Detjen Katharina M, Otto Raik, Giesecke Yvonne, Geisler Lukas, Riemer Pamela, Jann Henning, Grötzinger Carsten, Sers Christine, Pascher Andreas, Lüdde Tom, Leser Ulf, Wiedenmann Bertram, Sigal Michael, Tacke Frank, Roderburg Christoph, Hammerich Linda
Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
Knowledge Management in Bioinformatics, Institute for Computer Science, Humboldt-Universität zu Berlin, 12489 Berlin, Germany.
Cancers (Basel). 2021 Sep 4;13(17):4463. doi: 10.3390/cancers13174463.
The clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features.
We evaluated Flt3L gene expression in tumor tissue as well as circulating Flt3L levels as potential biomarkers in a cohort of 54 patients with GEP-NEN.
We detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted the disease-related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with the increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients' progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue.
We propose Flt3L as a prognostic biomarker for high grade GEP-NEN, harnessing its potential as a marker of an inflammatory tumor microenvironment. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, should be further evaluated to guide patient stratification and treatment decisions.
由于疾病的异质性，高级别胃肠胰神经内分泌肿瘤（GEP-NEN）的临床管理具有挑战性，这表明需要可靠的生物标志物来促进患者分层并指导治疗决策。FMS样酪氨酸激酶3配体（Flt3L）正在成为宿主肿瘤免疫反应的预后或预测替代标志物，可能有助于对具有其他类似肿瘤特征的患者进行分层。
我们评估了54例GEP-NEN患者队列中肿瘤组织中的Flt3L基因表达以及循环Flt3L水平作为潜在生物标志物。
我们在个别G2和G3神经内分泌肿瘤（NEN）中检测到Flt3L基因表达显著上调，但在G1神经内分泌肿瘤（NET）中未检测到。肿瘤组织中的Flt3L mRNA表达水平比传统的分级标准或神经内分泌癌/神经内分泌肿瘤（NEC/NET）分化更准确地预测了高增殖性G2和G3 NEN患者的疾病相关生存期。高水平的Flt3L mRNA表达与免疫原性细胞死亡、淋巴细胞效应功能和树突状细胞成熟相关基因的表达增加有关，表明Flt3L诱导的肿瘤具有较低的耐受性（更促炎）表型。重要的是，高级别NEN患者的循环Flt3L水平也升高，并且与患者的无进展生存期和疾病相关生存期相关，从而反映了在肿瘤组织中观察到的结果。
我们提出Flt3L作为高级别GEP-NEN的预后生物标志物，利用其作为炎症性肿瘤微环境标志物的潜力。血清中Flt3L的检测可以很容易地纳入临床常规，应进一步评估以指导患者分层和治疗决策。
