The bone marrow stroma in hematological neoplasms--a guilty bystander

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.

Figure 1

BM stroma and lymphoid infiltration. a | CD34 immunostaining highlights the presence of blood vessels in the osteoblastic compartment of the BM lining the bone trabeculae (red arrows). b | A high density of finely branching vessels (green arrows) is observed in the intertrabecular space of the BM, which corresponds to the vascular niche. c | CD20 immunostaining reveals the presence of neoplastic B cells (red arrows) lodged inside dilated bone marrow sinusoids in a case of splenic marginal zone lymphoma with prominent intrasinusoidal infiltration. d | Aggregates of CD20⁺ neoplastic B cells can be observed adjacent to the endosteal lining of the bone trabeculae (asterisk) in a case of follicular lymphoma with prominent BM paratrabecular infiltration. e | The follicular dendritic cell meshwork of a BM nodular infiltrate is highlighted by CD23 immunostaining in a case of splenic marginal zone lymphoma. f | In the same nodule, follicular dendritic cells provide an adhesive background to neoplastic B cells due to the expression of intercellular adhesion molecule 1. Abbreviation: BM, bone marrow.

Figure 2

Schematic representation of the interactions between lymphoid neoplastic cells and the BM stromal microenvironment. The lymphoid neoplastic clone can directly interact with BM stromal elements through several axes (gray arrows), including adhesion molecules and their cellular and extracellular ligands, growth factors, cytokines, and chemokines. The combined effects of these interactions sustain neoplastic clone growth and survival. The neoplastic clone can also induce modifications in the BM stromal environment either directly by influencing angiogenesis (blue arrow), or indirectly by recruiting other immune effectors such as macrophages and mast cells at sites of infiltration (dashed blue arrow). Through the synthesis of a whole plethora of mediators, these recruited cells induce changes in the BM stromal composition by promoting angiogenesis, ECM deposition, and stromal cell proliferation (red arrows). Abbreviations: bFGF, basic fibroblast growth factor; CCL, CC-motif chemokine ligand; CXCL, CXC-motif chemokine ligand; CXCR, CXC-motif chemokine receptor; ECM, extracellular matrix; IFN, interferon; IL, interleukin; MMP, metalloproteinase; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor.

Figure 3

Bone marrow stromal changes in myeloid malignancies. Bone marrow biopsy section stained for a | reticulin (Gomori stain) and b | trichrome. Both stains highlight the presence of severe myelofibrosis with abundant collagen deposition (MF-3 grade according to the European Consensus Grading System). c | A bone marrow biopsy section stained with hematoxylin and eosin showing compact aggregates of abnormal mast cells surrounded by dense fibrosis, typical of systemic mastocytosis. d | A corresponding trichrome-stained section confirms the presence of abundant collagen fibrosis.

Figure 4

Possible suppressive mechanisms of BM stromal cells. Through a direct suppressive mechanism, MSCs produce soluble factors, such as PGE, IL-10, TGF-β, HGF, that inhibit responding T cells or block DC maturation from BM progenitors (IL-6) into a tolerogenic phenotype. Through an indirect mechanism, MSCs induce regulatory T cells that can either suppress effectors or block APC function. Factors released by MSCs are also expected to induce MDSC, the other suppressive population that together with regulatory T cells increase in patients with hematological malignancies. Immune suppression by MSC might have a complex role in hematological neoplasms by directly contribute in controlling the proliferation of the malignant clone by limiting proinflammatory signals and then exerting a prevalent suppressive function on antitumor immunity, thus contributing to the uncontrolled growth of the malignant clone. Abbreviations: APC, antigen presenting cells; GM-CSF, granulocyte-macrophage colony-stimulating factor; HGF, hepatocyte growth factor; iDC, immature dendritic cell; IL, interleukin; mDC, mature dendritic cell; MDSC, myeloid-derived suppressor cell; MSC, mesenchymal stem cell; PBMC, peripheral blood mononuclear cell; PGE2, prostaglandin E2; TGF-β, transforming growth factor-β; T_REG, T regulatory cells; VEGF, vascular endothelial growth factor.