文章：

肿瘤中的IGF结合蛋白：机制和临床见解

IGF binding proteins in cancer: mechanistic and clinical insights

原文发布日期：2014-04-10

DOI: 10.1038/nrc3720

类型: Review Article

开放获取: 否

要点：

1. The insulin-like growth factor (IGF) binding proteins (IGFBPs) are a family of six proteins that function as transport proteins for IGF-I and IGF-II in the circulation and also regulate their access to the potentially oncogenic IGF-I receptor (IGF1R). 'Free' (unbound) IGFs have circulating half-lives of only a few minutes, whereas IGFBP-bound IGFs are much more stable.
2. IGFBPs modulate cell functions by both IGF-dependent mechanisms, which affect IGF1R signalling, and IGF-independent mechanisms, which do not involve changes in IGF1R signalling.
3. Many studies have examined the relationships between circulating IGFBP concentrations and cancer risk or prognosis, but few, if any, consistent associations have been found. By contrast, several studies suggest that tissue levels of IGFBPs or their mRNAs may be useful as prognostic markers.
4. No cancers have been attributed to IGFBP gene mutations, but some might be associated with epigenetic silencing of IGFBP gene expression (in particular, IGFBP3).
5. IGFBPs can function extracellularly but are also internalized into cells and can be transported into the nucleus. They inhibit tumour growth by promoting apoptosis and inhibiting cell proliferation, but in other circumstances they increase cell survival and stimulate proliferation.
6. Dichotomous effects on cell growth and survival are achieved by functional IGFBP interactions with many signalling systems, including both stimulatory and inhibitory cell-surface receptors (for example, the epidermal growth factor receptor and the transforming growth factor-β receptor, respectively), as well as nuclear receptors.
7. By regulating enzymes involved in sphingolipid metabolism, IGFBPs can affect the balance between growth-inhibitory lipids, such as ceramides, and growth-stimulatory lipids, such as sphingosine-1-phosphate. This could be a key mechanism by which IGFBP-3, IGFBP-5 and possibly other IGFBPs can regulate the balance between cell death and survival in response to certain cancer therapies.
8. These diverse properties of IGFBPs could make them, or pathways that they regulate, attractive targets for drug development.

要点翻译：

1. 胰岛素样生长因子（IGF）结合蛋白是一类由六种蛋白质组成的家族，它们在循环系统中作为IGF-I和IGF-II的转运蛋白，并调控这些生长因子与潜在致癌的IGF-I受体（IGF1R）的结合。“游离”（未结合）IGF在循环中的半衰期仅数分钟，而与IGFBP结合的IGF则稳定得多。
2. IGFBP通过IGF依赖机制（影响IGF1R信号传导）和IGF非依赖机制（不涉及IGF1R信号传导的改变）来调节细胞功能。
3. 许多研究探讨了循环IGFBP浓度与癌症风险或预后的关系，但鲜有一致的关联性发现。相比之下，多项研究表明组织中的IGFBP或其mRNA水平可能作为预后标志物。
4. 目前尚未发现由IGFBP基因突变直接导致的癌症，但某些癌症可能与IGFBP基因表达的表观遗传沉默（特别是IGFBP3）有关。
5. IGFBP既能在细胞外发挥作用，也能被内化进入细胞并转运至细胞核。它们通过促进细胞凋亡和抑制细胞增殖来抑制肿瘤生长，但在某些情况下也会增强细胞存活并刺激增殖。
6. 这种对细胞生长和存活的双重调节作用是通过IGFBP与多种信号系统的功能性相互作用实现的，包括刺激性和抑制性细胞表面受体（例如表皮生长因子受体和转化生长因子-β受体）以及核受体。
7. 通过调节参与鞘脂代谢的酶，IGFBP能够影响抑制生长的脂类（如神经酰胺）与促进生长的脂类（如1-磷酸鞘氨醇）之间的平衡。这可能是IGFBP-3、IGFBP-5及其他IGFBP成员在特定癌症治疗中调控细胞死亡与存活平衡的关键机制。
8. IGFBP的这些多样化特性使其本身及其调控通路成为药物开发中极具吸引力的靶点。

英文摘要：

The six members of the family of insulin-like growth factor (IGF) binding proteins (IGFBPs) were originally characterized as passive reservoirs of circulating IGFs, but they are now understood to have many actions beyond their endocrine role in IGF transport. IGFBPs also function in the pericellular and intracellular compartments to regulate cell growth and survival — they interact with many proteins, in addition to their canonical ligands IGF-I and IGF-II. Intranuclear roles of IGFBPs in transcriptional regulation, induction of apoptosis and DNA damage repair point to their intimate involvement in tumour development, progression and resistance to treatment. Tissue or circulating IGFBPs might also be useful as prognostic biomarkers.

摘要翻译： 

胰岛素样生长因子（IGF）结合蛋白（IGFBPs）家族的六个成员最初被描述为循环中IGF的被动储存库，但现在已知它们的作用远不止于IGF运输的内分泌功能。IGFBPs还在细胞周围和细胞内区域发挥作用，调节细胞生长与存活——除了其经典配体IGF-I和IGF-II外，它们还与多种蛋白质相互作用。IGFBPs在转录调控、诱导凋亡及DNA损伤修复中的核内作用表明它们与肿瘤的发生、进展及治疗耐药密切相关。组织或循环中的IGFBPs也可能作为预后生物标志物。

原文链接：

IGF binding proteins in cancer: mechanistic and clinical insights