Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria.
Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria; Department of Internal Medicine 2, University Hospital Krems, Mitterweg 10, 3500 Krems an der Donau, Austria.
Cytokine. 2023 Jan;161:156062. doi: 10.1016/j.cyto.2022.156062. Epub 2022 Nov 1.
In Multiple Myeloma (MM) the finely tuned homeostasis of the bone marrow (BM) microenvironment is disrupted. Evasion of programmed cell death (apoptosis) represents a hallmark of cancer. Besides genetic aberrations, the supportive and protective MM BM milieu, which is constituted by cytokines and growth factors, intercellular and cell: extracellular matrix (ECM) interactions and exosomes, in particular, plays a key role in the abundance of pro-survival members of the Bcl-2 family (i.e., Mcl-1, Bcl-2, and Bcl-xL) in tumor cells. Moreover, microenvironmental cues have also an impact on stability- regulating post-translational modifications of anti-apoptotic proteins including de/phosphorylation, polyubiquitination; on their intracellular binding affinities, and localization. Advances of our molecular knowledge on the escape of cancer cells from apoptosis have informed the development of a new class of small molecules that mimic the action of BH3-only proteins. Indeed, approaches to directly target anti-apoptotic Bcl-2 family members are among today's most promising therapeutic strategies and BH3-mimetics (i.e., venetoclax) are currently revolutionizing not only the treatment of CLL and AML, but also hold great therapeutic promise in MM. Furthermore, approaches that activate apoptotic pathways indirectly via modification of the tumor microenvironment have already entered clinical practice. The present review article will summarize our up-to-date knowledge on molecular mechanisms by which the MM BM microenvironment, cytokines, and growth factors in particular, mediates tumor cell evasion from apoptosis. Moreover, it will discuss some of the most promising science- derived therapeutic strategies to overcome Bcl-2- mediated tumor cell survival in order to further improve MM patient outcome.
在多发性骨髓瘤（MM）中，骨髓（BM）微环境中精细的动态平衡被打乱。逃避程序性细胞死亡（凋亡）是癌症的一个标志。除了遗传异常外，由细胞因子和生长因子、细胞间和细胞：细胞外基质（ECM）相互作用以及外泌体组成的支持和保护 MM BM 环境在肿瘤细胞中大量存在抗凋亡 Bcl-2 家族成员（即 Mcl-1、Bcl-2 和 Bcl-xL）中起着关键作用。此外，微环境线索也会影响稳定性调节包括去磷酸化、多泛素化在内的抗凋亡蛋白的翻译后修饰；对其细胞内结合亲和力和定位。我们对癌细胞逃避凋亡的分子知识的进展为开发模仿 BH3-only 蛋白作用的新型小分子提供了信息。事实上，直接针对抗凋亡 Bcl-2 家族成员的方法是当今最有前途的治疗策略之一，BH3 模拟物（即 venetoclax）不仅正在彻底改变 CLL 和 AML 的治疗方法，而且在 MM 中也具有很大的治疗潜力。此外，通过改变肿瘤微环境间接激活凋亡途径的方法已经进入临床实践。本文综述了我们目前对 MM BM 微环境，特别是细胞因子和生长因子介导肿瘤细胞逃避凋亡的分子机制的最新认识。此外，它还讨论了一些最有前途的科学衍生的治疗策略，以克服 Bcl-2 介导的肿瘤细胞存活，以进一步改善 MM 患者的预后。
