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Pathogenesis and Treatment of Cutaneous Lymphoma

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 May 2022) | Viewed by 19282

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Special Issue Editor

Prof. Dr. Makoto Sugaya

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Guest Editor

Department of Dermatology, International University of Health and Welfare, Chiba 286-8520, Japan
Interests: cutaneous lymphoma; chemokine; atopic dermatitis; tumor immunology; dendritic cells

Special Issue Information

Dear Colleagues,

Cutaneous lymphoma is a challenging disease. We can investigate this unique disease from a variety of perspectives, such as tumor immunity, Th2 dominance, and chemotaxis of tumor and inflammatory cells. The pathogenesis of cutaneous lymphoma is yet to be known, and molecular analysis is needed to find a future therapeutic target. Although CCR4 and CD30 are already used as target molecules for treatment of cutaneous lymphoma, it is still difficult to achieve a long remission at advanced stage. The finding of new molecules that can predict the clinical course is also important. This Special Issue of the International Journal of Molecular Sciences focuses on the pathogenesis and treatment of cutaneous lymphoma; it welcomes both original research articles and review papers on various topics, including molecular mechanisms linked to pathogenesis of cutaneous lymphoma, molecular prognostic markers that are expressed in the skin or in blood, and new treatment strategies targeting the molecules expressed by tumor cells or immune cells. I hope that this issue will deepen our understanding of the disease, leading to new treatment options.

Prof. Dr. Makoto Sugaya
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cutaneous lymphoma
mycosis fungoides
Sézary syndrome
chemokine
prognosis marker
tumor microenvironment
tumor immunity
Th2
autocrine

Published Papers (7 papers)

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Research

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14 pages, 3548 KiB

Open AccessArticle

Roles of OX40 and OX40 Ligand in Mycosis Fungoides and Sézary Syndrome

by Yuki Kawana, Hiraku Suga, Hiroaki Kamijo, Tomomitsu Miyagaki, Makoto Sugaya and Shinichi Sato

Int. J. Mol. Sci. 2021, 22(22), 12576; https://doi.org/10.3390/ijms222212576 - 22 Nov 2021

Cited by 2 | Viewed by 2196

Abstract

Mycosis fungoides (MF) and Sézary syndrome (SS), the most common types of cutaneous T-cell lymphoma (CTCL), are characterized by proliferation of mature CD4+ T-helper cells. Patients with advanced-stage MF and SS have poor prognosis, with 5-year survival rates of 52%. Although a variety of systemic therapies are currently available, there are no curative options for such patients except for stem cell transplantation, and thus the treatment of advanced MF and SS still remains challenging. Therefore, elucidation of the pathophysiology of MF/SS and development of medical treatments are desired. In this study, we focused on a molecule called OX40. We examined OX40 and OX40L expression and function using clinical samples of MF and SS and CTCL cell lines. OX40 and OX40L were co-expressed on tumor cells of MF and SS. OX40 and OX40L expression was increased and correlated with disease severity markers in MF/SS patients. Anti-OX40 antibody and anti-OX40L antibody suppressed the proliferation of CTCL cell lines both in vitro and in vivo. These results suggest that OX40–OX40L interactions could contribute to the proliferation of MF/SS tumor cells and that the disruption of OX40–OX40L interactions could become a new therapeutic strategy for the treatment of MF/SS. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Cutaneous Lymphoma)

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11 pages, 771 KiB

Open AccessArticle

Functional Depletion of HSP72 by siRNA and Quercetin Enhances Vorinostat-Induced Apoptosis in an HSP72-Overexpressing Cutaneous T-Cell Lymphoma Cell Line, Hut78

by Kazuyasu Fujii, Masashi Idogawa, Norihiro Suzuki, Keiji Iwatsuki and Takuro Kanekura

Int. J. Mol. Sci. 2021, 22(20), 11258; https://doi.org/10.3390/ijms222011258 - 19 Oct 2021

Cited by 7 | Viewed by 1829

Abstract

Histone deacetylase inhibitors (HDACis) are one of the therapeutic options for cutaneous T-cell lymphoma (CTCL), but they have limited effects. We previously demonstrated that HSP72 overexpression is associated with chemoresistance to HDACis in lymphoma cells. The purpose of this study was to investigate whether the functional depletion of HSP72 enhances the effect of the HDACi vorinostat. First, we established a stable HSP72-knockdown CTCL cell line and confirmed the influence of HSP72 reduction on the antitumor effects of vorinostat. Next, we studied the effect of quercetin, an inhibitor of HSP72, on the antineoplastic effects of vorinostat. In five CTCL cell lines examined, HSP72 expression was highest in Hut78 cells, and HSP72 knockdown enhanced vorinostat-induced apoptosis in these cells. Low-dose quercetin reduced HSP72 expression, increased HDAC activity, and enhanced vorinostat-induced suppression of Hut78 cell proliferation. A single low dose of quercetin induced G2 arrest and only slightly increased the sub-G1 cell fraction. Quercetin also significantly enhanced vorinostat-induced apoptosis, caspase-3, caspase-8, and caspase-9 activity, and the loss of mitochondrial membrane potential. HSP72 knockdown enhanced vorinostat-induced apoptosis in an HSP72-overexpressing CTCL cell line, and thus, quercetin may be a suitable candidate for combination therapy with vorinostat in clinical settings. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Cutaneous Lymphoma)

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13 pages, 3301 KiB

Open AccessArticle

CD147-Cyclophilin a Interactions Promote Proliferation and Survival of Cutaneous T-Cell Lymphoma

by Minami Sakamoto, Tomomitsu Miyagaki, Hiroaki Kamijo, Tomonori Oka, Hikari Boki, Naomi Takahashi-Shishido, Hiraku Suga, Makoto Sugaya and Shinichi Sato

Int. J. Mol. Sci. 2021, 22(15), 7889; https://doi.org/10.3390/ijms22157889 - 23 Jul 2021

Cited by 11 | Viewed by 2159

Abstract

CD147, a transmembrane glycoprotein that belongs to the immunoglobulin superfamily, and cyclophilin A (CypA), one of the binding partners of CD147, are overexpressed in tumor cells and associated with the progression of several malignancies, including both solid and hematological malignancies. However, CD147 and CypA involvement in cutaneous T-cell lymphoma (CTCL) has not been reported. In this study, we examined CD147 and CypA expression and function using clinical samples of mycosis fungoides (MF) and Sézary syndrome (SS) and CTCL cell lines. CD147 and CypA were overexpressed by tumor cells of MF/SS, and CypA was also expressed by epidermal keratinocytes in MF/SS lesional skin. Serum CypA levels were increased and correlated with disease severity markers in MF/SS patients. Anti-CD147 antibody and/or anti-CypA antibody suppressed the proliferation of CTCL cell lines, both in vitro and in vivo, via downregulation of phosphorylated extracellular-regulated kinase 1/2 and Akt. These results suggest that CD147-CypA interactions can contribute to the proliferation of MF/SS tumor cells in both a autocrine and paracrine manner, and that the disruption of CD147-CypA interactions could be a new therapeutic strategy for the treatment of MF/SS. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Cutaneous Lymphoma)

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Review

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23 pages, 2990 KiB

Open AccessReview

The Role of Tumor Microenvironment in the Pathogenesis of Sézary Syndrome

by Denis Miyashiro, Bruno de Castro e Souza, Marina Passos Torrealba, Kelly Cristina Gomes Manfrere, Maria Notomi Sato and José Antonio Sanches

Int. J. Mol. Sci. 2022, 23(2), 936; https://doi.org/10.3390/ijms23020936 - 15 Jan 2022

Cited by 6 | Viewed by 2372

Abstract

Sézary syndrome is an aggressive leukemic variant of cutaneous T-cell lymphomas, characterized by erythroderma, lymphadenopathy, and peripheral blood involvement by CD4+ malignant T-cells. The pathogenesis of Sézary syndrome is not fully understood. However, the course of the disease is strongly influenced by the tumor microenvironment, which is altered by a combination of cytokines, chemokines, and growth factors. The crosstalk between malignant and reactive cells affects the immunologic response against tumor cells causing immune dysregulation. This review focuses on the interaction of malignant Sézary cells and the tumor microenvironment. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Cutaneous Lymphoma)

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21 pages, 3420 KiB

Open AccessReview

Safety and Danger Considerations of Novel Treatments for Atopic Dermatitis in Context of Primary Cutaneous Lymphomas

by Karol Kołkowski, Magdalena Trzeciak and Małgorzata Sokołowska-Wojdyło

Int. J. Mol. Sci. 2021, 22(24), 13388; https://doi.org/10.3390/ijms222413388 - 13 Dec 2021

Cited by 16 | Viewed by 4850

Abstract

The impact of new and emerging therapies on the microenvironment of primary cutaneous lymphomas (PCLs) has been recently raised in the literature. Concomitantly, novel treatments are already used or registered (dupilumab, upadacitinib) and others seem to be added to the armamentarium against atopic dermatitis. Our aim was to review the literature on interleukins 4, 13, 22, and 31, and JAK/STAT pathways in PCLs to elucidate the safety of using biologics (dupilumab, tralokinumab, fezakinumab, nemolizumab) and small molecule inhibitors (upadacitinib, baricitinib, abrocitinib, ruxolitinib, tofacitinib) in the treatment of atopic dermatitis. We summarized the current state of knowledge on this topic based on the search of the PubMed database and related references published before 21 October 2021. Our analysis suggests that some of the mentioned agents (dupilumab, ruxolitinib) and others may have a direct impact on the progression of cutaneous lymphomas. This issue requires further study and meticulous monitoring of patients receiving these drugs to ensure their safety, especially in light of the FDA warning on tofacitinib. In conclusion, in the case of the rapid progression of atopic dermatitis/eczema, especially in patients older than 40 years old, there is a necessity to perform a biopsy followed by a very careful pathological examination. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Cutaneous Lymphoma)

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15 pages, 1186 KiB

Open AccessReview

Malignant and Benign T Cells Constituting Cutaneous T-Cell Lymphoma

by Shuichi Nakai, Eiji Kiyohara and Rei Watanabe

Int. J. Mol. Sci. 2021, 22(23), 12933; https://doi.org/10.3390/ijms222312933 - 29 Nov 2021

Cited by 5 | Viewed by 2884

Abstract

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin lymphoma, including various clinical manifestations, such as mycosis fungoides (MF) and Sézary syndrome (SS). CTCL mostly develops from CD4 T cells with the skin-tropic memory phenotype. Malignant T cells in MF lesions show the phenotype of skin resident memory T cells (T_RM), which reside in the peripheral tissues for long periods and do not recirculate. On the other hand, malignant T cells in SS represent the phenotype of central memory T cells (T_CM), which are characterized by recirculation to and from the blood and lymphoid tissues. The kinetics and the functional characteristics of malignant cells in CTCL are still unclear due, in part, to the fact that both the malignant cells and the T cells exerting anti-tumor activity possess the same characteristics as T cells. Capturing the features of both the malignant and the benign T cells is necessary for understanding the pathogenesis of CTCL and would lead to new therapeutic strategies specifically targeting the skin malignant T cells or benign T cells. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Cutaneous Lymphoma)

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Graphical abstract

13 pages, 1377 KiB

Open AccessReview

Clinical Guidelines and New Molecular Targets for Cutaneous Lymphomas

by Makoto Sugaya

Int. J. Mol. Sci. 2021, 22(20), 11079; https://doi.org/10.3390/ijms222011079 - 14 Oct 2021

Cited by 5 | Viewed by 2273

Abstract

Primary cutaneous lymphomas are heterogenous lymphoproliferative disorders. Some patients show rapid progression and the need for treatment of advanced disease is still unmet. The frequency of each subtype of cutaneous lymphoma varies among different ethnic groups, as do the medical systems found in different countries. It is important to know the differences in clinical guidelines in different areas of the world. Although current monochemotherapy with gemcitabine or pegylated liposomal doxorubicin is temporarily effective for mycosis funogides (MF) and Sézary syndrome (SS)—representative types of cutaneous lymphomas—the duration of response is usually limited. Therefore, treatment strategies targeting tumor-specific molecules have been developed. Molecular targets for MS/SS are currently CD30, CCR4, CD25, CD52, and histone deacetylases, most of which are surface molecules specifically expressed on tumor cells. As a result of advances in research techniques, different kinds of genomic alterations in MF/SS have been revealed. Molecular targets for MS/SS in the near future would be CD158k, JAK, PIK3, the mammalian target of rapamycin, and microRNAs, most of which mediate intracellular signaling pathways. Personalized therapy based on the detection of the genetic signatures of tumors and inhibition of the most suitable target molecules constitutes a future treatment strategy for MF/SS. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Cutaneous Lymphoma)

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