文章：

超越TGFβ：其他TGFβ超家族成员在癌症中的作用

Beyond TGFβ: roles of other TGFβ superfamily members in cancer

原文发布日期：2013-01-10

DOI: 10.1038/nrc3500

类型: Review Article

开放获取: 否

要点：

1. The bone morphogenetic proteins (BMPs), activins, NODAL, and growth and differentiation factors (GDFs) (collectively referred to as BANGs) have essential roles in early embryonic development and in regulating tissue homeostasis in adults, frequently acting in gradients shaped by the activity of ligand antagonists. Their roles in human cancer frequently constitute a redeployment of their activities in embryonic development or a perturbation of their roles in tissue homeostasis.
2. Abberant BMP signalling disrupts stem cell self-renewal and differentiation, and can contribute to tumour formation. This may occur, for example, at the level of genetic or epigenetic changes resulting in the overexpression of BMP antagonists, or the loss of BMP receptors, ligands or SMAD4.
3. NODAL is not expressed in most normal adult tissues, but is expressed, along with the co-receptor CRIPTO, in many different tumours. It promotes phenotypic plasticity, which is important for tumour progression, and can positively regulate cancer stem cell self-renewal.
4. High BMP signalling provides a natural barrier to tumour progression and metastasis. In the primary tumour, BMP signalling inhibits epithelial-to-mesenchymal transition (EMT), which can prevent tumour invasion. At metastatic sites, high BMP signalling prevents tumour cell colonization by enforcing a dormant state. This can be reversed by tumour-expressed BMP antagonists.
5. BANGs sculpt the tumour microenvironment by promoting angiogenesis and suppressing immune responses.
6. Increased expression of BANGs in tumours and as a result of chemotherapy can contribute to severe complications of cancer such as cachexia, anaemia and bone loss.
7. Strategies are under development to target BANG signalling for therapeutic ends. These include inhibiting NODAL–CRIPTO signalling in the tumour cells, reducing tumour angiogenesis by inhibiting activin receptor-like kinase 1 (ALK1), and inhibiting activin receptors and myostatin to treat cachexia, anaemia and bone loss. Therapies that aim to increase BMP activity are also being developed.

要点翻译：

1. 骨形态发生蛋白（BMPs）、激活素、NODAL以及生长分化因子（GDFs）（统称为BANGs）在早期胚胎发育和调节成年组织稳态中具有重要作用，其功能常通过配体拮抗剂形成的梯度浓度来实现。这些因子在人类癌症中的作用往往是对其胚胎发育功能的重新激活或组织稳态调节功能的紊乱。
2. 异常的BMP信号会破坏干细胞的自我更新与分化，并可能促进肿瘤形成。例如，这种异常可能源于遗传或表观遗传改变导致BMP拮抗剂过表达，或BMP受体、配体及SMAD4的缺失。
3. NODAL在大多数正常成人组织中不表达，但在多种肿瘤中与辅助受体CRIPTO共同表达。它通过促进表型可塑性（对肿瘤进展至关重要）来正向调控癌症干细胞的自我更新。
4. 强BMP信号天然阻碍肿瘤进展与转移。在原发性肿瘤中，BMP信号通过抑制上皮-间质转化（EMT）来阻止肿瘤侵袭；在转移灶中，则通过迫使肿瘤细胞进入休眠状态以阻止其定植，而这一过程可被肿瘤表达的BMP拮抗剂逆转。
5. BANGs通过促进血管生成和抑制免疫反应塑造肿瘤微环境。
6. 肿瘤中BANGs表达升高及化疗诱导的表达增强可能导致癌症严重并发症，如恶病质、贫血和骨质流失。
7. 目前正在开发针对BANG信号通路的治疗策略：包括抑制肿瘤细胞中NODAL-CRIPTO信号传导、通过抑制激活素受体样激酶1（ALK1）减少肿瘤血管生成、以及阻断激活素受体和肌生长抑制素以治疗恶病质、贫血和骨质流失。同时，旨在增强BMP活性的疗法也在研发中。

英文摘要：

Much of the focus on the transforming growth factor-β (TGFβ) superfamily in cancer has revolved around the TGFβ ligands themselves. However, it is now becoming apparent that deregulated signalling by many of the other superfamily members also has crucial roles in both the development of tumours and metastasis. Furthermore, these signalling pathways are emerging as plausible therapeutic targets. Their roles in tumorigenesis frequently reflect their function in embryonic development or in adult tissue homeostasis, and their influence extends beyond the tumours themselves, to the tumour microenvironment and more widely to complications of cancer such as cachexia and bone loss.

摘要翻译： 

转化生长因子-β（TGFβ）超家族在癌症中的研究大多聚焦于TGFβ配体本身。然而，现已越来越清楚，该超家族其他众多成员的信号失调同样在肿瘤发展和转移中扮演关键角色。此外，这些信号通路正成为可行的治疗靶点。它们在肿瘤发生中的作用常常反映了其在胚胎发育或成体组织稳态中的功能，其影响不仅限于肿瘤本身，还波及肿瘤微环境，并更广泛地涉及癌症并发症如恶病质和骨丢失。

原文链接：

Beyond TGFβ: roles of other TGFβ superfamily members in cancer