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CXCL13 Is Highly Produced by Sézary Cells and Enhances Their Migratory Ability via a Synergistic Mechanism Involving CCL19 and CCL21 Chemokines

¹ Istituto Dermopatico dell'Immacolata, Istituto Dermopatico dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Laboratorio di Oncologia Molecolare, Laboratorio di Allergologia Clinica e Sperimentale, III Divisione Dermatologica, Laboratorio di Patologia Vascolare and Laboratorio di Istopatologia and ² Azienda Ospedaliera San Camillo-Forlanini, Unità Operativa di Anatomia Patologica, Rome, Italy; and ³ Ospedale S.Bortolo, Unità Operativa di Anatomia Patologica, Vicenza, Italy

Requests for reprints: Giandomenico Russo, Laboratorio Oncologia Molecolare Istituto Dermopatico dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Via dei Monti dei Creta 104, 00167, Rome, Italy. Phone: 39-06-66462433; Fax: 39-06-66462430; E-mail: russo{at}idi.it.

Key Words: CXCL13 • chemokine • CCL21 • CCL19 • CCR7 • skin and lymph node homing • Sézary Syndrome • CTCLs

Chemokine and chemokine receptors expressed by normal and neoplastic lymphocytes play a key role in cell recruitment into skin and lymph nodes. The aim of this study was to get further insights into the role of chemokines in pathogenesis and progression of cutaneous T-cell lymphoma (CTCL) with particular regard to Sézary Syndrome (SS), a CTCL variant with blood involvement. Here, we show that functional CXCL13 homeostatic chemokine is strongly up-regulated in SS cells, well-detectable in skin lesions and lymph nodes, and measurable at high concentration in plasma of SS patients, at different levels during disease progression. Furthermore, we show that the addition of CXCL13 to CCL19 or to CCL21, the selective CCR7 agonists responsible for lymph node homing, strongly enhances the migration of CCR7+ SS cells. We also show that neutralization of the CCR7 receptor strongly impairs CCL19/21-induced chemotaxis of SS cells both in the absence or presence of CXCL13. Additional experiments performed to investigate the survival, adhesion, and metalloproteases secretion indicate that CXCL13 combined with CCL19 and CCL21 mainly affects the chemotaxis of SS cells. Our findings suggest that this newly described CXCL13 expression in SS represents a new pathogenetic mechanism of diagnostic significance. [Cancer Res 2008;68(17):7137–46]