本帖最后由 定江定海 于 2014-1-13 10:47 编辑
The bone marrow stroma in hematological neoplasms—a guilty bystander
血液肿瘤中的骨髓间质 ---- 一个有罪的旁观者
Abstract | In the setting of hematological neoplasms, changes in the bone marrow (BM) stroma might arise from pressure exerted by the neoplastic clone in shaping a supportive microenvironment, or from chronic perturbation of the BM homeostasis. Under such conditions, alterations in the composition of the BM stroma can be profound, and could emerge as relevant prognostic factors. In this Review, we delineate the multifaceted contribution of the BM stroma to the pathobiology of several hematological neoplasms, and discuss the impact of stromal modifications on the natural course of these diseases. Specifically, we highlight the involvement of BM stromal components in lymphoid and myeloid malignancies, and present the most relevant processes responsible for remodeling the BM stroma. The role of bystander BM stromal elements in the setting of hematological neoplasms is discussed, strengthening the rationale for treatment strategies that target the BM stroma.
摘要|在血液肿瘤中，骨髓（BM）间质的改变可能是由于在形成有利的微环境时肿瘤性克隆所产生的压力，或是由于BM动态平衡的慢性扰动所引起的。在这种情况下，BM间质组成的变化会是非常大的，并且可能成为相关的预后因素。在本综述中，我们描述了BM间质对一些血液肿瘤的病理生物学有着多方面的贡献，并讨论了在这些疾病的自然病程中基质变化的影响。具体来说，我们强调了骨髓间质成分在淋巴和髓系恶性肿瘤中的参与作用，并提出了与重塑骨髓间质最相关的进程。我们对旁观者骨髓间质成分在血液肿瘤中的作用进行了讨论，以强化针对骨髓间质的治疗方法的基本原理。
Introduction
The interaction between hematopoietic stem cells (HSCs) and bone marrow (BM) mesenchymal cells occurs within functional niches and is responsible for the maintenance of BM homeostasis. Two distinct niches with specialized microenvironments can be identified in the BM that are able to support localization, survival, and self-renewal of stem cells—the osteoblastic (or endosteal) niche and the vascular niche.1 The osteoblastic niche, in close proximity to bone trabeculae and mainly composed of endosteal fibrocytes and osteoblasts, is associated with HSCs showing a maturation gradient towards the intertrabecular areas of the BM parenchyma. 2 The vascular niche displays a broad distribution along the BM parenchyma and is composed of endothelial cells and other vascular components, such as smooth muscle cells and adventitial reticular cells. 3 The microenvironment of each niche is interconnected, forming a complex network, but the two niches differentially influence HSCs. The osteoblastic niche favors HSC homing during development through chemotactic signals that originate from the interaction between CXCL-12 (SDF-1) and its receptor CXCR-4 on HSCs. This process is recapitulated by transplanted HSCs and several neoplastic populations that display BM tropism. 4 The osteoblastic niche also provides a nest for HSCs, in which signals from endosteal fibroblasts and osteoblasts maintain their quiescence while enabling self-renewal. These signals include cell-cell and cell-matrix adhesive interactions mediated by p1 integrins (a4, a7, and a9) and their ligands VCAM-1, type I collagen, tenascin-C, fibronectin, laminin, and osteopontin. 5 In addition to cell adhesion pathways, the Notch pathway is involved in both BM homeostasis and in the pathogenesis of lymphoid and myeloid malignancies.6 In particular, engagement of Notch on HCSs prevents HSC differentiation, and contributes to their quiescence in the osteoblastic niche.5,7 In addition to cellular components, soluble factors such as growth factors, cytokines, and matrix components also contribute to the composition of the BM osteoblastic and vascular niches to differently regulate HSC proliferation, mobilization, and differentiation dynamics (Table 1).
介绍
造血干细胞（HSCs）和骨髓（BM）间质细胞之间的相互作用发生在功能龛中并负责维持BM稳态。有着特定微环境的两个不同的龛-成骨（或内膜）龛和血管龛可以在能支持干细胞的定位，生存和自我更新的BM中被识别。1成骨龛，靠近骨小梁，主要由骨内膜纤维细胞和成骨细胞组成，与对BM实质的小梁区显示成熟梯度的造血干细胞相关联。2血管龛在BM实质中显示出广泛的分布，由内皮细胞和其他血管成分组成，如平滑肌细胞及外膜网状细胞。3每个龛的微环境是相互连接的，形成了一个复杂的网络，但两个不同的龛对造血干细胞的影响也不一样。通过CXCL -12（SDF-1）与其受体CXCR-4对造血干细胞的相互作用所引发的趋化信号，成骨龛在发展过程中更有利于HSC的归巢。这个过程由显示BM向性的移植造血干细胞和一些肿瘤群体所重演。4成骨龛也为造血干细胞提供了一个适宜的位置，其中来自内膜成纤维细胞和成骨细胞的信号在使自我更新的同时也维持了其静止状态。这些信号包括由p1整合素和它们的配体VCAM-1，I型胶原蛋白，腱生蛋白-C，纤连蛋白，层粘连蛋白和骨桥蛋白所介导的细胞-细胞和细胞-基质粘附相互作用（a4，a7和a9）。5除了细胞粘附的途径以外，Notch途径也参与在BM稳态和淋巴系和髓系恶性肿瘤的发病机制中。6特别的是，Notch与HCSS的结合阻止了HSC的分化，并有助于它们在成骨龛中的稳态。5,7除了作为细胞组分，可溶性因子如生长因子，细胞因子和基质成分也有助于BM成骨龛和血管龛的组成，并以不同的方式调控HSC的增殖，动员和分化动力学（表1）。
The vascular niche delivers maturation and activation signals to differentiating cells and controls the intravasation and extravasation of BM and foreign elements. 2 Blood vessels are evenly distributed throughout the BM parenchyma and considerable vascularity is also observed in the BM osteoblastic niche (Figure 1), where the unique composition of the extracellular matrix (ECM) and soluble mediator milieu renders the osteoblastic niche functionally different from that of the vascular niche. Cells that are characteristic of the vascular niche include endothelial cells, BM mesenchymal stem cells (BM-MSCs) that express the markers Nestin and CD146, and stromal cells expressing CD10, which all display different activation and adhesion phenotypes that influence their preference for selective hematopoietic elements. 8,9 Lineage fate can be determined by stromal cues. Multipotent, transformed CD34+ human cord blood cells transplanted into immunodeficient mice either lacking β2-microglobulin or expressing myeloid growth factors resulted in leukemias of lymphoid or myeloid lineages, respectively. 10
血管龛传递成熟和活化信号以分化细胞，并控制BM和外来成分的血管内渗和外渗。2血管均匀地分布在整个BM实质中，骨髓成骨龛中也能观察到相当多的血管供应（图1），其中细胞外基质（ECM）和可溶性介质环境的独特组合，使该成骨龛与血管龛在功能上有所不同。血管龛中特征性的细胞包括表达标记物Nestin和CD146的内皮细胞和骨髓间充质干细胞（BM- MSCs），以及表达CD10的间质细胞，它们都显示出影响其偏好选择性造血成分的不同的活化和粘附表型。8,9谱系结局可以通过间质线索来确定。多功能的转化型CD34+人脐带血细胞移植到缺乏β2-微球蛋白或表达髓细胞生长因子的免疫缺陷小鼠后会分别导致淋巴或骨髓谱系的白血病。10
The adipocyte component of the BM cannot be easily assigned to either of the two specialized niches. BM adipocyte content shows an inverse correlation with the hematopoietic cellularity in physiological (age-related changes) and pathological (BM failure) conditions. Adipocytes have an active role in regulating hematopoietic homeostasis through a direct suppressive influence on HSCs by reducing G-CSF and GM-CSF, and the release of adiponectin and tumor necrosis factor (TNF). 11
骨髓的脂肪细胞成分很难被归属到两个专门的龛其中之一。骨髓脂肪含量表明，在生理（年龄相关的变化）和病理（骨髓衰竭）条件下其与造血细胞数呈负相关。脂肪细胞在通过减少G-CSF和GM-CSF直接抑制影响造血干细胞来调节造血的动态平衡中以及在脂联素和肿瘤坏死因子（TNF）的释放中发挥着积极作用。11
The BM stroma has a critical role in the maintenance, renewal, and differentiation of HSCs. In lymphoid malignancies, the crosstalk between the BM stroma and neoplastic cells eventually contributes to the establishment of a permissive microenvironment for clone survival and progression. In myeloid malignancies, the stromal involvement is frequently characterized by profound changes, including angiogenesis, fibrosis, and/or new bone formation (osteosclerosis), which may retain clinical and prognostic significance as predictors of BM failure. 12-15 We highlight the role of the BM stroma in the development and course of lymphoid, plasma cell, and myeloid malignancies. The direct interactions of neoplastic elements with the BM stroma, its clone-related modifications, and its emerging immunomodulatory role eventually favoring the generation and progression of clones are discussed.
BM间质在造血干细胞的维护，更新以及分化中具有关键作用。在淋巴组织的恶性肿瘤中，BM间质和肿瘤细胞之间的串扰，最终有助于建立一个适宜克隆生存和发展的微环境。在髓系恶性肿瘤中，间质受累常常有着深刻的变化，包括血管形成，纤维化和/或新骨形成（骨硬化），这可能保留其预测BM衰竭的临床和预后意义。12-15我们重点描述了BM间质在淋巴，浆细胞和骨髓恶性肿瘤的发展和进程中的作用。我们还对肿瘤分子与BM间质，及其克隆相关的变化和新兴的免疫调节作用之间的直接相互作用最终促进克隆的产生和进展进行了讨论。
The BM stroma in lymphoid neoplasms
BM infiltration is a common feature of lymphoproliferative disorders, characterized by specific patterns depending on the disease entity. The relationship between BM infiltration and other histological parameters (including tissue architecture, stromal organization, and fibrosis) possibly reflects specific interactions with microenvironmental factors of the BM. 16-18 In most low-grade lymphomas, BM infiltration is associated with blood vessel proliferation and marked differences in the distribution of lymphoma and stromal cells. 19 Aggregates in follicular lymphoma, lymphoplasmacytic lymphoma, and mantle-cell lymphoma seem to maintain contact, at least initially, with the BM stromal architecture, whereas aggregates in chronic lymphocytic leukemia (CLL) and marginal zone lymphomas predominantly displace the pre-existing stroma. 19 Several factors, including adhesion molecules, contribute to the variation in BM-infiltration dynamics among lymphoid neoplasms. Indeed, leukemias and lymphomas that express BM-homing markers, such as CD44 (hyaluronan receptor) and/or CD22, but lack adhesive ligands required for the stable adhesion to the sinusoidal endothelium (E-selectin and P-selectin ligands), display a specific intrasinusoidal infiltration (Figure 1c). 20
淋巴组织肿瘤中的BM间质
骨髓浸润是淋巴增生性疾病的一个共同特征，这种特征取决于疾病实体的特定模式。骨髓浸润和其他组织学参数（包括组织架构，间质组织，纤维化）之间的关系很可能反映与BM的微环境因子的特异性相互作用。16-18在最低等的淋巴瘤中，骨髓浸润与血管增生以及淋巴瘤和间质细胞分布的显著性差异相关联。19滤泡性淋巴瘤，淋巴质浆细胞性淋巴瘤和外套细胞淋巴瘤中的聚集物似乎保持着联系，至少在最初阶段，与骨髓间质架构有关联，而慢性淋巴细胞白血病（CLL）和边缘区淋巴瘤中的聚集物大部分取代了预先存在的间质。19有几个因子，包括粘附分子，可促进淋巴系肿瘤中骨髓浸润动态的变化。事实上，在可表达BM-归巢标记物，如CD44（透明质酸受体）和/或CD22，但缺乏稳定附着在窦状内皮细胞上所需要的粘附性配体（E-选择素和P -选择素配体）的白血病和淋巴瘤中，显示出特定的窦内浸润（图1c）。20
Lymphoma cells that spread to the BM interstitium or form nodules are associated with the expression of a broader spectrum of adhesion markers, including P-selectin glycoprotein ligand-1 (CD162), and the integrins aLp2 and a4p1 (ligands of VCAM-1 and ICAM-1, respectively). 20 B-cell and T-cell leukemias and lymphomas characterized by an intrasinusoidal infiltration pattern in the BM, such as splenic marginal zone lymphomas, hairy-cell leukemia, and hepatosplenic T-cell lymphoma, frequently involve the spleen and the liver, where they display a prominent intravascular distribution. 21 Such characteristic behavior might imply a neoplastic cell preference for the BM vascular niche, which shares several features with the spleen and liver sinusoidal compartment, characterized by fenestrated sinusoids abundantly exposing hyaluronan and prominent subendothelial reticular cells expressing CXCL12. The tight interaction with the vascular niche through the CXCL12/CXCR4 axis may represent a drug resistance mechanism, and anti-CXCR4 therapeutic strategies have been proposed. 22
扩散到骨髓间质或形成结节的淋巴瘤细胞与粘附标记物更广谱的表达相关联，包括P-选择素糖蛋白配体-1（CD162），以及整合素αLβ2和α4β1（分别是VCAM-1和ICAM-1的配体）。 20 B-细胞和T-细胞白血病和淋巴瘤的特征是骨髓的窦内浸润模式，如脾边缘区淋巴瘤，多毛细胞白血病，和肝脾T-细胞淋巴瘤，常常累及显示出显著的血管分布的脾脏和肝脏。21这些特征性行为可能意味着肿瘤细胞偏向于BM血管龛，与脾脏和肝脏窦舱具有几个共同的特点，即有孔的血窦大量暴露着透明质酸和大量表达CXCL12的内皮下网状细胞。与经过CXCL12/CXCR4轴的血管龛的紧密相互作用可能代表了一种抗药机制，并且抗-CXCR4的治疗策略已经被提出。22
Key points
■ BM stromal changes in lymphoid malignancies are engendered by neoplastic cells to support their localization, proliferation and survival, and to suppress effective antitumor immune responses
■ Lymphoid neoplastic clones are able to manipulate the BM environment either directly, or through the co-optation of accessory cells such as macrophages and mast cells
■ Treatment strategies interfering with the axes involved in crosstalk between neoplastic cells and BM stroma may prove effective in lymphoid malignancies, when combined with therapies that target the neoplastic clones
■ Stromal alterations associated with myeloid malignancies, such as BM fibrosis, could be profound and negatively influence the clinical course of the disease and response to therapy
■ Drugs that could potentially control the proliferation of BM stromal components, such as tyrosine kinase inhibitors, proteasome inhibitors, and immunomodulatory agents are promising for the treatment of myeloid malignancies
要点
■在淋巴系统恶性肿瘤中骨髓间质的变化是由肿瘤细胞所引起的，以支持它们的定位，增殖和存活，并抑制有效的抗肿瘤免疫应答
■淋巴肿瘤性克隆是能够直接或通过吸收辅助细胞如巨噬细胞和肥大细胞来管理BM环境
■干扰参与肿瘤细胞和骨髓间质之间串扰的轴的治疗策略，当与靶向肿瘤克隆的疗法相结合时，可能被证明对淋巴组织的恶性肿瘤是有效的
■与髓系恶性肿瘤相关的间质的改变，如骨髓纤维化，可能是深刻的，并对疾病的临床过程和对治疗的反应产生负面影响
■能潜在地控制骨髓间质组分的药物，如酪氨酸激酶抑制剂，蛋白酶体抑制剂和免疫调节剂对髓系恶性肿瘤的治疗是很有前景的
Other lymphomas that infiltrate the BM, display a specific paratrabecular pattern in the osteoblastic niche (Figure 1d). 16,17 Non-Hodgkin lymphomas derived from germinal centers are often associated with large infiltrates, BM fibrosis, and megakaryocyte hyperplasia. 17 The pro- totypic example is follicular lymphoma, commonly presenting with paratrabecular aggregates containing small T lymphocytes, probably recruited through CCL17/CCL22, and possibly sustaining the neoplastic clone. 23 A similar BM histopathology also extends to other B-cell malignancies (for example, T-cell/histiocyte-rich diffuse large B-cell lymphoma) and T-cell lymphomas of follicular derivation (angioimmunoblastic T-cell lymphoma). 24-26 The extracellular meshwork of lymphoid follicles is associated with the stromal follicular dendritic cell and microvascular network, and shares several components with that of the BM osteoblastic niche, including integrin-p1, type I collagen, and matricellular protein expression. 27,28 These elements might provide a common adhesive background to neoplastic cells by favoring their location in the BM osteoblastic compartment, and signaling through the Notch stromal ligands Delta-like-1 and Jagged-1. 29
浸润骨髓的其他淋巴瘤，在成骨龛中显示出特定的小梁旁模式（图1d）。16,17来源于生发中心的非霍奇金淋巴瘤往往与大型浸润，骨髓纤维化，以及骨髓巨核细胞的增生有关。17原型的例子是滤泡性淋巴瘤，通常呈现小梁旁聚集，含有小T淋巴细胞，很可能通过招募CCL17/CCL22，进而维持肿瘤克隆。23类似的BM组织病理学还延伸到其它B细胞恶性肿瘤中（例如，T-细胞/组织细胞丰富的弥漫性大B细胞淋巴瘤）和滤泡衍生的T-细胞淋巴瘤（血管免疫母细胞性T细胞淋巴瘤）。24-26淋巴滤泡胞外网状组织与间质小结树突细胞和微血管网络相关联，并与BM成骨龛共有一些组分，包括整合素P1， I型胶原蛋白和胞外基质糖蛋白的表达。27,28这些分子可能通过帮助它们在骨髓成骨细胞隔室中的定位，并借助Notch基质配体Delta-样-1和Jagged-1传递信号为肿瘤细胞提供一个共同的粘附背景。29
Lymphoid neoplastic clone 淋巴肿瘤克隆
CCL-3/-4/-5 趋化因子CCL-3/-4/-5
CXCL-13 基质细胞源性因子-13
CXCR-4 C-X-C家族趋化因子受体
Integrins 整合素
Notch Notch信号
Clone survival 克隆存活率
VEGF bFGF Angiopoietins 血管内皮细胞生长因子，碱性成纤维细胞生长因子，血管生成素
CXCL12 VCAM-1 Notch ligands 基质细胞源性因子-12，血管细胞粘附分子-1，Notch配体
Stromal proliferation 间质增生
Stromal reticular cells 间质网状细胞
Fibronectin Collagens 纤连蛋白胶原
ECM deposition 细胞外基质沉积
IL-6 IL-8 TNF MMPs VEGF IFNs 白细胞介素-6，白细胞介素-8，肿瘤坏死因子，金属蛋白酶，血管内皮细胞生长，干扰素
Accessory cells 辅助细胞
Attraction 吸引
Mast cell 肥大细胞
Macrophage 巨噬细胞
Angiogenesis 血管发生
Vessels 脉管
VCAM-1 血管细胞粘附分子-1
Thus, the BM stroma may condition the degree and pattern of lymphoid infiltration and contribute to neoplastic cell survival. Notably, besides selectively homing to specific favorable microenvironments, neoplastic lymphocytes can actively promote BM stroma modifications to produce an ad hoc neoplastic niche. 30 These modifications mainly include blood vessel formation, and changes in the adhesion profile of the stromal meshwork (Figure 2).
因此，BM间质可以调节淋巴样浸润的程度和模式，并有助于肿瘤细胞的存活。值得注意的是，除了选择性归巢到特定的良好微环境中，肿瘤细胞还可以积极促进骨髓间质的改变以产生一个特定的肿瘤龛。30这些改变主要包括血管形成，以及间质网状组织的粘附外观的变化（图2）。
T cell T细胞
Antigens Mitogens 抗原，有丝分裂原
T effector cell 效应T细胞
PGE2 IL-10 TGF-βHGF 前列腺素E2，白细胞介素-10，转化生长因子-β，造血生长因子
Direct 直接的作用
CD8+ TREG CD8+ 调节性T细胞
CD4 TREG CD4 调节性T细胞
MSC 骨髓基质细胞
Indirect 间接地作用
TREG development 调节性T细胞的发展
Monocyte 单核细胞
IL-6 VEGF GM-CSF 白细胞介素-6，血管内皮细胞生长因子，粒细胞-巨噬细胞集落刺激因子
iDC 树突状细胞
mDC 单核细胞树突状细胞
MDSC 髓系抑制性细胞
Indirect 间接地作用
Tolerogenic microenvironment 致耐受性的微环境
Malignant clone 恶性克隆
Controlled growth 控制性增长
Immune suppression 免疫抑制
Malignant clones 恶性克隆
Uncontrolled growth 失控增长
In xenograft models of B-cell and T-cell acute lymphoblastic leukemia (ALL), leukemic cells affect the BM vascular niche by promoting angiogenesis through the release of proangiogenic molecules, including VEGF, bFGF, angiopoietins, metalloproteinases, interleukin (IL)-6 and IL-8, and eventually establishing a niche that promotes ALL survival via IL-7 and IL-3. 30 The leukemic niche is characterized by low HSC support capability owing to down- regulated CXCL12 stromal expression, yet it outcompetes native stromal niches for HSC engraftment owing to production of stem-cell factor by neoplastic cells.31 In addition to ALL, increased BM angiogenesis is associated with unfavorable prognosis in several other lymphoid malignancies, including CLL.32,33 In specific settings, such as in angioimmunoblastic T-cell lymphoma, overexpression of VEGF may not only sustain the increase in microvessel density, but also promote tumor cell proliferation and survival by autocrine and paracrine loops.34 Expression of CD38 and CD49d adhesion molecules by the neoplastic clone in CLL has been associated with a more-aggressive disease course.35 CD38 engagement by CD31 favors the synthesis and release of CCL3 and CCL4 chemokines by neoplastic cells, which induce the recruitment of CD68+ macrophages at sites of lymphoid infiltration.35 Recruited macrophages influence the activation of BM stromal cells, inducing expression of VCAM-1 and release of proinflammatory cytokines such as TNF (Figure 2).35 A strong prosurvival feedback signal is delivered to CLL cells by the concomitant CD38/CD31 and CD49d/VCAM-1 pathway. Similarly, other lymphoid neoplasms may benefit from the recruitment of cellular partners for the induction of stromal modifications at sites of infiltration. This process may occur in lymphoplasmacytic lymphoma and in angioimmunoblastic T-cell lymphoma, in which lymphomatous infiltrates may be enriched by mast cells attracted by neoplastic cell-derived CCL5 and CXCL13. 36 Lymphoma-infiltrating mast cells may foster neoplastic growth and survival through the CD40L/CD40 or 0X40L/ OX40 axes, and also contribute to the orchestration and maintenance of a supportive stromal microenvironment through the synthesis of mediators, including TNF, IL-6, matrix metalloproteinase-9, and interferon-y.36
在B细胞和T细胞急性淋巴细胞白血病（ALL）的异种移植模型中，白血病细胞通过促血管生成分子的释放，包括VEGF，bFGF，血管生成素，金属蛋白酶，白细胞介素-6和白细胞介素- 8，促进血管生成以影响骨髓血管龛，并通过IL- 7和IL- 3促进ALL的生存最终建立一个龛。30白血病龛的特点是由于下调CXCL12间质的表达导致HSC支持能力低下，但又由于肿瘤细胞产生的干细胞因子，竞争性取代HSC移植的原生基质龛。31除了ALL，在一些其他淋巴组织的恶性肿瘤中包括白血病，骨髓血管形成的增加与预后不良相关。32,33在特定的背景下，如在血管免疫母细胞性T细胞淋巴瘤中，血管内皮生长因子的过表达不仅可以维持微血管密度的增加，而且还能通过自分泌和旁分泌循环促进肿瘤细胞的增殖和存活。34 在白血病肿瘤性克隆中CD38和CD49d粘附分子的表达已与不断发展的病程相关。35 CD31和CD38的参与可促进肿瘤细胞中CCL3和CCL4趋化因子的合成和释放，从而诱导淋巴浸润部位CD68+巨噬细胞的招募。35招募的巨噬细胞会影响骨髓间质细胞的活化，诱导VCAM-1的表达和促炎性细胞因子如肿瘤坏死因子的释放（图2）。35强大的促存活反馈信号是由CD38/CD31和CD49d/VCAM-1途径共同传递到CLL细胞中。同样，其他淋巴组织肿瘤可能会受益于在浸润部位诱导间质修饰的细胞伙伴的的招募。这个过程也可能发生在淋巴浆细胞淋巴瘤和血管免疫母细胞T细胞淋巴瘤中，其中淋巴瘤浸润可能由于肿瘤细胞源性CCL5和CXCL13诱导产生肥大细胞而增加。 36淋巴瘤浸润的肥大细胞可通过CD40L/CD40或0X40L/OX40轴促进肿瘤的生长和存活，并且还可通过合成介质，包括TNF，IL- 6，基质金属蛋白酶-9和干扰素- γ，帮助支持性间质微环境的构建和维护。36
Nodular BM infiltrates from mature B-cell lymphoproliferative disorders may foster a meshwork of mesenchymal cells that express markers of follicular dendritic cells, such as CD21, conferring to neoplastic aggregates the appearance of 'true follicles' (Figure 1e). Although the occurrence of a follicular organization in BM lymphoid infiltrates has never been related with specific biological features of the neoplastic clone, interplay between such follicular dendritic cells and neoplastic cells can be predicted in terms of cell adhesion (for example, mediated by ICAM-1 expression) and antigenic stimulation (Figure 1f). Interestingly, signals stemming from surface antigen receptors and signals derived from the actin network may support activation and survival of lymphoid cancer cells through a common pathway. 22,37
成熟B-细胞淋巴增殖性疾病中的结节性BM浸润可以促进表达滤泡树突状细胞标记物如CD21的间充质细胞中的网状组织形成，赋予肿瘤聚集物“真正卵泡'（图1e）的外观。尽管在骨髓淋巴浸润中毛囊组织的存在从未与肿瘤性克隆的特定生物功能相关，滤泡性树突状细胞和肿瘤细胞之间的相互作用可以在细胞粘附（例如，通过ICAM-1表达介导的）和抗原刺激方面进行预测（图1F）。有趣的是，来自表面抗原受体的信号和源于肌动蛋白网络的信号可以通过一个共同的途径支持淋巴肿瘤细胞的活化和生存。22,37
BM stromal changes associated with lymphoid neoplasms might also comprise reticulin fibrosis and fibroblastic proliferation. The former is often slight to moderate and associated with specific lymphoproliferative neoplasms, such as hairy-cell leukemia or peripheral T-cell lymphomas, whereas the latter is mainly observed in BM infiltrates from classic Hodgkin lymphoma.38 Importantly, the degree of fibrosis may be helpful in differentiating non-Hodgkin lymphoma and benign lymphoid hyperplasia characterized by central localization and absence of considerable amounts of reticulin. 39
与淋巴组织肿瘤相关的骨髓间质的变化也可能包括网状纤维化和成纤维细胞增殖。前者通常是轻度到中度，并与特定的淋巴增生肿瘤有关，如多毛细胞白血病或外周T细胞淋巴瘤，而后者主要见于经典型霍奇金淋巴瘤中的骨髓浸润。38重要的是，纤维化程度可以帮助鉴别非霍奇金淋巴瘤和良性淋巴组织增生，其特征在于中央的定位和大量的网硬蛋白的缺乏。39
Available evidence indicates that neoplastic lymphocytes can shape the neighboring BM microenvironment by directly affecting stromal composition or co-opting other immune effectors that are active in tissue remodeling (Figure 2). Notably, such changes in the BM microenvironment eventually favor neoplastic cell survival and influence the clinical course of the disease.
有证据表明，肿瘤细胞可以通过直接影响基质成分或增选其他活跃于组织重建的免疫效应器
（图2）来塑造邻近的骨髓微环境。值得注意的是，在骨髓微环境中这些变化最终将有利于肿瘤细胞的存活并影响疾病的临床过程。
The BM stroma in multiple myeloma
多发性骨髓瘤中的BM间质
Although the BM is the primary site of multiple myeloma, it is not the site of origin. Emerging data indicate that the malignant plasma cell arises from a postgerminal center B cell that has undergone somatic hypermutation, lacks intraclonal variation, and expresses CD19 and CD27, consistent with a central memory B-cell phenotype. 40 Interestingly, several groups have identified critical cell populations for multiple myeloma BM engraftment, ranging from CD38high/CD19+/CD138- to CD19+/CD27+/ CD138-. 41'42'43'44 This latter population has self-renewal potential, which supports the hypothesis of a memory B cell as the cell responsible for sustaining the malignant phenotype in plasma cell dyscrasias. The presence of this population in the peripheral circulation raises the question of what mechanisms regulate trafficking and homing to the BM in plasma cell dyscrasias and how neoplastic-cell survival is maintained within the BM microenvironment.
虽然BM为多发性骨髓瘤的原发部位，但并不是起源的部位。新的数据表明，恶性浆细胞来源于已发生体细胞高度突变，缺乏克隆内变化，并且能表达与中央记忆B细胞表型一致的CD19和CD27的B记忆细胞。40有趣的是，一些研究小组已经确定了多发性骨髓瘤骨髓移植的关键的细胞群，从CD38high/CD19+/ CD138-到CD19+/ CD27+/ CD138-。41,42,43,44后面的细胞群具有自我更新潜力，这支持了记忆B细胞是负责维持浆细胞恶液质的恶性表型的细胞的假说。外周循环中这种细胞群的存在引发了在浆细胞恶液中调节运输和归巢到骨髓的机制问题以及在BM微环境中肿瘤细胞的存活是如何维持的。
Many factors are involved in the crosstalk between multiple myeloma cells and the BM stroma, including soluble factors, such as chemokines, cytokines, growth factors, cell-surface receptors, ECM proteins, and cellular constituents of the BM stromal niches. BM stromal cells contribute to IL-6 synthesis, which in turn stimulates multiple myeloma-cell proliferation and confers chemo- resistance through activation of pathways, such as PI3K/ Akt, MAPK, and Janus-kinase/STAT3, and synergizes with adhesive p1-integrin signals to increase survival of multiple myeloma cells. 45,46 Interestingly, IL-6 production by BM stromal cells requires multiple myeloma-cell binding and subsequent activation through nuclear factor kappa B signaling. 47 IGF-1 can overcome the effects of IL-6-blockade in multiple myeloma through binding to its receptor IGF- 1R.48 IGF-1R expression has been associated with more- aggressive disease and is found to a greater extent in the poor prognosis t(4;14) multiple myeloma. 48 High circulating levels of IGF-1 are associated with a dismal prognosis. 49 Through binding of IGFBP-3, IGF1 is targeted to multiple myeloma cells that express high levels of the cell surface adhesion molecule syndecan-1 (CD138). CD138 mediates IGF-1 uncoupling from IGFBP-3 and enables IGF-1 interaction with its receptor on multiple myeloma cells, in turn promoting cell survival and proliferation.48 Furthermore, soluble CD138 also binds IGF-1, leading to further increased local delivery of IGF-1 to myeloma cells, representing a link between adhesion and soluble mediator-induced cell survival.48
许多因素都参与在多发性骨髓瘤细胞和骨髓基质之间的串扰中，包括可溶性因子，如趋化因子，细胞因子，生长因子，细胞表面受体，细胞外基质蛋白和BM基质龛的细胞成分。骨髓基质细胞促进IL-6的合成，反过来又刺激多发性骨髓瘤细胞的增殖，并通过活化途径产生化疗抗性，如PI3K/Akt，MAPK和Janus-kinase/STAT3，并且与粘附性β1-整合素信号协同作用，以增加多发性骨髓瘤细胞的存活。45,46有趣的是，骨髓间质细胞IL-6的产量需要多发性骨髓瘤细胞的结合和随后通过核因子κB信号的激活。47IGF-1在多发性骨髓瘤中可以通过与其受体IGF- 1R结合克服IL- 6-阻滞的效果。48 IGF- 1R的表达一直伴随在更严重的疾病中，并发现在预后较差的（4; 14）多发性骨髓瘤中表达更多。48 IGF-1的高循环水平与预后不佳有关。49通过与IGFBP-3的结合，IGF1可靶向高水平表达细胞表面粘附分子配体蛋白聚糖-1（CD138）的多发性骨髓瘤细胞。 CD138介导IGF-1与IGFBP-3的解偶联，使IGF-1
与多发性骨髓瘤细胞上其对应的受体相互作用，从而促进细胞的存活和增殖。48此外，可溶性CD138也能结合IGF-1，从而进一步增加了IGF-1局部运输到骨髓瘤细胞，说明了粘附性和可溶性介质诱导的细胞存活率之间的关系。48
Role of RANKL
Additional soluble factors have been implicated in the osteoclast activation leading to lytic bone disease. RANKL produced by stromal cells and osteoblasts binds to RANK on osteoclasts resulting in osteoclast differentiation. 50 Osteoprotegrin is a stromal-derived RANKL inhibitor that regulates the amount of functional RANKL. Myeloma induces upregulation of RANKL and inhibition of osteoprotegrin, thus altering the ratio of these proteins and enhancing osteoclast activation.51 Macrophage inflammatory protein 1a (MIP-1a) is produced by myeloma cells, stimulates multiple myeloma cell proliferation and survival, macrophage recruitment, and osteoclast formation. Moreover, it increases interactions between myeloma and stromal cells through upregulation of RANKL. Interestingly, MIP-1a levels in the BM correlated with disease stage and activity.52 Another link between multiple myeloma and BM stroma is Dickkopf-1, a Wnt antagonist that increases BM-MSC survival, inhibits osteoblast differentiation, and increases osteoclast-mediated bone resorption, which eventually alters the osteoblastic BM stromal niche.53 The complex network of soluble factors produced by the myeloma-associated microenvironment is critical for promoting and maintaining multiple myeloma survival within the BM niche.
RANKL的作用
其他的可溶性因子也参与了破骨细胞的活化，导致溶解性骨病。由间质细胞和成骨细胞产生的RANKL与破骨细胞上的RANK结合导致破骨细胞的分化。50护骨素是间质源性RANKL抑制剂，可调节功能性RANKL的数量。骨髓瘤诱导RANKL的上调并抑制护骨素，从而改变这些蛋白质的比率并增加破骨细胞的激活。51巨噬细胞炎性蛋白1α（MIP -1α）是由骨髓瘤细胞产生，能刺激多发性骨髓瘤细胞的增殖和存活，巨噬细胞的浸润以及破骨细胞的形成。另外，它能通过上调RANKL的表达，增加骨髓瘤细胞和间质细胞之间的相互作用。有趣的是，在骨髓中MIP -1α的水平与疾病阶段和活性相关。52多发性骨髓瘤和骨髓间质之间的另一个链接是Dickkopf-1，一种Wnt信号的拮抗剂，能增加BM-MSC的存活，抑制成骨细胞的分化，以及增加破骨细胞介导的骨再吸收，并最终改变成骨细胞的骨髓间质定位。53由骨髓瘤相关的微环境产生的可溶性因子的复杂网络对于促进和维持多发性骨髓瘤在骨髓龛中的生存是至关重要的。
Role of the immune system
The clinical manifestations of multiple myeloma result from the complex interactions between tumor cells, BM stromal elements, and the immune system. Effective T-cell recognition of the embryonal antigen SOX2 in the premalignant condition known as monoclonal gammopathy of unknown significance (MGUS), inhibits the clonogenic growth of MGUS cells. Cellular immunity to SOX2 is lost as disease progresses to more active forms, indicating a role in immune surveillance; however, the factors responsible for this loss of immunity remain unknown.54
免疫系统的作用
多发性骨髓瘤的临床表现是肿瘤细胞，骨髓间质成分和免疫系统之间复杂的相互作用的结果。癌前状况下，胚胎抗原SOX2的效应T细胞识别被称为不明意义的的单克隆丙种球蛋白病（MGUS），抑制MGUS细胞的克隆性生长。当病情发展到更活跃的情形，对SOX2的
细胞免疫将会失去，表明其在免疫监视中的作用，然而，引起这种免疫力损失的因素仍是未知的。54
In multiple myeloma, a Th17-oriented immunological microenvironment could also have a relevant role in maintaining myeloma cell survival. Resident BM dendritic cells can induce a Th17 phenotype in multiple myeloma.55 The Th17 phenotype in the BM tightly correlates with the development of osteoclast-induced bone disease, independently of tumor burden. In one study, activation of BM-infiltrating lymphocytes to a Th1 phenotype dramatically reduced osteoclast differentiation.56 Moreover, an interaction between IL-17 and IL-17R with the BM microenvironment and myeloma cells augments myeloma cell growth.57 Taken together, these findings suggest an intricate immune network of multiple myeloma cells, T cells, and stromal cells that all contribute to multiple myeloma cell survival and osteolytic bone disease. Notably, immunomodulatory agents, such as thalidomide, lenalidomide, and the proteasome inhibitor bortezomib for the treatment of multiple myeloma, 58 interfere with the malignant immunological and stromal BM microenvironment restoring an effective immune response against the neo- plastic clone. These drugs also limit the proinflammatory pressure of multiple myeloma-associated BM accessory cells, such as dendritic cells and macrophages,59 and contribute to the normalization of angiogenesis,60 thus rendering the BM milieu less supportive of multiple myeloma growth and survival.
在多发性骨髓瘤中，Th17细胞导向的免疫微环境也可能在维持骨髓瘤细胞的存活中有着相关的作用。原BM树突状细胞在多发性骨髓瘤中可诱导Th17细胞的表型。55 在骨髓中Th17细胞的表型与破骨细胞引起的骨疾病的发展紧密关联，不依赖于肿瘤负荷。一项研究表明，激活骨髓浸润淋巴细胞产生Th1表型可显著减少破骨细胞分化。56此外，在骨髓微环境和骨髓瘤细胞中IL- 17与IL- 17R之间的相互作用能增强骨髓瘤细胞的生长。57综上所述，这些结果表明多发性骨髓瘤细胞，T细胞和间质细胞之间存在一种复杂的免疫网络，均有助于多发性骨髓瘤细胞的存活和溶骨性骨疾病。值得注意的是，免疫调节剂，例如用于治疗多发性骨髓瘤的沙利度胺，来那度胺，和蛋白酶体抑制剂硼替佐米，58可干扰对肿瘤克隆有效免疫反应的恢复的恶性免疫和间质骨髓微环境。这些药物也限制多发性骨髓瘤相关的BM辅助细胞的促炎压力，如树突状细胞和巨噬细胞，59并有助于血管生成的标准化，60从而减少BM环境对多发性骨髓瘤的生长和存活的支持。
The BM stroma in myeloid neoplasms
Myeloid neoplasms are a heterogeneous group of clonal HSC disorders. Although alterations in the BM stroma in these neoplasms are considered secondary to cytokine effects, the BM stroma is not just an 'innocent bystander' but has an active role in the pathogenesis and disease progression, affecting both clinical course and response to therapy. The major morphologically recognizable BM stromal alterations include fibrosis (Box 1), angiogenesis, and osteosclerosis. Such stromal changes have been described in acute myeloid leukemia (AML), myelodysplastic syndromes, and myeloproliferative neoplasms.
髓系肿瘤中的BM间质
髓系肿瘤是克隆性HSC疾病中的一种多相群。尽管在这些肿瘤中骨髓间质的改变被认为是继发于细胞因子的影响，但BM间质不只是一个“无辜的旁观者”，它在发病机制和疾病进展中发挥着积极作用，并影响临床病程和对治疗的反应。BM间质在形态学上可识别的主要改变包括纤维化（Box 1）, 血管生成和骨硬化。此类间质的变化在急性髓性白血病（AML），骨髓增生异常综合征和骨髓增生性肿瘤中已经有过描述。
Acute myeloid leukemia with fibrosis
Two AML subtypes are consistently associated with stromal fibrosis: acute panmyelosis with myelofibrosis (APMF), and acute megakaryoblastic leukemia. APMF accounts for <1% of AML cases and its diagnostic criteria have been clearly outlined.61,62 Acute megakaryoblastic leukemia accounts for 3-5% of AML and its diagnosis requires >20% blasts, with >50% showing megakaryocytic differentiation. 62 Both diseases are characterized by dysplastic dwarf megakaryocytes with hypo-obulated or non-lobulated nuclei, and a marked degree of reticulin fibrosis; the latter is most likely owing to abnormal cytokine release from megakaryocytes. The BM stroma composition is altered in AML as a result of cytokine and growth factor production from the neoplastic clone, which increases leukemia growth and progression through the interaction with the modified BM stroma.63,64 It is not known whether the altered BM microenvironment occurring in AML actively promotes leukemia development or is a secondary change. New therapeutic approaches targeting the BM environment in AML, such as inhibitors of CXCL12/ CXCR4 axis, integrin inhibitors, and antiangiogenic agents are being evaluated.65-67
急性髓系白血病伴纤维化
两种AML亚型始终与间质纤维化相关：急性全骨髓增生伴骨髓纤维化（APMF）和急性巨核细胞白血病。APMF在AML中的比例不到1% ，其诊断标准已有明确的阐述。61,62急性巨核细胞白血病占白血病的3-5%，其诊断需要超过20%的原始细胞，若高于50%表明巨核细胞的分化。62这两种疾病的特征是发育异常的侏儒巨核细胞，核呈小叶状或非叶状，有显著的网硬蛋白纤维化；而后者最有可能是由于巨核细胞释放的异常细胞因子引起的。在AML中BM间质组成的改变是肿瘤性克隆产生的细胞因子和生长因子的结果，通过与改变后的BM间质相互作用促进白血病的生长与发展。63,64在AML中改变后的骨髓微环境是否能积极促进白血病的发展或者只是一种继发性的改变尚未知晓。在AML中靶向骨髓微环境的新的治疗方法，如CXCL12/CXCR4轴的抑制剂，整合酶抑制剂，以及抗血管生成剂正在评估中。65-67
Myelodysplastic syndromes with fibrosis
Myelodysplastic syndromes with fibrosis refer to cases with fibrosis grade >2 based on the European Consensus Grading System (Box 1).68 Most patients with this condition have multilineage dysplasia, high transfusion requirement, and aggressive disease course.15,69 In patients stratified according to the International Prognostic Scoring System (IPSS) and WHO classification-based Prognostic Scoring System (WPSS),70,71 the presence of fibrosis places the patient in a more-advanced risk group, representing an independent prognostic factor that could be useful in clinical decision making.15 Patients with grade 2 or grade 3 fibrosis might be considered for aggressive treatment earlier than the prognostic score would indicate.15
骨髓增生异常综合征伴纤维化
骨髓增生异常综合征伴纤维化是指病例中基于欧洲共识分级系统 (Box 1)的纤维化分级大于2。68大多数有这种情况的患者也多系发育异常，有较高的输液要求和进展性的疾病进程。15,69在根据国际预后评分系统（IPSS）分层以及基于预后评分系统的WHO分类（WPSS）的患者中，70,71纤维化的存在使患者处于较高危的人群，代表了一种可用于临床决策制定的独立的预后因素。152级或3级纤维化的患者可能会被考虑在预后评分指示之前就进行积极的治疗。15
Myeloproliferative neoplasms
The group of myeloproliferative neoplasms (MPN) is broadly divided into Philadelphia-chromosome-positive/BCR-ABL-positive chronic myelogenous leukemia (CML) and Philadelphia-chromosome-negative/ BCR-ABL-negative MPN (Ph-MPN). In CML, the presence of marked fibrosis has been associated with a worse outcome than cases without fibrosis, which remains true even in the current imatinibera. 72 Ph-MPN includes essential thrombocythemia, polycythemia vera, and primary myelofibrosis (PMF).73 Common stromal alterations in these diseases are BM fibrosis, osteosclerosis, and increased angiogenesis.74 Patients with essential thrombocythemia usually display no or only minimal fibrosis; the presence of fibrosis in such patients should prompt exclusion of early polycythemia vera or PMF as an alternative diagnosis.74 This diagnosis has a considerable prognostic implication since most cases of essential thrombocythemia do not progress to myelofibrosis and have a favorable outcome.75
骨髓增生性肿瘤
骨髓增生性肿瘤（MPN）的组别大致分为费城染色体阳性/ BCR-ABL阳性的慢性髓性白血病（CML）和费城染色体阴性/ BCR-ABL阴性的MPN（PH-MPN）。在慢性粒细胞白血病中，显著纤维化的存在与相比没有纤维化的病例出现的更坏结果相关，甚至在当前的伊马替尼时代仍是如此。72PH-MPN包括原发性血小板增多症，真性红细胞增多症和原发性骨髓纤维化（PMF）。73在这些疾病中共有的间质改变是骨髓纤维化，骨硬化，并且血管发生增加。74原发性血小板增多症的患者通常会显示出没有或只有很少的纤维化；在此类患者中纤维化的存在应及时排除早期真性红细胞增多症或PMF作为替代诊断。74这种诊断具有相当的预测意义，因为大多数原发性血小板增多症不会发展为骨髓纤维化，且都有较好的结果。75
Box 1 | Assessment of bone marrow fibrosis
In routine clinical practice, evaluation of bone marrow fibrosis includes assessing the quantity and pattern of reticulin fiber deposition as demonstrated by a reticulin stain, such as Gomori methenamine silver stain. Reticulin stains all types of fibers, including mature collagen (type I collagen). The presence of type I collagen, as seen in cases of severe myelofibrosis, can be most specifically demonstrated by Masson's trichrome stain. The evaluation of fibrosis in the clinical setting is performed using Gomori-stained bone marrow biopsies in which the amount of fibrosis is assessed semi-quantitatively by using, for example, the European Consensus Grading System.47 This method, originally proposed for assessing fibrosis in primary myelofibrosis, distinguishes four degrees of fibrosis (MF-0 to MF-3) with MF-0 indicating normal fiber content:
■ MF-0: Scattered linear reticulin with no intersections (crossovers) corresponding to normal bone marrow
■ MF-1: Loose network of reticulin with many intersections, especially in perivascular areas
■ MF-2: Diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis
■ MF-3: Diffuse and dense increase in reticulin with extensive intersections of coarse collagen bundles, often associated with substantial osteosclerosis
Box 1 | 骨髓纤维化的评估
在日常临床实践中，骨髓纤维化的评估包括评估网硬蛋白纤维沉积量和模式，通过网状纤维染色证明，如戈莫里六胺银染色。网状纤维能染色所有类型的纤维，包括成熟的胶原（I型胶原）。I型胶原的存在，在严重骨髓纤维化病例中可见，可由Masson三色染色法特异性证实。在临床上纤维化是采用Gomori染色骨髓活检进行评估，纤维化的值通过采用如欧洲共识分级系统进行半定量评价。47这种方法，最初提出用于原发性骨髓纤维化中纤维化的评估，区分了4种不同程度的纤维化（MF-0为MF-3），其中MF-0指示纤维含量正常：
■MF-0：分散的线性网状纤维，对应于正常骨髓没有交点（交叉）
■MF-1：松散的网状纤维，具有多个交叉点，尤其是在血管周围区域
■MF-2：弥漫性和密集度增加的网状纤维，具有广泛的交叉点，偶尔与胶原蛋白的唯一焦点束和/或局灶性骨硬化
■MF-3：弥漫性和密集度增加的网状纤维，与粗胶原束有广泛的交叉点，常常与大量的骨硬化相关
Patients with PMF and polycythemia vera can develop overt marrow fibrosis as the disease progresses from a cellular phase to a 'terminal' myelofibrotic/osteosclerotic phase associated with leukoerythroblastosis and extramedullary hematopoiesis, where the latter is usually manifested as splenomegaly. In the fibrotic stage of PMF, the marrow cellularity shows patchy hematopoiesis alternated with hypo-cellular fibrotic areas often surrounded by osteosclerotic bone (Figure 3a,b). Atypical megakaryocytes forming tight clusters can be found even in the hypocellular areas, and dilated marrow sinuses, often containing intravascular hematopoiesis, are other typical findings.
Disease progression occurs within the first 5 years of observation in about 30% of patients with PMF diagnosed with early-stage disease. 74 The degree of BM fibrosis is an important prognostic factor in PMF as patients with grade 3 fibrosis have a significantly shorter overall survival than patients with grade 0, 1, or 2 fibrosis (P = 0.001 and P = 0.003, respectively).14 In patients with advanced PMF, the stromal changes are the most prominent feature of the pathology, and are related to the development of extra-medullary hematopoiesis, whose clinical manifestations account for significant morbidity.74
随着病情从细胞阶段发展到与骨髓病性贫血和髓外造血相关的“终端” 骨髓纤维化/骨硬化阶段时，PMF和真性红细胞增多症的患者可出现明显的骨髓纤维化，后者通常表现为脾肿大。在PMF的纤维化阶段，髓细胞性可见部分造血被低细胞纤维化区域取代，周围常围绕着骨硬化骨（图3a，b）。形成紧簇的不典型巨核细胞甚至可以在低细胞区域中看见，扩张的髓窦，往往含有血管内血细胞，是其他的典型的发现。在诊断为PMF早期的患者中大约30%在前5年的观察中会发生病情的恶化。74 BM纤维化的程度在PMF中是一个重要的预后因素，因为3级纤维化的患者相比0级，1级或2级纤维化患者有非常短的总存活率（分别为P=0.001和P=0.003）。14在晚期PMF的患者中，间质的变化是最突出的病理特征，并且与髓外造血的发展相关，其临床表现占有显著的发病率。74
The myelofibrosis and osteosclerosis seen in MPN have a complex pathogenesis. The release of profibrogenic and proangiogenic cytokines, such as PDGF, FGF, TGF-p, and VEGF, from neoplastic myeloid cells, activate BM stromal cells, which induces excess ECM deposition and triggers angiogenesis.76-78 Stromal changes relating to MPN indicate a proliferation of adventitial reticular cells, which can be assessed with the use of antibodies for low-affinity nerve growth factor, and the enrichment of the MSC component, which can be identified by CD146 immunostaining.79,80 Increased production of osteoprotegerin and synthesis of bone morphogenetic protein-1 might also contribute to the unbalanced osteoblastic activity, which results in the osteosclerosis frequently seen in patients with APMF.76,77
MPN中看到的骨髓纤维化和骨硬化有着复杂的发病机制。肿瘤性髓样细胞释放的促纤维化形成和促血管生成细胞因子，如PDGF，FGF，TGF-β和血管内皮生长因子，可激活骨髓间质细胞，进而诱导ECM的过量沉积，并触发血管生成。76-78 MPN相关的间质变化表明外膜网状细胞的增殖，其可通过使用低亲和神经生长因子的抗体进行评估，并且MSC成分的富集，可通过CD146免疫染色来识别。79,80骨保护素的生成增加和骨形态发生蛋白-1的合成可能也会促进成骨细胞活性的不平衡，从而导致APMF患者中经常出现骨硬化。76.77
Alterations of the CXCL12/CXCR4 axis have been extensively investigated in myeloid neoplasms. In PMF, HSCs display decreased CXCR4 expression and the BM milieu is deprived of functional CXCL12 because of increased CXCL12 uptake by neoplastic megakaryocytes and truncated inactive CXCL12 owing to action of matrix metalloproteinases.81,82 The lack of CXCL12 in conjunction with decreased CXCR4 might prevent HSCs from localizing to the osteoblastic niche, thus facilitating their exit from the BM into the peripheral circulation, and homing to extramedullary sites. Since therapies targeted at HSC alone have limited efficacy in advanced MPN, attempts at correcting stromal abnormalities might represent a useful approach. In patients with PMF, a total regression of the pre-existing fibrosis is usually seen within 6-12 months of successful stem-cell transplantation,83 although osteosclerosis was unchanged during this timeframe.83
CXCL12/CXCR4轴的变化在髓系肿瘤中已经得到了广泛的研究。在PMF中，由于肿瘤巨核细胞对CXCL12的摄取增加以及由于基质金属蛋白酶的作用导致CXCL12失活，造血干细胞中显示CXCR4表达减少且BM环境中缺乏功能性的CXCL12。81,82 与CXCR4的减少相关联的CXCL12的缺乏可能会阻止造血干细胞定位到成骨细胞龛，进而促进它们从骨髓进入外周循环，并归巢到髓外部位。由于单独定位于HSC的疗法在晚期MPN中疗效有限，尝试纠正异常的间质可能代表一种有效的方法。在PMF患者中，成功进行了干细胞移植后的6-12个月，预先存在的纤维化通常会出现总体减退，尽管这段时间内骨硬化不会发生改变。83
Systemic mastocytosis
Systemic mastocytosis is another myeloid neoplasm with characteristic stromal alterations. Systemic mastocytosis BM lesions are characterized by abundant reticulin and collagen fibrosis, reduced vascularization, and a paucity of cells that express low-affinity nerve growth factor receptor and/or show myofibroblasts differentiation (Figure 3c,d).79 The stromal changes in systemic mastocytosis are different, therefore, from those observed in PMF. The paucity of microvessels in systemic mastocytosis fibrotic aggregates raise doubts about the effectiveness of antiangiogenic treatments in this disease.84 Therapies for systemic mastocytosis include observation or cytoreductive therapy including IFN alpha, 2-chlorodeoxyadenosine, and
imatinib mesylate. 85
系统性肥大细胞增多症
系统性肥大细胞增多症是另一种具有特征性间质改变的髓系肿瘤。系统性肥大细胞增多症中骨髓病变的特点是丰富的网状纤维和胶原纤维，血管形成减少以及表达低亲和力神经生长因子受体和/或显示肌纤维母细胞分化的细胞的缺乏（图3c，d）。79因此，在全身性肥大细胞增多症中与PMF中观察到的间质变化是不同的。在系统性肥大细胞增多症纤维化聚集物中微血管的缺乏引起了我们对这种疾病中的抗血管生成疗法有效性的怀疑。84系统性肥大细胞增多症的疗法包括观察或减瘤治疗，包括干扰素-α，2-氯脱氧腺苷和甲磺酸伊马替尼。85
Angiogenesis in myeloid neoplasms
Increased angiogenesis has been found in the BM of patients with AML, myelodysplastic syndromes, and MPN. 12,79,86-91 Results obtained from patients with myelodysplastic syndromes indicate a correlation between increased angiogenesis and progression to AML and CML transformation. 90,91 In patients with CML treated with imatinib, a decrease in microvessel density attributed to reduction in BCR-ABL-mediated secretion of VEGF, has been associated with reversal of fibrosis and cytogenetic and molecular response. 92 In Ph-MPN, the extent of angiogenesis was much greater in PMF than in polycythemia vera or essential thrombocythemia. 12 In PMF, microvascular proliferation is thought to be associated with increased passage of progenitor or precursor cells from the BM, their circulation in the peripheral blood, and subsequent development of extramedullary hematopoiesis.12 Use of therapeutic agents with anti- angiogenic activity in PMF is being evaluated in several clinical trials. 93-96 Ongoing studies support the hypothesis that angiogenesis has an important role in the pathogenesis of myeloid neoplasms, and the promise of a possible role for antiangiogenic therapies in this setting.97
髓系肿瘤中的血管生成
在AML，增生异常综合征和MPN的患者的骨髓中可见血管生成增加。12,79,86-91从骨髓增生异常综合征的患者中所获得的结果表明AML中血管生成增加和其进展与CML转化之间存在关联。90,91在用伊马替尼治疗的CML患者中，微血管密度的降低归因于BCR-ABL介导的血管内皮生长因子分泌的减少，且与纤维化的逆转，细胞生成以及分子学反应相关。92在Ph-MPN中，PMF中血管生成的程度要比真性红细胞增多症或原发性血小板增多症大得多。12在PMF中，微血管增殖被认为与来自骨髓的祖细胞或前体细胞传代的增加，以及其在外周血中的循环和髓外造血的后续发展有关。12在PMF中，抗血管生成活性的治疗剂的使用正在几项临床试验中进行评估。93-96正在进行的研究支持了血管生成在髓系肿瘤的发病机制中具有重要作用的这一假说，并且承认了抗血管生成疗法在此疾病中可能发挥的作用。97
Immunomodulation by BM stromal cells
BM stromal cells have a distinct immunological role from that of stromal cells of secondary lymphoid organs, which organize the memory response, or initiate the adaptive immune response, respectively.98 Specialized BM stromal cells provide a survival niche for plasma cells and helper T lymphocytes. Similar mechanisms can operate to support survival of lymphoid malignant clones, whereas opposing mechanisms could enable hematological malignancies to escape from the control of the immune system.
骨髓间质细胞的免疫调节
骨髓间质细胞具有与次级淋巴器官的间质细胞不同的免疫学作用，它们能分别组织记忆应答，或引发适应性免疫应答。98特定的BM间质细胞为浆细胞和辅助性T淋巴细胞提供了可供生存的微环境。类似的机制也可用于支持淋巴样恶性细胞系的存活，然而相反的机制可使血液恶性肿瘤不受免疫系统的控制。
Immune escape could occur in malignancies whose immunogenicity is confirmed by the identification of specific tumor-associated antigens. Chromosomal translocation can generate new antigens potentially perceived as non-self by the immune system. An example of this is the BCR-ABL fusion protein in CML, which is recognized by T lymphocytes. 99,100 Also, the proteins elastase and proteinase 3 induce cytotoxic T-cell responses against CML. 101 In both AML and CML, the Wilms tumor gene product, WT1, is a target of cytotoxic T cells and a potential candidate for immunotherapy. 102 These examples support the existence of immune suppression, which enables escape from immune control.
免疫逃逸可能发生在通过鉴定特定肿瘤相关的抗原而证实免疫原性的恶性肿瘤中。染色体易位可产生新的抗原，很可能被免疫系统识别为非自身的抗原。这方面的一个例子是慢性髓细胞性白血病CML中的BCR-ABL融合蛋白，它是由T淋巴细胞识别的。99,100此外，蛋白质弹性蛋白酶和蛋白酶3可诱导对抗慢性粒细胞白血病的细胞毒性T细胞应答。101在急性髓性白血病和慢性髓细胞性白血病中，肾母细胞瘤基因产物，WT1，是细胞毒性T细胞的靶标和免疫疗法的潜在候选者。102这些例子都支持了免疫抑制的存在，从而产生免疫控制的逃避。
In the BM environment, BM-MSCs are capable of immune regulation in several settings, including transplantation, tolerance and, indeed, tumor evasion.103 BM-MSCs exert their immunosuppressive functions directly on B cells, T cells, and dendritic cells via the release of specific soluble mediators, and indirectly through regulatory cells such as T regulatory (TREG) cells and, probably, myeloid-derived suppressor cells (Figure 4).
在BM的环境中，骨髓间充质干细胞（BM-MSCs）在一些情况下具有免疫调节作用，包括移植手术，耐受产生，事实上还有肿瘤逃避。103 BM-MSCs通过释放特定的水溶性介质发挥其直接作用于B细胞，T细胞和树突状细胞的免疫抑制作用，并间接通过调节细胞发挥作用，如调节性T细胞（Treg），可能还包括髓源性抑制细胞（图4）。
BM-MSCs can inhibit the proliferation of T cells in response to alloantigens, mitogens, CD3 and CD28 as well as the proliferation and immunoglobulin secretion of reactive B cells to CD40 or IL-4.104-106 The most relevant mediators of such effects include TGF-p, hepatocyte growth factor, IL-10, IL-6 and prostaglandin E2. 106 BM-MSCs also secrete galectin-1 and semaphorin-3A, which inhibit T-cell proliferation via neuropilin-1. 107,108 IL-6 derived from BM-MSCs, in particular, seems to inhibit the differentiation of CD34+ and monocyte precursors into mature dendritic cells, maintaining them in an immature, tolerogenic state. 109 Dendritic-cell differentiation from HSCs requires the activation of the Notch pathway and Wnt, whose ligands are produced by nearby stromal cells, a regulatory model that further implicates BM-MSCs in the immune response.110
BM-MSCs可抑制响应于同种抗原，分裂素，CD3和CD28的T细胞的增殖以及抑制对CD40和IL-4响应的反应性B细胞的增殖和免疫球蛋白的分泌。104-106这种效应最相关的介质包括TGF-β，肝细胞生长因子，IL-10，IL-6和前列腺素E2。106 BM-MSCs还可分泌半乳糖凝集素1和脑信号蛋白-3A，并通过神经纤毛蛋白1抑制T细胞的增殖。107,108特别是来源于BM-MSCs的IL-6，似乎能抑制CD34+的分化以及单核细胞前体转化为成熟的树突状细胞，使它们维持在一种不成熟的，致耐受性的状态下。109从造血干细胞分化而来的树突状细胞需要Notch信号通路和Wnt的激活，其配体是由附近的间质细胞产生，这种调控模式进一步说明在免疫应答中有BM-MSCs的参与。110
BM-MSCs induce a TREG cell fate from CD4 or CD8 T cells upon their interaction. 111 Once TREG cells are activated, they suppress nearby lymphocyte and natural killer cells and as such can also offer escape from immune control to tumors. Tumor progression is associated with the expansion of the TREG cell compartment, partially explaining the tumor-associated immune suppression; whether TREG cells have a role in the initial phase of transformation and immune surveillance is less clear.112 Regardless of their thymic origin or peripheral conversion, Treg cells are endowed with plasticity and sensing different microenvironments can deflect toward the prevalent cytokine milieu including the inflammatory Th17.113 Even in the context of lymphoid neoplasms, such as angio-immunoblastic T-cell lymphoma, TREG cells can be skewed towards Th17 cells, which in turn maintain the proinflammatory conditions and promote remodeling of the infiltrated tissue.36 In hematological malignancies, increased numbers of TREG cells have been reported in patients with MGUS, multiple myeloma, and AML.114-115 AML cells can induce T-cell tolerance by directly converting CD4+CD25- T cells into TREG cells through indoleamine 2,3-dioxygenase,116 a mechanism that, originally described immunosuppressive in placenta, might characterize BM-MSCs. 117'118
BM-MSCs因CD4或CD8 T细胞的相互作用而诱导Treg细胞的命运。111一旦Treg细胞被激活，它们会抑制附近的淋巴细胞和自然杀伤细胞，因此也可以使肿瘤逃离免疫控制。肿瘤进展与Treg细胞室的扩张有关，部分解释了与肿瘤相关的免疫抑制; 而Treg细胞在转化和免疫监视的初期是否具有一定的作用还不太清楚。112不考虑它们的胸腺来源或周边的转换， Treg细胞被赋予的可塑性和感应不同的微环境，可使该细胞转向普遍的细胞因子环境中，包括炎性的Th17细胞。113即使是在淋巴组织肿瘤中，如血管免疫母细胞性T细胞淋巴瘤，Treg细胞也可偏向Th17细胞，从而维持促炎性条件，并促进渗透组织的重塑。36在血液系统恶性肿瘤中，已有报道在MGUS，多发性骨髓瘤和AML的患者中Treg细胞的数量有所增加。114 -115白血病细胞可通过吲哚胺2, 3-双加氧酶直接将CD4+CD25- T细胞转化为Treg细胞以诱导T细胞耐受，116最初在胎盘中描述的免疫机制可以表征BM-MSCs。117, 118
The other immunosuppressive population potentially induced by BM-MSCs in the BM environment is that of myeloid-derived suppressor cells. In the presence of solid tumors, the BM responds and produces abundant immature myeloid cells unable to complete their differentiation program and collectively named myeloid-derived suppressor cells, which provide potent immune suppression.119 Factors inducing the expansion of myeloid-derived suppressor cells are prostaglandins, IL-6, GM-CSF, and indoledamine 2,3-dioxygenase produced by BM-MSCs, which indicates a potential complementary mechanism through which BM-MSCs might induce a tolerogenic BM microenvironment.119 Myeloid-derived suppressor cells can inhibit immune cell responses through different mechanisms: T-cell activation is suppressed by the production of arginase and reactive oxygen species, the nitration of the T-cell receptor, cysteine deprivation, and the induction of Treg cells. Innate immunity is impaired by the down- regulation of IL-12 from macrophages, the increase in IL-10 from myeloid-derived suppressor cells, and the suppression of natural killer cell cytotoxicity. Antigen presentation is limited by the expansion of myeloid-derived suppressor cells at the expense of dendritic cells.120
在骨髓环境中可能由BM-MSCs诱发的其它免疫抑制细胞群是髓源性抑制细胞群。在实体肿瘤的存在下，骨髓响应并产生大量无法完成其分化过程的未成熟髓样细胞，统称为髓源性抑制细胞，从而提供有效的免疫抑制。119诱导髓源抑制细胞扩增的因子包括BM-MSCs产生的前列腺素，IL-6，GM-CSF和吲哚胺2, 3-双加氧酶，这表明，通过潜在的互补机制，BM-MSCs可能诱导免疫耐受的骨髓微环境。119髓源抑制细胞可以通过不同的机制抑制免疫细胞应答： T细胞活化是由于精氨酸酶和活性氧的产生，T细胞受体的硝化，半胱氨酸的缺失和Treg细胞的诱导而受到抑制。由于巨噬细胞下调IL-12，髓源抑制细胞上调IL-10，以及自然杀伤细胞的细胞毒性的抑制，先天免疫性会因此受到损害。抗原呈递会由于以树突状细胞为代价的髓源抑制细胞扩增而受到限制。120
The outcome of the immunosuppressive functions of BM-MSCs in vivo has been investigated in animal models and human pathological settings. In rats and mice, administration of BM-MSCs ameliorated autoimmune myasthenia gravis or enabled successful immune escape of cancer cells in an allogenic background, respectively.121,122 Moreover, BM-MSCs have been used in patients with severe graft-versus-host disease following solid organ and HSC transplantation, where they proved to be safe and showed substantial clinical efficacy in association with conventional immunosuppressive therapy.123 The immunomodulatory properties of BM-MSCs discussed above may also impact on the establishment and progression of hematologic neoplasms. TREG cells, which might be induced directly by BM-MSCs from effector cells, or recruited in the BM via the CXCL12/CXCR4 axis, may directly control the proliferation of the malignant clone and help maintain an homeostatic condition in the BM. They might also impair the establishment of an effective antitumoral immune response, thus favoring uncontrolled growth of the clones. 115,124 In myeloid malignancies, the detrimental contribution of BM-MSC-induced and/or BM-MSC-recruited TREG cells might be enriched by the direct participation of TREG cells to myeloid cancer-related stromal changes via the release of TGF-p, which directly contributes to remodeling of the BM stroma.
体内骨髓间充质干细胞BM-MSCs的免疫抑制功能的结果已经在动物模型中和人体病理的条件下进行了研究。在大鼠和小鼠中， 给予BM-MSC可分别改善自身免疫性重症肌无力或使癌细胞在同种异体背景下实现成功的免疫逃逸。121,122此外， BM- MSCs已被用于实体器官和HSC移植中，它们被证明是安全的，并表现出与传统免疫抑制剂疗法相关的重要的临床疗效。123上面讨论的BM-MSCs的免疫调节特性也可能影响血液系统肿瘤的建立和发展。 Treg细胞，可能是直接由BM-MSCs从效应细胞诱导而来，或在骨髓中通过CXCL12/CXCR4轴招募而来，可以直接控制恶性克隆的增殖，并帮助维持BM的体内平衡条件。他们也可能损害有效的抗肿瘤免疫应答的建立，进而促进克隆的失控生长。115,124在髓系肿瘤中，由于Treg细胞通过TGF-β的释放直接参与到骨髓瘤相关的间质变化中，BM-MSC诱导的和/或BM-MSC招募的Treg细胞的有害作用可能会累加，进而直接促进骨髓间质的重塑。
Conclusions
In hematological malignancies, the BM stroma is not an innocent bystander, but rather an accomplice of tumor development by favoring neoplastic cell growth and survival in the BM microenvironment, co-evolving alongside tumor progression, and forming part of the tumor microenvironment at extramedullary sites. Thus, treatment strategies that interfere with the major axes involved in crosstalk between neoplastic cells and BM stromal cells, such as monoclonal antibodies that target cell-adhesion or cytokine pathways, may prove effective in lymphoid malignancies, when combined with therapies that target the neoplastic clones. Efforts should also focus on limiting the stromal alterations that eventually determine BM failure in several types of myeloid neoplasms. The adoption of drugs that control the proliferation of BM stromal and vascular cells, such as tyrosine kinase inhibitors, proteasome inhibitors, and immunomodulatory agents could represent a promising perspective.
结论
在血液系统恶性肿瘤中，骨髓间质并不是骨髓微环境中一个无辜的旁观者，而是通过利于肿瘤细胞生长和存活促进肿瘤发展的帮凶，随肿瘤的发展共同进化，并在髓外部位形成部分的肿瘤微环境。因此，干扰肿瘤细胞和骨髓间质细胞之间的串扰的主要轴的治疗方法，如靶向细胞粘附或细胞因子途径的单克隆抗体，当与靶向肿瘤克隆疗法联用时，可能被证明在淋巴样恶性肿瘤中是有效的。同时也应努力着眼于限制几种类型的髓系肿瘤中最终确定骨髓的衰竭的间质改变。采用能控制骨髓间质和血管细胞增殖的药物，如酪氨酸激酶抑制剂，蛋白酶体抑制剂和免疫调节剂，这可能代表一个有前景的方向。
Review criteria
Data for this Review was compiled by searching the PubMed database for articles published before 1 September 2010. Only articles published in English were considered. The search terms included "bone marrow" and "stroma" in association with "lymphoma", "leukemia", "lymphoproliferative", "myeloproliferative", "stem cell", "niche", "fibrosis", and "angiogenesis". Where possible, primary sources have been quoted. References were chosen on the basis of the best experimental, clinical or laboratory evidence, especially if the results had been corroborated by published work from other centers.
审查标准
这篇综述的数据是通过搜索PubMed数据库中2010年9月1日前发表的文章编译而来。只采用了英文发表的文章。检索词包括 “淋巴瘤”，“白血病”，“淋巴组织增生性”，“骨髓增生性”，“干细胞”，“龛”，“纤维化”和“血管生成”相关的“骨髓”和“间质”。我们都尽可能引用初始来源的文献。参考文献是基于最佳的实验，临床或实验室证据而选择的，特别是那些结果已被其他研究中心发表的文章所证实的文献。
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Author contributions
C. Tripodo, S. Sangaletti, P. P. Piccaluga, S. Prakash, G. Franco, and I. Borrello researched data to include in the article. C. Tripodo, S. Sangaletti, I. Borrello, A. Orazi, M. P. Colombo, and S. A. Pileri contributed to discussion to of content for the article. All the authors contributed to the writing of the manuscript. C. Tripodo, S. Sangaletti, A. Orazi, M. P. Colombo, and S. A. Pileri reviewed/edited the manuscript before submission. |
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