Gastrointestinal Pathobiology Research Group, Department of Gastroenterological Surgery, Yale University School of Medicine, New Haven, CT 06520-8062, USA.
Neuroendocrinology. 2013;97(1):35-44. doi: 10.1159/000334891. Epub 2012 Jun 15.
Neuroendocrine neoplasms (NENs) are a heterogeneous family of malignancies whose proliferation is partially dependent on growth factors secreted by the microenvironment and the tumor itself. Growth factors which were demonstrated to be important in experimental models of NENs include EGF (epidermal growth factor), TGF (transforming growth factor) α, TGFβ and CTGF (connective tissue growth factor). EGF and TGFα bind to the EGF receptor to stimulate an intact RAS/RAF/MAPK pathway, leading to the transcription of genes associated with cell proliferation, invasion and metastasis. Theoretically, TGFα stimulation can be inhibited at several points of the MAPK pathway, but success is limited to NEN models and is not evident in the clinical setting. TGFβ1 stimulates TGFβ receptors (TGFβRI and TGFβRII) resulting in inhibition of neuroendocrine cell growth through SMAD-mediated activation of the growth inhibitor P21(WAF1/CIP1). Although some NENs are inhibited by TGFβ1, paradoxical growth is seen in experimental models of gastric and small intestinal (SI) NENs. Therapeutic targeting of TGFβ1 in NENs is therefore complicated by uncertainty of the effect of TGFβ1 secretion on the direction of proliferative regulation. CTGF expression is associated with more malignant clinical phenotypes in a variety of cancers, including NENs. CTGF promotes growth in gastric and SI-NEN models, and is implicated as a mediator of local and distant fibrosis caused by NENs of enterochromaffin cell origin. CTGF inhibitors are available, but their anti-proliferative effect has not been tested in NENs. In summary, growth factors are essential for NEN proliferation, and although interventions targeting these proteins are effective in experimental models, only limited clinical efficacy has been identified.
神经内分泌肿瘤（NENs）是一组异质性的恶性肿瘤，其增殖部分依赖于由微环境和肿瘤本身分泌的生长因子。在 NENs 的实验模型中，已证实重要的生长因子包括 EGF（表皮生长因子）、TGF（转化生长因子）α、TGFβ 和 CTGF（结缔组织生长因子）。EGF 和 TGFα 与 EGF 受体结合，刺激完整的 RAS/RAF/MAPK 途径，导致与细胞增殖、侵袭和转移相关的基因转录。从理论上讲，TGFα 刺激可以在 MAPK 途径的几个点被抑制，但成功仅限于 NEN 模型，在临床环境中并不明显。TGFβ1 刺激 TGFβ 受体（TGFβRI 和 TGFβRII），通过 SMAD 介导的生长抑制剂 P21（WAF1/CIP1）的激活抑制神经内分泌细胞生长。尽管一些 NEN 受到 TGFβ1 的抑制，但在胃和小肠（SI）NEN 的实验模型中观察到矛盾的生长。因此，TGFβ1 在 NEN 中的治疗靶向受到 TGFβ1 分泌对增殖调节方向的影响的不确定性的复杂化。CTGF 在各种癌症中与更恶性的临床表型相关，包括 NENs。CTGF 促进胃和 SI-NEN 模型的生长，并被认为是神经内分泌细胞来源的 NEN 引起的局部和远处纤维化的介质。CTGF 抑制剂可用，但它们在 NEN 中的抗增殖作用尚未得到测试。总之，生长因子是 NEN 增殖所必需的，尽管针对这些蛋白的干预在实验模型中有效，但仅确定了有限的临床疗效。
