Picchio Maria Cristina, Scala Enrico, Pomponi Debora, Caprini Elisabetta, Frontani Marina, Angelucci Irene, Mangoni Antonella, Lazzeri Cristina, Perez Marie, Remotti Daniele, Bonoldi Emanuela, Benucci Roberto, Baliva Giannandrea, Lombardo Giuseppe Alfonso, Napolitano Monica, Russo Giandomenico, Narducci Maria Grazia
Istituto Dermopatico dell'Immacolata, Laboratorio di Oncologia Molecolare, III Divisione Dermatologica, Rome, Italy.
Cancer Res. 2008 Sep 1;68(17):7137-46. doi: 10.1158/0008-5472.CAN-08-0602.
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.
正常淋巴细胞和肿瘤性淋巴细胞表达的趋化因子及趋化因子受体在细胞向皮肤和淋巴结募集中起关键作用。本研究的目的是进一步深入了解趋化因子在皮肤T细胞淋巴瘤（CTCL）发病机制和进展中的作用，特别是针对Sezary综合征（SS），这是一种伴有血液受累的CTCL变异型。在此，我们发现功能性CXCL13稳态趋化因子在SS细胞中强烈上调，在皮肤病变和淋巴结中可良好检测到，并且在SS患者血浆中疾病进展的不同阶段可检测到高浓度。此外，我们发现将CXCL13添加到CCL19或CCL21（负责淋巴结归巢的选择性CCR7激动剂）中，可强烈增强CCR7+ SS细胞的迁移。我们还发现，中和CCR7受体在不存在或存在CXCL13的情况下均会强烈损害CCL19/21诱导的SS细胞趋化性。为研究生存、黏附和金属蛋白酶分泌而进行的其他实验表明，CXCL13与CCL19和CCL21联合主要影响SS细胞的趋化性。我们的研究结果表明，在SS中新描述的这种CXCL13表达代表了一种具有诊断意义的新发病机制。
