Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
Adv Cancer Res. 2019;144:137-191. doi: 10.1016/bs.acr.2019.03.011. Epub 2019 Apr 24.
With few exceptions, metastasis is the terminal stage of cancer with limited therapeutic options. Metastasis consists of numerous phenotypic and genotypic alterations of cells that are directly and indirectly induced by multiple intrinsic (cellular) and extrinsic (micro-environmental) factors. To metastasize, a cancer cell often transitions from an epithelial to mesenchymal morphology (EMT), modifies the extracellular matrix, forms emboli and survives in the circulation, escapes immune surveillance, adheres to sites distant from the initial tumor and finally develops a blood supply (angiogenesis) and colonizes in a secondary niche (a micrometastasis). Scientific advances have greatly enhanced our understanding of the precise molecular and genetic changes, operating independently or collectively, that lead to metastasis. This review focuses on a unique gene, melanoma differentiation associated gene-9 (also known as Syntenin-1; Syndecan Binding Protein (sdcbp); mda-9/syntenin), initially cloned and characterized from metastatic human melanoma and shown to be a pro-metastatic gene. In the last two decades, our comprehension of the diversity of actions of MDA-9/Syntenin on cellular phenotype has emerged. MDA-9/Sytenin plays pivotal regulatory roles in multiple signaling cascades and orchestrates both metastatic and non-metastatic events. Considering the relevance of this gene in controlling cancer invasion and metastasis, approaches have been developed to uniquely and selectively target this gene. We also provide recent updates on strategies that have been successfully employed in targeting MDA-9/Syntenin resulting in profound pre-clinical anti-cancer activity.
除了少数例外，转移是癌症的终末期，治疗选择有限。转移由大量细胞的表型和基因型改变组成，这些改变直接和间接地由多种内在（细胞）和外在（微环境）因素诱导。为了转移，癌细胞通常从上皮形态转变为间充质形态（EMT），改变细胞外基质，形成栓塞并在循环中存活，逃避免疫监视，黏附在远离初始肿瘤的部位，最终发展出供血（血管生成）并在继发性小生境（微转移）中定植。科学的进步极大地增强了我们对导致转移的精确分子和遗传变化的理解，这些变化独立或共同作用。这篇综述集中讨论了一个独特的基因，黑色素瘤分化相关基因 9（也称为 Syntenin-1；黏附素结合蛋白（sdcbp）；mda-9/syntenin），最初从转移性人黑色素瘤中克隆并鉴定，被证明是一个促进转移的基因。在过去的二十年中，我们对 MDA-9/Syntenin 对细胞表型的多种作用的理解已经出现。MDA-9/Sytenin 在多种信号级联中发挥关键的调节作用，并协调转移和非转移事件。考虑到该基因在控制癌症侵袭和转移中的相关性，已经开发出了针对该基因的独特和选择性的方法。我们还提供了最近在靶向 MDA-9/Syntenin 方面取得的成功策略的更新，这些策略导致了深刻的临床前抗癌活性。
