Friedrich Reinhard E, Beer Carolin, Glatzel Markus, Hagel Christian
Department of Oral and Craniomaxillofacial Surgery, Eppendorf University Hospital, University of Hamburg, Hamburg, Germany
Institute of Neuropathology, Eppendorf University Hospital, University of Hamburg, Hamburg, Germany.
Anticancer Res. 2015 Jan;35(1):137-44.
BACKGROUND/AIM: Neurofibromas, benign tumors of the nerve sheaths, are the hallmark of neurofibromatosis type 1 (NF1), an autosomal-dominant inherited tumor predisposition syndrome. Malignant tumors arising from nerve sheath cells are an important factor influencing the life expectancy of NF1 patients. Expression of growth factors and growth factor receptors play a key role in the development of tumors. Therapy of peripheral nerve sheath (PNS) tumors is predominantly surgical. The outcome in malignant entities of NF1-affected patients remains poor, despite many efforts to implement pharmacological therapy into the treatment modalities. Growth of peripheral nerve sheath tumors is finely-adjusted by growth factors and PNS tumors express growth factor receptors. However, quantification of receptor expression and comparison to the expression of other related factors are not available. The aim of the present study was to determine growth factor expression relevant for growth control in neurofibromas of NF1.
Fifty-eight dermal, dermal/diffuse and plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNST) of NF1-affected patients were analyzed immunohistochemically for the expression of growth factors relevant for angiogenesis: vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and epithelial growth factor receptor (EGFR). The vessel density was also determined quantitatively by light microscopy.
Plexiform neurofibroma revealed a higher expression level for VEGF compared to dermal/diffuse neurofibroma. However, statistical significant differences for VEGF expression and of all other proteins investigated were found in comparison to MPNST only. EGFR expression was remarkably high in NF1 patients in their first decade of life. However, this result has to be interpreted with caution in view of the high number of young patients with MPNST in this age group. Vessel density correlated with tumor type. Vessel density increased significantly comparing benign nerve sheath tumors and MPNST (p<0.05).
DISCUSSION/CONCLUSION: This study revealed the presence of factors and receptors involved in angiogenesis as a prerequisite for tumor development and maintenance of PNS in NF1. These factors are highly expressed in all tumors of this study. This study reveals these relevant factors in nerve sheath tumors and also described the significant increase of vessel density in MPNST compared to benign counterparts. Anti-angiogenic drugs are presently investigated for application in NF1 tumor treatment, in particular for patients with a surgically-intractable high tumor burden. Drugs capable of blocking the EGFR receptor-mediated pathway are promising tools within the pharmacological repertoires to treat these patients.
背景/目的：神经纤维瘤是神经鞘的良性肿瘤，是1型神经纤维瘤病（NF1）的标志，NF1是一种常染色体显性遗传的肿瘤易感性综合征。神经鞘细胞来源的恶性肿瘤是影响NF1患者预期寿命的重要因素。生长因子和生长因子受体的表达在肿瘤发展中起关键作用。外周神经鞘（PNS）肿瘤的治疗主要是手术治疗。尽管在治疗模式中进行了许多实施药物治疗的努力，但NF1患者恶性肿瘤的治疗结果仍然很差。外周神经鞘肿瘤的生长由生长因子精细调节，且PNS肿瘤表达生长因子受体。然而，受体表达的定量以及与其他相关因子表达的比较尚无相关研究。本研究的目的是确定与NF1神经纤维瘤生长控制相关的生长因子表达。
对58例NF1患者的皮肤、皮肤/弥漫性和丛状神经纤维瘤以及恶性外周神经鞘瘤（MPNST）进行免疫组织化学分析，以检测与血管生成相关的生长因子的表达：血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF）和表皮生长因子受体（EGFR）。还通过光学显微镜对血管密度进行定量测定。
与皮肤/弥漫性神经纤维瘤相比，丛状神经纤维瘤的VEGF表达水平更高。然而，仅与MPNST相比，VEGF表达及所有其他研究蛋白的表达存在统计学显著差异。NF1患者在生命的第一个十年中EGFR表达显著升高。然而，鉴于该年龄组中MPNST年轻患者数量众多，该结果必须谨慎解读。血管密度与肿瘤类型相关。与良性神经鞘瘤和MPNST相比，血管密度显著增加（p<0.05）。
讨论/结论：本研究揭示了血管生成中涉及的因子和受体的存在，这是NF1中肿瘤发展和PNS维持的先决条件。这些因子在本研究的所有肿瘤中均高表达。本研究揭示了神经鞘瘤中的这些相关因子，并描述了与良性肿瘤相比MPNST中血管密度的显著增加。目前正在研究抗血管生成药物在NF1肿瘤治疗中的应用，特别是对于手术难以处理的高肿瘤负荷患者。能够阻断EGFR受体介导途径的药物是治疗这些患者的药理学方法中有前景的工具。
