The Tumor Microenvironment in Neuroendocrine Tumors: Biology and Therapeutic Implications
The Tumor Microenvironment in Neuroendocrine Tumors: Biology and Therapeutic Implications
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DOI：
10.1159/000497355
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发表时间：
2019-08-01
影响因子：
4.1
通讯作者：
Silvestris, Franco
中科院分区：
文献类型：
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作者：
Cives, Mauro;Pelle', Eleonora;Silvestris, Franco
神经内分泌肿瘤（NETs）包括弥漫性神经内分泌系统中产生的一组异质性恶性肿瘤，其特征为惰性生长。这些肿瘤微环境的细胞组分之间发生复杂的相互作用，识别其相互作用和串扰的分子介质对于发现新的治疗靶点至关重要。NET细胞过表达过多的促血管生成分子，包括血管内皮生长因子、血小板衍生生长因子、成纤维细胞生长因子、脑信号蛋白和促血管生成素，其促进内皮细胞前体的募集和增殖，从而导致大多数血管化癌症的微血管密度比上皮肿瘤高10倍。此外，NET与基质细胞在局部和远端位点进行多方面的相互作用，以及它们的5-羟色胺、结缔组织生长因子和转化生长因子β的旁分泌是否主要驱动成纤维细胞活化以增强肿瘤增殖，另一方面，NET衍生的促纤维化因子加速细胞外基质重塑并有助于心脏瓣膜和/或肠系膜纤维化发展，也就是说，英语教师的功能出现了重大的并发症。然而，目前，对NET的免疫景观知之甚少，但越来越多的证据表明，肿瘤浸润性中性粒细胞，肥大细胞和/或巨噬细胞通过直接或间接的机制共同促进这些肿瘤的新血管生成开关。另一方面，免疫检查点分子在NET周围细胞中异质表达，并且鉴于其低突变负荷，尚不清楚肿瘤浸润淋巴细胞是否在微环境中具有抗肿瘤武装。在这里，我们回顾了胃肠胰腺和肺NET的微环境以及旨在靶向肿瘤-宿主相互作用的既定和创新治疗的现有知识。
Neuroendocrine tumors (NETs) include a heterogeneous group of malignancies arising in the diffuse neuroendocrine system and characterized by indolent growth. Complex interactions take place among the cellular components of the microenvironment of these tumors, and the recognition of the molecular mediators of their interplay and cross talk is crucial to discover novel therapeutic targets. NET cells overexpress a plethora of proangiogenic molecules including vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, semaphorins, and angiopoietins that promote both recruitment and proliferation of endothelial cell precursors, thus resulting among the most vascularized cancers with a microvessel density 10-fold higher than epithelial tumors. Also, NETs operate multifaceted interactions with stromal cells, both at local and distant sites, and whether their paracrine secretion of serotonin, connective tissue growth factor, and transforming growth factor beta primarily drives the fibroblast activation to enhance the tumor proliferation, on the other side NET-derived profibrotic factors accelerate the extracellular matrix remodeling and contribute to heart valves and/or mesenteric fibrosis development, namely, major complications of functioning NETs. However, at present, little is known on the immune landscape of NETs, but accumulating evidence shows that tumor-infiltrating neutrophils, mast cells, and/or macrophages concur to promote the neoangiogenic switch of these tumors by either direct or indirect mechanisms. On the other hand, immune checkpoint molecules are heterogeneously expressed in NETs' surrounding cells, and it is unclear whether or not tumor-infiltrating lymphocytes are antitumor armed within the microenvironment, given their low mutational load. Here, we review the current knowledge on both gastroenteropancreatic and pulmonary NETs' microenvironment as well as both established and innovative treatments aimed at targeting the tumor-host interplay.