Aggressive B-cell lymphomas share high proliferative and invasive attitudes and dismal prognosis despite heterogeneous biological features. In the interchained sequence of events leading to cancer progression, neoplastic clone-intrinsic molecular events play a major role. Nevertheless, microenvironment-related cues have progressively come into focus as true determinants for this process. The cancer-associated microenvironment is a complex network of nonneoplastic immune and stromal cells embedded in extracellular components, giving rise to a multifarious crosstalk with neoplastic cells towards the induction of a supportive milieu. The immunological and stromal microenvironments have been classically regarded as essential partners of indolent lymphomas, while considered mainly negligible in the setting of aggressive B-cell lymphomas that, by their nature, are less reliant on external stimuli. By this paper we try to delineate the cardinal microenvironment-centred dynamics exerting an influence over lymphoid clone progression in aggressive B-cell lymphomas. 1. Introduction B-cell malignancies represent a heterogeneous group of diseases characterized by different biological features and clinical behaviour, the latter ranging from indolent to highly aggressive. As for most neoplasms, the natural course of B-cell malignancies is characterized by tumour progression, featured by a flow of events leading to the enhancement of proliferative and invasive capabilities, towards the establishment of a more aggressive phenotype. Even if most of the processes involved in cancer progression are inherent to the neoplastic clone, this event is, actually, the result of an articulated mechanism, which seems to require the constant crosstalk between neoplastic cells and the faulty surrounding microenvironment. An ever-increasing amount of evidences suggest that this bijective relationship is a prime determinant of cancer natural history and evolution. Much has been so far discovered about the role of tumour intrinsic mechanisms of neoplastic progression, and the focus of research has been progressively shifting toward the study of microenvironment-centred dynamics. Cancer-associated microenvironment represents a multifaceted entity, which not only provides structural support to neoplastic cells (proper stroma) but also acts as a “fertile soil” that, through humoral factors (bioactive molecules such as cytokines, chemokines, and adhesion molecules), nonmalignant cellular elements of the stroma (fibroblasts and endothelial cells) and the immune system (macrophages, mast
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