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Sezary syndrome (SeS) represents a leukemic variant of cutaneous T-cell lymphoma, whose etiology is still unknown. To identify dyregulated genes in SeS, we performed transcriptional profiling of Sezary cells (SCs) obtained from peripheral blood of patients with SeS. We identified versican as the highest upregulated gene in SCs. VCAN is an extracellular matrix proteoglycan, which is known to interfere with different cellular processes in cancer. Versican isoform V1 was the most commonly upregulated isoform in SCs. Using a lentiviral plasmid, we overexpressed versican V1 isoform in lymphoid cell lines, which altered their growth behavior by promoting formation of smaller cell clusters and by increasing their migratory capacity towards stromal cell-derived factor 1, thus promoting skin homing. Versican V1 overexpression exerted an inhibitory effect on cell proliferation, partially by promoting activation-induced cell death. Furthermore, V1 overexpression in lymphoid cell lines increased their sensitivity to doxorubicin and gemcitabine. In conclusion, we confirm versican as one of the dysregulated genes in SeS and describe its effects on the biology of SCs. Although versican overexpression confers lymphoid cells with increased migratory capacity, it also makes them more sensitive to activation-induced cell death and some chemotherapeutics, which could be exploited further for therapeutic purposes.

Sézary syndrome (SS) is regarded as a leukemic, aggressive subtype of cutaneous T-cell lymphoma (CTCL) characterized by the accumulation of malignant T-cells in the skin, as well as by blood and lymph node involvement. To date there have been no data on the extent of lymphangiogenesis in SS or erythrodermic mycosis fungoides (eMF). Lymphangiogenesis represents the de novo formation of lymphatic vasculature and has been associated with the occurrence of metastatic disease and poor prognosis. In this study we investigated lymphangiogenesis in skin biopsies from patients with SS and eMF. The expression of VEGFR-3 was significantly higher in patients with SS (p = 0.0285) as compared to patients with eMF. LYVE-1, podoplanin (PDPN), and VEGF-C stainings showed a similar tendency. The number of PDPN-expressing lymphatic vessels (p = 0.025) as well as CD31-positive blood vessels (p = 0.0065) correlated with disease progression in patients with SS. We show for the first time a non-vascular pattern of VEGF-C and VEGFR-3, i.e. their epidermal expression in erythrodermic CTCLs, suggesting their role in lymphocyte trafficking to the skin.

Primary cutaneous lymphomas represent the second most frequent type of extranodal non-Hodgkin lymphomas (NHLs) after gastrointestinal lymphomas [9]. The worldwide annual incidence of primary cutaneous lymphomas is estimated to be 1:100,000 [1, 6, 9]. Despite the existence of several large, often clinic-based registries dealing with cutaneous lymphomas (Netherlands Lymphoma Registry, Lymphoma Registry Graz/Austria, Lymphoma Registry Stanford/USA, German Registry for Cutaneous Lymphomas, National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (NCI SEER)) there is a paucity of comparable population-based data concerning this group of diseases. Until 2005, one of the main obstacles for the correct reporting was the lack of appropriate classification to cover all clinicopathological entities, when the new WHO-EORTC was introduced [23]. The comparison of age distribution in different lymphoma registries shows that primary cutaneous lymphomas most commonly arise in older adults, with a median onset time after 60 years of age [1]. One exception to this distribution is lymphomatoid papulosis, which often develops in young adults and can even manifest in childhood [2]. Males seem to be more affected than females, with a male/female ratio reaching up to 4:1 [7, 11, 27].