Importance of Crosstalk Between Chronic Lymphocytic Leukemia Cells and the Stromal Microenvironment: Direct Contact, Soluble Factors, and Extracellular Vesicles

Abstract

Chronic lymphocytic leukemia (CLL) is caused by the accumulation of malignant B cells due to a defect in apoptosis and the presence of small population of proliferating cells principally in the lymph nodes. The abnormal survival of CLL B cells is explained by a plethora of supportive stimuli produced by the surrounding cells of the microenvironment, including follicular dendritic cells (FDCs), and mesenchymal stromal cells (MSCs). This crosstalk between malignant cells and normal cells can take place directly by cell-to-cell contact (assisted by adhesion molecules such as VLA-4 or CD100), indirectly by soluble factors (chemokines such as CXCL12, CXCL13, or CCL2) interacting with their receptors or by the exchange of material (protein, microRNAs or long non-coding RNAs) via extracellular vesicles. These different communication methods lead to different activation pathways (including BCR and NFκB pathways), gene expression modifications (chemokines, antiapoptotic protein increase, prognostic biomarkers), chemotaxis, homing in lymphoid tissues and survival of leukemic cells. In addition, these interactions are bidirectional, and CLL cells can manipulate the normal surrounding stromal cells in different ways to establish a supportive microenvironment. Here, we review this complex crosstalk between CLL cells and stromal cells, focusing on the different types of interactions, activated pathways, treatment strategies to disrupt this bidirectional communication, and the prognostic impact of these induced modifications.

Understanding the Immune-Stroma Microenvironment in B Cell Malignancies for Effective Immunotherapy

“…To complicate the picture further, endothelial and mesenchymal cells are intimately linked to each other as exemplified by PDGF-activated MSCs in CLL that were shown to up-regulate VEGF production and promote the ‘angiogenic switch’ associated with disease progression ( 239 ). The importance of crosstalk in CLL between tumor cells and stroma cells has been recently reviewed by Dubois et al ( 240 ).…”

Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers

“…Most of these MSC features seem to be induced by the interaction with CLL cells, as demonstrated by a coculture experience reported by Ding and colleagues: a transcriptome analysis revealed an altered expression profile concerning genes mostly involved in senescence and cell cycle regulation, such as LIF, CDKN2B, DKK2, HGF, and FOXQ1 [ 162 ]. EVs also play a key role in this cross-talk mechanism among CLL cells and MSCs, as demonstrated in several studies [ 163 ]. In comparison to HD-MSCs, CLL-MSCs produced more EVs able to rescue CLL cells from apoptosis and induce higher migration activity and gene modifications than healthy Evs [ 140 ].…”

Targeting the tumor microenvironment in chronic lymphocytic leukemia

“…The survival and growth of CLL cells is highly dependent on support from these surrounding microenvironmental cells that include T cells, monocytes/macrophages, endothelial and mesenchymal stroma cells, and natural killer (NK) cells. [2][3][4][5] The complex crosstalk between CLL cells and these essential microenvironmental components is still poorly defined but studies have revealed how these interactions support disease progression and drug resistance. [6][7][8][9] For an extensive and detailed overview of the CLL-TME constituents and interactions, we refer the reader to previously published reviews, [3][4][5] as a complete review of the CLL TME is beyond the scope of this review.…”

“…26 Furthermore, through direct cell-cell contact by coexpressed adhesion molecules such as lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1, and chemokine signaling via the CXC motif chemokine receptor (CXCR)4/CXC ligand (CXCL)12 axis, TME constituents, such as NLC and stromal cells, aid migration and homing of CLL cells into protective niches. 4,18,19,24 Reciprocally, CLL cells release cytokines including interleukin (IL)-6 and IL-10, 27,28 chemokines such as CCL2, 12 and extracellular vesicles, 4,29 through which they recruit and alter microenvironmental cells, thus inducing a tumor-supportive niche. The above highlighted CLL-TME constituents and interactions are summarized in Online Supplementary Figure S1.…”