Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), accounting for about 40% of all cases of NHL. Analysis of the tumor microenvironment is an important aspect of the assessment of the progression of DLBCL. In this review article, we analyzed the role of different cellular components of the tumor microenvironment, including mast cells, macrophages, and lymphocytes, in the tumor progression of DLBCL. We examined several approaches to confront the available pieces of evidence, whereby three key points emerged. DLBCL is a disease of malignant B cells spreading and accumulating both at nodal and at extranodal sites. In patients with both nodal and extranodal lesions, the subsequent induction of a cancer-friendly environment appears pivotal. The DLBCL cell interaction with mature stromal cells and vessels confers tumor protection and inhibition of immune response while delivering nutrients and oxygen supply. Single cells may also reside and survive in protected niches in the nodal and extranodal sites as a source for residual disease and relapse. This review aims to molecularly and functionally recapitulate the DLBCL–milieu crosstalk, to relate niche and pathological angiogenic constitution and interaction factors to DLBCL progression.
Highlights
Diffuse large B-cell lymphoma (DLBCL) classified by the 2008 World Health Organization (WHO)classification as one of the B-cell lymphomas types is the most common non-Hodgkin B-cell lymphoma (NHL), accounting for about 40% of all cases of non-Hodgkin lymphoma (NHL) [1]
Based on several pieces of compelling evidence highlighting the impact of the DLBCL niche in nursing cancer cells, by promoting a favorable stromal environment, several prospective clinical studies are needed to validate the clinical utility of the stromal gene expression profile in DLBCL and dissect subtypes which would profit the most from anti-angiogenic and milieu-targeting strategies [68,69]
STAT3 expression being associated with higher CD163- and CD8-positive cell infiltration, which induces a strong angiogenic response in activated B cells (ABCs) DLBCL as compared with germinal center B cell (GCB) DLBCL [116]
Summary
Diffuse large B-cell lymphoma (DLBCL) classified by the 2008 World Health Organization (WHO). The gene expression profiling technique allowed identifying at least two molecular subtypes of DLBCL with different prognoses [5]. Activated STAT3 is correlated with a more advanced clinical stage and overall poor survival in DLBCL [10,11]. In ABC DLBCL, the activation of the Janus kinases (JAKs)/STAT3 pathway correlates with autocrine production of intereukin-6 (IL-6) and IL-10, which promotes cancer progression [12,13]. The STAT3 gene is a transcriptional target of BCL6 and is highly expressed and activated in ABC. As in other hematological niche addicted malignancies [21,22,23,24], the current evidence pinpoints that DLBCL disease progression is a multistep transformation process characterized by a complex vicious cycle between lymphoma cells and the tumor milieu. We show the latest findings on the disease evolution of DLBCL, by providing a specific focus on the role of new players within the cancer immune microenvironment in order to envision novel theragnostic windows
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