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Cancer Discov. 2014 Jan;4(1):110-29. doi: 10.1158/2159-8290.CD-13-0276. Epub 2013 Nov 4.

Defective stromal remodeling and neutrophil extracellular traps in lymphoid tissues favor the transition from autoimmunity to lymphoma.

Author information

1
1Molecular Immunology Unit, 2Molecular Targeting Unit, and 3Molecular Therapies Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan; 4Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo; 5Hematopathology Section, Department of Hematology and Oncology L. and A. Seràgnoli, S. Orsola-Malpighi Hospital, University of Bologna, Bologna; and 6Human Anatomy Section, Department of Experimental Medicine, University of Genova, Genova, Italy.

Abstract

Altered expression of matricellular proteins can become pathogenic in the presence of persistent perturbations in tissue homeostasis. Here, we show that autoimmunity associated with Fas mutation was exacerbated and transitioned to lymphomagenesis in the absence of SPARC (secreted protein acidic rich in cysteine). The absence of SPARC resulted in defective collagen assembly, with uneven compartmentalization of lymphoid and myeloid populations within secondary lymphoid organs (SLO), and faulty delivery of inhibitory signals from the extracellular matrix. These conditions promoted aberrant interactions between neutrophil extracellular traps and CD5(+) B cells, which underwent malignant transformation due to defective apoptosis under the pressure of neutrophil-derived trophic factors and NF-κB activation. Furthermore, this model of defective stromal remodeling during lymphomagenesis correlates with human lymphomas arising in a SPARC-defective environment, which is prototypical of CD5(+) B-cell chronic lymphocytic leukemia (CLL).

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PMID:
24189145
DOI:
10.1158/2159-8290.CD-13-0276
[Indexed for MEDLINE]
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