和 MF-福尔马林固定、石蜡包埋（FFPE）患者样本中相关蛋白水平的验证，对最有趣的差异表达基因进行了逆转录定量聚合酶链反应（RT-qPCR）验证。总体而言，在 MF+患者中，与 MF-相比，14 个用 2549 个基因表达谱测量的基因差异表达。其中，9 个在 LNM 中差异表达，5 个在基质组织中差异表达（>2 倍变化，p<0.05）。排名靠前的基因包括与 MF+患者相比，基质中 COMP 和 COL11A1 的表达增加，以及与 MF-患者相比，LNM 中 HMGA2、COL6A6 和 SLC22A3 的表达减少。RT-qPCR 证实了与 MF-患者相比，MF+患者基质样本中 COMP 的高表达。IHC 染色证实了与 MF-患者相比，MF+患者中 α-平滑肌肌动蛋白阳性纤维化的富集，以及与 MF+患者中 COMP 表达的基质细胞的相应增加。由于 COMP 与已知的纤维化发展驱动因子转化生长因子-β有关，并且与富含癌症相关成纤维细胞的环境有关，因此它似乎是 MF 研究的一个很有前途的新靶点。
