Department of Pathology, Christian-Albrechts-University, Arnold-Heller-Str. 3, Haus 14, 24105, Kiel, Germany.
Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
Gastric Cancer. 2019 Nov;22(6):1130-1142. doi: 10.1007/s10120-019-00964-6. Epub 2019 Apr 15.
Metabolic reprogramming in gastric cancer (GC) involves not only an alteration of glucose metabolism, but also of insulin receptor (IR) expression. We investigated if (1) GCs express the IR in cancer cells (CC-IR) and vasculature (VIR), (2) IR expression is clinically relevant and may be a novel target of GC treatment.
467 primary GCs were studied by immunohistochemistry using an IR-specific antibody. CD31-immunostaining ensured the presence of representative intratumoral microvasculature. VIR, and membranous and cytoplasmic CC-IR (mCC-IR, cCC-IR) were evaluated using a modified HistoScore (HScore) and subsequently dichotomized into low or high IR expressions. The IR status was correlated with clinico-pathological patient characteristics, including survival and HER2 status.
VIR, mCC-IR, and cCC-IR (HScore > 0) were found in 97.0%, 87.6%, and 95.7% of all GCs. After dichotomization of the HScores, 50.7, 48.8, and 50.3% were classified as VIR-high, mCC-IR-high, and cCC-IR-high, respectively. IR was associated with the Laurén phenotype, tumor localization, local tumor growth, vascular invasion, perineural invasion, tumor budding, mucin phenotype, UICC stage, worse survival, and the HER2 status. On multivariate analysis, VIR status was an independent prognosticator of overall (p = 0.010) and tumor-specific (p = 0.006) patient survival.
VIR and CC-IR expressions are frequent in GC, biologically significant and even correlate with the HER2 status, opening avenues for novel putative therapeutic interventions in GC.
胃癌（GC）的代谢重编程不仅涉及葡萄糖代谢的改变，还涉及胰岛素受体（IR）的表达。我们研究了（1）GC 是否在癌细胞（CC-IR）和脉管系统（VIR）中表达 IR，（2）IR 表达是否具有临床意义，并且可能成为 GC 治疗的新靶点。
使用特异性 IR 抗体的免疫组织化学方法研究了 467 例原发性 GC。CD31 免疫染色确保了代表性肿瘤内微血管的存在。使用改良的 HistoScore（HScore）评估 VIR 以及膜和细胞质 CC-IR（mCC-IR、cCC-IR），并随后将其分为低或高 IR 表达。IR 状态与临床病理患者特征相关，包括生存和 HER2 状态。
97.0%、87.6%和 95.7%的所有 GC 中均发现了 VIR、mCC-IR 和 cCC-IR（HScore>0）。HScores 二分化后，分别有 50.7%、48.8%和 50.3%被归类为 VIR-high、mCC-IR-high 和 cCC-IR-high。IR 与 Lauren 表型、肿瘤定位、局部肿瘤生长、血管侵犯、神经周围侵犯、肿瘤芽生、粘蛋白表型、UICC 分期、较差的生存和 HER2 状态相关。多变量分析显示，VIR 状态是总生存（p=0.010）和肿瘤特异性生存（p=0.006）的独立预后因素。
GC 中 VIR 和 CC-IR 的表达频繁，具有生物学意义，甚至与 HER2 状态相关，为 GC 中的新型潜在治疗干预开辟了途径。
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