骨髓微环境与多发性骨髓瘤

 骨髓微环境不仅支持正常造血细胞的生长和分化,而且有助于肿瘤细胞的生长,它在多发性骨髓瘤细胞的增生、分化、凋亡中起重要作用。多发性骨髓瘤（MM）的瘤细胞定居在骨髓很少浸润骨髓以外的器官,与肿瘤细胞所处的骨髓造血微环境密切相关。骨髓瘤细胞与骨髓基质细胞及细胞外基质相互黏附,并产生细胞因子,进而影响肿瘤细胞的存活,而且还影响瘤细胞对治疗的反应。MM是一个进展性、致死性疾病,传统的化疗很易发生耐药。目前随着免疫学、分子生物学的发展及对骨髓微环境的研究,一些新型的以生物学为基础的药物不仅针对瘤细胞本身,而且以骨髓微环境为靶子,通过改变骨髓微环境而达到克服耐药的目的,从而延长骨髓瘤患者的无病生存期。     

多发性骨髓瘤微环境中免疫细胞的作用及其机制

多发性骨髓瘤（MM）是一种浆细胞的恶性增殖性疾病。在MM的发生发展过程中,骨髓微环境（BMME）的作用不容忽视。通过产生免疫抑制细胞、效应细胞功能失调和产生细胞因子和代谢物等抑制抗肿瘤免疫等方式,诱发免疫微环境逐渐失衡,最终导致肿瘤的发生与发展。因此,深入研究BMME可增强人们对MM的认识,对于MM的治疗亦有重要意义。基于近年来BMME的研究进展,笔者论述了抗MM免疫细胞和促MM免疫细胞的作用及其机制,探讨了MM免疫微环境对免疫治疗效果的影响,并展望了未来MM的免疫治疗方法,为探索新的MM的免疫治疗手段提供了方向。     

Notch信号通路与多发性骨髓瘤发病机制的关系

 Notch信号通路调控机体正常组织器官形态发生、细胞凋亡和增殖等生理过程,是造血微环境调节造血细胞增殖与分化的重要信号通路。多发性骨髓瘤(MM)的发生、发展与骨髓微环境密切相关,有多种信号通路参与。新近研究发现Notch信号通路参与包括MM在内的多种肿瘤的发生发展,且是影响肿瘤侵袭、耐药的关键因素,为多发性骨髓瘤治疗的新靶点。     

多发性骨髓瘤与骨髓微环境关系的研究进展

多发性骨髓瘤(multiple myeloma,MM)是浆细胞克隆性增殖的恶性肿瘤,为血液系统的第二大恶性肿瘤。肿瘤细胞在骨髓环境中处于优势地位,其局部微环境为肿瘤细胞的生存和增殖提供了良好的基础,同时保护MM细胞免受药物诱导的凋亡[1]。骨髓微环境中的重要细胞成分(基质细胞、破骨细胞、骨髓源性抑制细胞等)和非细胞成分(细胞因子和液体环境)[2],对骨髓瘤的发生和发展具有重要作用,并影响疾病的临床表现和预后。     

异常代谢生物标志物在多发性骨髓瘤诊治中的研究进展

摘 要：多发性骨髓瘤是一种浆细胞恶性肿瘤。近年以多发性骨髓瘤的代谢水平为突破点研究其发病机制、治疗策略引起很多学者的关注。全文主要从多发性骨髓瘤肿瘤微环境出发,对其代谢及免疫微环境、微环境调节的分子机制及异常代谢物测定在骨髓瘤诊断、治疗反应、生存,以及异常代谢物在骨髓瘤治疗中的治疗前景进行综述。多发性骨髓瘤细胞的生长与增殖涉及葡萄糖、脂质和氨基酸代谢途径及其调节,其发生可能与己糖激酶1水平升高,部分脂质水平下降,天冬氨酸水平的升高有关。运用高通量质谱技术检测多发性骨髓瘤患者血清代谢组学的变化,部分代谢标志物可作为多发性骨髓瘤诊断、评估治疗反应和预后的敏感的生物标志物。     

CAR-T细胞治疗多发性骨髓瘤：问题及对策

多发性骨髓瘤是骨髓中浆细胞异常增生导致的恶性肿瘤,是第二大常见的血液系统恶性肿瘤。日益增多的生物治疗 方法为多发性骨髓瘤治疗提供新的思路和方向,CAR-T细胞疗法更是为复发/难治性多发性骨髓瘤患者带来治愈新希望。已有 多种靶向多发性骨髓瘤特异性靶标分子CAR-T细胞在临床试验中显示出较好的疗效,然而CAR-T细胞疗法仍存在疗效持续时 间不够长、肿瘤易复发等问题,这可能与CAR-T细胞持续性不足、肿瘤细胞表面抗原表达丢失、抗原逃逸、免疫抑制微环境损害T 细胞活性等因素相关。已有临床研究通过优化CAR设计、调整制备过程以产生富含特定T细胞亚群的CAR-T细胞、构建健康志 愿者来源的通用型CAR-T细胞、引入修饰基因以调节免疫抑制微环境或改善CAR-T细胞增殖能力等方法来提高CAR-T细胞的 效应功能并延长其持续作用时间,通过降低CAR结构中抗体免疫原性、引入开关机制等方法来提高CAR-T细胞疗法安全性。众 多研究为多发性骨髓瘤的CAR-T细胞治疗注入新的活力,也为抗肿瘤免疫治疗提供新的方法与选择。     

单细胞测序技术在多发性骨髓瘤中的研究进展

多发性骨髓瘤（MM）是一种由单克隆浆细胞异常增殖引起的恶性血液疾病。传统的高通量细胞测序仅仅反应细胞群体的异质性，却忽略单细胞中的遗传信息。单细胞测序技术的发展能够更清楚了解肿瘤和骨髓微环境中的细胞差异，深入探索MM的发病机制，并指导临床治疗。文章综述了单细胞测序技术的最新进展及其在MM发病机制、疾病进展监测、免疫治疗和治疗反应方面的应用。     

乏氧及Notch1在多发性骨髓瘤中的作用

多发性骨髓瘤(MM)存在明显的骨髓乏氧微环境,骨髓高表达乏氧诱导因子-1α(HIF-1α),其与预后不良相关.Notch信号通路是造血微环境中调控细胞增殖与分化的重要信号转导系统,与多发性骨髓瘤的发生和耐药有关.新近研究显示乏氧与Notch通路在多种恶性肿瘤发生发展中存在密切联系.乏氧微环境、HIF-1α及Notch相关信号通路的相互作用为开拓MM分子靶向治疗提供理论依据.     

多发性骨髓瘤综合治疗现状与进展

多发性骨髓瘤（MM）是浆细胞克隆增生性恶性肿瘤,其治疗效果较差,迄今仍视为不可治愈的疾病。近年来着眼于MM细胞内信号通路、骨髓微环境及二者的相互作用,MM的治疗有了很大进展。该文综述了MM的化学治疗、造血干细胞移植、生物治疗、支持治疗及免疫治疗现状及其进展。     

调节性免疫细胞在多发性骨髓瘤中的临床价值研究进展

多发性骨髓瘤（multiple myeloma,MM）是骨髓浆细胞恶性增殖性疾病。尽管新药的出现显著改善了MM患者的预后,复发与耐药的问题仍有待解决,深入分析MM免疫微环境可能是潜在的突破口。免疫抑制微环境的形成是MM的突出特征,导致抗肿瘤免疫监视受损,恶性浆细胞发生免疫逃逸。调节性免疫细胞是免疫抑制微环境形成的重要因素,与MM的发病、进展和耐药密切相关。随着MM进入免疫治疗时代,调节性免疫细胞在MM诊断、治疗和预后中的价值逐渐被发现,其数量或比例变化可能有助于MM早期诊断和预后评估,并有望成为新的治疗靶点。本文将对调节性免疫细胞在MM临床诊治中的研究进展进行综述。      

Molecular Crosstalk between Chromatin Remodeling and Tumor Microenvironment in Multiple Myeloma

Multiple myeloma (MM) is a complex disease driven by numerous genetic and epigenetic alterations that are acquired over time. Despite recent progress in the understanding of MM pathobiology and the availability of innovative drugs, which have pronounced clinical outcome, this malignancy eventually progresses to a drug-resistant lethal stage and, thus, novel therapeutic drugs/models always play an important role in effective management of MM. Modulation of tumor microenvironment is one of the hallmarks of cancer biology, including MM, which affects the myeloma genomic architecture and disease progression subtly through chromatin modifications. The bone marrow niche has a prime role in progression, survival, and drug resistance of multiple myeloma cells. Therefore, it is important to develop means for targeting the ecosystem between multiple myeloma bone marrow microenvironment and chromatin remodeling. Extensive gene expression profile analysis has indeed provided the framework for new risk stratification of MM patients and identifying novel molecular targets and therapeutics. However, key tumor microenvironment factors/immune cells and their interactions with chromatin remodeling complex proteins that drive MM cell growth and progression remain grossly undefined.     

Input of DNA microarrays to identify novel mechanisms in multiple myeloma biology and therapeutic applications.

Multiple myeloma is a B-cell neoplasia characterized by the proliferation of a clone of malignant plasma cells in the bone marrow. We review here the input of gene expression profiling of myeloma cells and of their tumor microenvironment to develop new tumor classifiers, to better understand the biology of myeloma cells, to identify some mechanisms of drug sensitivity and resistance, to identify new myeloma growth factors, and to depict the complex interactions between tumor cells and their microenvironment. We discuss how these findings may improve the clinical outcome of this still incurable disease.     

Bone marrow stromal cells create a permissive microenvironment for myeloma development: a new stromal role for Wnt inhibitor Dkk1

The rapid progression of multiple myeloma is dependent upon cellular interactions within the bone marrow microenvironment. In vitro studies suggest that bone marrow stromal cells (BMSC) can promote myeloma growth and survival and osteolytic bone disease. However, it is not possible to recreate all cellular aspects of the bone marrow microenvironment in an in vitro system, and the contributions of BMSCs to myeloma pathogenesis in an intact, immune competent, in vivo system are unknown. To investigate this, we used a murine myeloma model that replicates many features of the human disease. Coinoculation of myeloma cells and a BMSC line, isolated from myeloma-permissive mice, into otherwise nonpermissive mice resulted in myeloma development, associated with tumor growth within bone marrow and osteolytic bone disease. In contrast, inoculation of myeloma cells alone did not result in myeloma. BMSCs inoculated alone induced osteoblast suppression, associated with an increase in serum concentrations of the Wnt signaling inhibitor, Dkk1. Dkk1 was highly expressed in BMSCs and in myeloma-permissive bone marrow. Knockdown of Dkk1 expression in BMSCs decreased their ability to promote myeloma and the associated bone disease in mice. Collectively, our results show novel roles of BMSCs and BMSC-derived Dkk1 in the pathogenesis of multiple myeloma in vivo.     

Targeting the vascular endothelial growth factor pathway in the treatment of multiple myeloma

Multiple myeloma is a clonal plasma cell malignancy within the bone marrow associated with bone loss, renal disease and immunodeficiency. Despite new insights into the pathogenesis of multiple myeloma and novel targeted therapies, the median survival remains 3-5 years. It is now well established that the intimate relation between the tumor cells and components of the microenvironment plays a key role in multiple myeloma pathogenesis. Specifically, tumor cells impact the bone marrow and thereby cause immune suppression and lytic bone lesions; conversely, components of the bone marrow provide signals that influence the behavior of multiple myeloma cells, including tumor cell growth, survival, migration and drug resistance. Important contributing effectors are tumor cell-stroma cell and cell-extracellular matrix contacts, the bone marrow vasculature, and a variety of cytokines and growth factors in the bone marrow milieu.     

Differential expression of DKK-1 binding receptors on stromal cells and myeloma cells results in their distinct response to secreted DKK-1 in myeloma

Background  

The canonical Wnt signaling is concurrently important for osteoblast differentiation and myeloma cell proliferation. Its activation in myeloma cells and its inhibition in osteoblasts and their progenitors have been identified in the previous studies. Osteoblast progenitors and myeloma cells from a myeloma patient share the same bone marrow (BM) microenvironment, but respond differently to DKK-1 secreted by myeloma cells. The mechanisms remain unclear.     

Adhesion molecules—The lifelines of multiple myeloma cells

Multiple myeloma is an incurable hematological malignancy of terminally differentiated immunoglobulin-producing plasma cells. As a common presentation of the disease, the malignant plasma cells accumulate and proliferate in the bone marrow, where they disrupt normal hematopoiesis and bone physiology. Multiple myeloma cells and the bone marrow microenvironment are linked by a composite network of interactions mediated by soluble factors and adhesion molecules. Integrins and syndecan-1/CD138 are the principal multiple myeloma receptor systems of extracellular matrix components, as well as of surface molecules of stromal cells. CD44 and RHAMM are the major hyaluronan receptors of multiple myeloma cells. The SDF-1/CXCR4 axis is a key factor in the homing of multiple myeloma cells to the bone marrow. The levels of expression and activity of these adhesion molecules are controlled by cytoplasmic operating mechanisms, as well as by extracellular factors including enzymes, growth factors and microenvironmental conditions. Several signaling responses are activated by adhesive interactions of multiple myeloma cells, and their outcomes affect the survival, proliferation and migration of these cells, and in many cases generate a drug-resistant phenotype. Hence, the adhesion systems of multiple myeloma cells are attractive potential therapeutic targets. Several approaches are being developed to disrupt the activities of adhesion molecules in multiple myeloma cells, including small antagonist molecules, direct targeting by immunoconjugates, stimulation of immune responses against these molecules, and signal transduction inhibitors. These potential novel therapeutics may be incorporated into current treatment schemes, or directed against minimal residual malignant cells during remission.     

Targeting the vascular endothelial growth factor pathway in the treatment of multiple myeloma

Multiple myeloma is a clonal plasma cell malignancy within the bone marrow associated with bone loss, renal disease and immunodeficiency. Despite new insights into the pathogenesis of multiple myeloma and novel targeted therapies, the median survival remains 3–5 years. It is now well established that the intimate relation between the tumor cells and components of the microenvironment plays a key role in multiple myeloma pathogenesis. Specifically, tumor cells impact the bone marrow and thereby cause immune suppression and lytic bone lesions; conversely, components of the bone marrow provide signals that influence the behavior of multiple myeloma cells, including tumor cell growth, survival, migration and drug resistance. Important contributing effectors are tumor cell–stroma cell and cell–extracellular matrix contacts, the bone marrow vasculature, and a variety of cytokines and growth factors in the bone marrow milieu.     

Multiple myeloma: present and future.

Multiple myeloma is a clonal B-cell tumor of slowly proliferating plasma cells within the bone marrow. Among hematologic malignancies, it constitutes 10% of the cancers and ranks as the second most frequently occurring hematologic cancer in the United States, after non-Hodgkin lymphoma. Interleukin-6 is an important cytokine in myeloma cell growth and proliferation. Close cell-to-cell contact between myeloma cells and the bone marrow stromal cells triggers a large amount of interleukin-6 production, which supports the growth of these cells, as well as protecting them from apoptosis induced by dexamethasone and other chemotherapeutic agents. Therapies modulating the tumor and its microenvironment are being actively pursued with the goal of converting multiple myeloma to a chronic disease with the patients maintaining a normal lifestyle.     

Implication of bone marrow microenvironment in pathogenesis of multiple myeloma

Multiple myeloma is a hematooncological disease characterized by malignant proliferation of plasma cells. These cells accumulate in the bone marrow where they suppress physiological hematopoiesis; at the same time, these cells interact with a wide variety of cytokines, growth factors and adhesion molecules. It is obvious that the bone marrow microenvironment plays an important role in disease pathogenesis as well as treatment resistance.