Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Pharmacol Res. 2020 May;155:104695. doi: 10.1016/j.phrs.2020.104695. Epub 2020 Feb 13.
The primary cause of cancer-related death from solid tumors is metastasis. While unraveling the mechanisms of this complicated process continues, our ability to effectively target and treat it to decrease patient morbidity and mortality remains disappointing. Early detection of metastatic lesions and approaches to treat metastases (both pharmacological and genetic) are of prime importance to obstruct this process clinically. Metastasis is complex involving both genetic and epigenetic changes in the constantly evolving tumor cell. Moreover, many discrete steps have been identified in metastatic spread, including invasion, intravasation, angiogenesis, attachment at a distant site (secondary seeding), extravasation and micrometastasis and tumor dormancy development. Here, we provide an overview of the metastatic process and highlight a unique pro-metastatic gene, melanoma differentiation associated gene-9/Syntenin (MDA-9/Syntenin) also called syndecan binding protein (SDCBP), which is a major contributor to the majority of independent metastatic events. MDA-9 expression is elevated in a wide range of carcinomas and other cancers, including melanoma, glioblastoma multiforme and neuroblastoma, suggesting that it may provide an appropriate target to intervene in metastasis. Pre-clinical studies confirm that inhibiting MDA-9 either genetically or pharmacologically profoundly suppresses metastasis. An additional benefit to blocking MDA-9 in metastatic cells is sensitization of these cells to a second therapeutic agent, which converts anti-invasion effects to tumor cytocidal effects. Continued mechanistic and therapeutic insights hold promise to advance development of truly effective therapies for metastasis in the future.
实体肿瘤相关癌症死亡的主要原因是转移。虽然解开这个复杂过程的机制仍在继续，但我们有效靶向和治疗它以降低患者发病率和死亡率的能力仍然令人失望。早期发现转移病灶以及治疗转移的方法（包括药理学和遗传学方法）对于阻止这一过程在临床上具有重要意义。转移是一个复杂的过程，涉及不断进化的肿瘤细胞中的遗传和表观遗传变化。此外，在转移扩散中已经确定了许多离散的步骤，包括侵袭、血管内渗、血管生成、在远处部位的附着（二次播种）、外渗和微转移以及肿瘤休眠的发展。在这里，我们概述了转移过程，并强调了一个独特的促转移基因，黑色素瘤分化相关基因 9/衔接蛋白（MDA-9/衔接蛋白），也称为连接蛋白结合蛋白（SDCBP），它是大多数独立转移事件的主要贡献者。MDA-9 在广泛的癌和其他癌症中表达上调，包括黑色素瘤、多形性胶质母细胞瘤和神经母细胞瘤，这表明它可能提供一个适当的靶点来干预转移。临床前研究证实，无论是通过遗传还是药理学抑制 MDA-9，都能显著抑制转移。阻断转移性细胞中的 MDA-9 还有一个额外的好处，即这些细胞对第二种治疗药物变得敏感，从而将抗侵袭作用转化为肿瘤细胞杀伤作用。对机制和治疗的进一步深入了解有望为未来开发真正有效的转移性治疗方法提供前景。
