Cancer Discovery 4: 1448-1465 (2014-12)

Heinig K.; Gaetjen M.; Grau M.; Stache V.; Anagnostopoulos I.; Gerlach K.; Niesner R.A.; Cseresnyes Z.; Hauser A.E.; Lenz P.; Hehlgans T.; Brink R.; Westermann J.; Doerken B.; Lipp M.; Lenz G.; Rehm A.; Hoepken U.E.

Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B cell activation and proliferation

In human chronic lymphocytic leukemia (CLL) pathogenesis B cell antigen receptor signaling seems important for leukemia B cell ontogeny, whereas the microenvironment influences B cell activation, tumor cell lodging and provision of antigenic stimuli. Using the murine Eμ-Tcl1 CLL model, we demonstrate that CXCR5-controlled access to follicular dendritic cells (FDCs) confers proliferative stimuli to leukemia B cells. Intravital imaging revealed a marginal zone B cell-like leukemia cell trafficking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin-{beta}-receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin-{beta}-receptor signaling or of CXCR5 signaling retards leukemia progression. Thus, CXCR5 activity links tumor cell homing, shaping a survival niche, and access to localized proliferation stimuli. Significance: CLL and other indolent lymphoma are not curable and usually relapse after treatment, a process in which the tumor microenvironment plays a pivotal role. We dissect the consecutive steps of CXCR5-dependent tumor cell lodging and LTβR-dependent stroma–leukemia cell interaction; moreover, we provide therapeutic solutions to interfere with this reciprocal tumor–stroma cross-talk.

Keywords: Animal Disease Models, B-Cell Chronic Lymphocytic Leukemia, Cell Communication, Cell Movement, Cell Proliferation, Cluster Analysis, Complement 3b Receptors, Complement 3d Receptors, CXCR5 Receptors, Disease Progression, Follicular Dendritic Cells, Gene Expression, Gene Expression Profiling, Germinal Center, Intracellular Signaling Peptides and Proteins, Knockout Mice, Lymphotoxin {beta} Receptor, Protein-Tyrosine Kinases, Signal Transduction, Spleen, Stromal Cells, Tumor Microenvironment, ZAP-70 Protein-Tyrosine Kinase, Animals, Mice

Type: Article

PubMed: 25252690
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