Cancer-Associated Fibroblasts in Mycosis Fungoides Promote Tumor Cell Migration and Drug Resistance through CXCL12/CXCR4.

Cancer cells are known to reprogram normal fibroblasts into cancer-associated fibroblasts (CAFs) to act as tumor supporters. The presence and role of CAFs in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, are unknown. This study sought to characterize CAFs in MF and their cross talk with the lymphoma cells using primary fibroblast cultures from punch biopsies of patients with early-stage MF and healthy subjects. MF cultures yielded significantly increased levels of FAPα, a CAF marker, and CAF-associated genes and proteins: CXCL12 (ligand of CXCR4 expressed on MF cells), collagen XI, and matrix metalloproteinase 2. Cultured MF fibroblasts showed greater proliferation than normal fibroblasts in ex vivo experiments. A coculture with MyLa cells (MF cell line) increased normal fibroblast growth, reduced the sensitivity of MyLa cells to doxorubicin, and enhanced their migration. Inhibiting the CXCL12/CXCR4 axis increased doxorubicin-induced apoptosis of MyLa cells and reduced MyLa cell motility. Our data suggest that the fibroblasts in MF lesions are more proliferative than fibroblasts in normal skin and that CAFs protect MF cells from doxorubicin-induced cell death and increase their migration through the secretion of CXCL12. Reversing the CAF-mediated tumor microenvironment in MF may improve the efficiency of anticancer therapy.

Familial mycosis fungoides: report of 6 kindreds and a study of the HLA system.

BACKGROUND: The familial occurrence of mycosis fungoides (MF) has been reported only in 8 families. Recently, the HLA class II alleles DRB1* 11 and DQB1* 03 have been found to be significantly increased for patients with sporadic MF, suggesting a possible immunogenetic basis for the pathogenesis of this malignancy. OBJECTIVE: We sought to detect familial occurrences of MF, to describe familial features, and to investigate the possible association or linkage with the HLA system in such cases. METHODS: The files of 300 patients with MF were reviewed to search for familial occurrence in at least two first-degree relatives. A group of 252 healthy unrelated individuals served as control subjects. Tissue typing for HLA class I was performed using the microlymphocytotoxicity technique. DNA-based analysis for DRB1* and DQB1* alleles was performed using polymerase chain reaction amplification. RESULTS: Six families comprising 12 Jewish patients (9 male and 3 female) were detected: in 5, two first-degree relatives had MF; and in one, one member had MF and another had parapsoriasis en plaque. There were 5 families with two affected siblings and one family with a parent-child pair. In all but one family, the age of onset, clinical features, and response to therapy were similar to those in sporadic MF. One family, however, was exceptional: both affected siblings were children and both exhibited a similar but unusual morphology in the form of a hypopigmented variant of MF in conjunction with a psoriasiform variant. The allele frequency of HLA DQB1* 03 was found to be significantly greater among the patients than in the control group (66.7% vs 33%, respectively; P = .027), supporting an association of this allele with familial MF. Analysis of the HLA typing in the affected sibling pairs, when grouped together, did not support linkage to the HLA locus because no segregation distortion could be demonstrated ( P = .76). CONCLUSIONS: Familial aggregation of MF among Israeli Jews may not be as rare as is reflected in the literature. This familial clustering, together with the detection of certain HLA class II alleles with this malignancy (sporadic and familial), suggests that genetic factors may play a role in MF.

An open trial of climatotherapy at the Dead Sea for patch-stage mycosis fungoides.

BACKGROUND: Climatotherapy at the Dead Sea (CDS) is a well-established therapeutic modality for moderate to severe psoriasis vulgaris, resulting in sustained remissions. It has also been found to be effective for atopic dermatitis, another T-cell-mediated dermatosis. OBJECTIVE: We sought to prospectively evaluate the efficacy of CDS in patch-stage mycosis fungoides. METHODS: A total of 12 patients with patch-stage mycosis fungoides (6 with stage IA and 6 with stage IB) were treated with CDS as monotherapy for 28 consecutive days according to the protocol for psoriasis, ie, a gradual increase of sun exposure to a maximum of 3 hours daily. RESULTS: A total of 9 patients achieved a complete clinical response (CCR), defined as no disease activity present; 2 achieved an almost CCR, defined as the reduction by more than 90% of disease activity; and 1 achieved a partial response, ie, reduction by more than 50% of disease activity. A CCR was achieved in all the patients with stage IA disease and in 3 of the 6 patients with stage IB disease. Of the 9 with a CCR, 6 also showed histopathologic clearing. Duration of the remissions, during which no therapy was allowed except for emollients, lasted from 2 to 9 months (mean: 5 months). No serious short-term side effects were recorded. CONCLUSION: CDS appears to be an effective, well-tolerated therapy for patch-stage mycosis fungoides.

Climatotherapy at the Dead Sea is a remittive therapy for psoriasis: combined effects on epidermal and immunologic activation.

BACKGROUND: The beneficial effect of climatotherapy at the Dead Sea (CDS) for psoriasis has been established clinically but there is a striking lack of studies assessing its in vivo effect at the molecular and cellular levels. OBJECTIVE: We sought to study the response of activated immunologic cells and keratinocytes in psoriatic lesions to CDS. METHODS: A total of 27 patients with chronic, stable, plaque-type psoriasis treated with CDS for 28 consecutive days were evaluated with the Psoriasis Area and Severity Index score and quantitative histologic measures. RESULTS: After 4 weeks of treatment, the overall Psoriasis Area and Severity Index score decreased by 81.5%. Complete clearance was achieved in 48% of the patients, and moderate to marked improvement in 41%. The average duration of remission was 3.3 months. Histologically, there was an overall reduction in malpighian layer thickness by 63.4%, and keratinocyte hyperplasia, assessed by Ki-67 cell cycle antigen expression, decreased by 78%; residual cell proliferation was confined mainly to the basal layer. These changes were accompanied by normalization of keratin 16 expression in 90% of the patients. T lymphocytes were almost totally eliminated from the epidermis (depletion of >90% of CD3(+) and CD25(+) cells), with only a low number remaining in the dermis (depletion of 69.4% of CD3(+) cells and 77.4% of CD25(+) cells). This reduction in activated T cells was accompanied by a marked reduction in HLA-DR expression by epidermal keratinocytes. CONCLUSIONS: CDS is a highly effective and remittive treatment for moderate to severe plaque-type psoriasis, leading to a reversal of both pathologic epidermal and immunologic activation.