Pathogenesis Of Cutaneous Lymphoma Research Articles

Hist-P-02 - CD74 overexpression in cutaneous T-cell lymphoma and its inhibition as a potential therapeutic approach

Cutaneous T-cell lymphomas form a heterogeneous group of non-Hodgkin lymphomas characterized by only poor prognosis in advanced stage. Despite significant progress made in the identification of novel genes and pathways involved in the pathogenesis of cutaneous lymphoma, the therapeutic value of these findings has still to be proven. CD74 is a type II membrane glycoprotein that plays an important role in MHC class II antigen presentation. It is expressed by a number of immune cells, including B cells and macrophages. CD74 conveys proliferative and provital signals. This can lead to procarcinogenic effects and thus increase the survival of malignant cells. So far, as far as is known, neither the analysis of CD74 expression nor a therapeutic approach via CD74 blockade in cutaneous T-cell lymphomas has been described. In the presented study, CD74 expression in cutaneous T-cell lymphomas (CTCL), including subentities, and its association with clinical features were analyzed. Here, we demonstrate by quantitative RT-PCR, Western blotting, FACS analyzes and immunohistochemistry in CTCL cell lines and primary patient samples that CD74 is highly overexpressed in tumor cells. Moreover, treatment with a specific CD74 inhibitor blocks cell viability. These new data provide a promising rationale for using CD74 inhibition as a therapeutic modality in CTCL.

Angiogenesis in cutaneous T-cell lymphoma - proteomic approaches.

Neoangiogenesis plays an important role in cutaneous lymphoma pathogenesis. Cutaneous T-cell lymphoma (CTCL) is characterized by the presence of malignant T-cell clones in the skin. Vascular microenvironment of lymphomas accelerates neoangiogenesis through several factors released by tumoral cells: VEGF family, bFGF and PIGF. Tumor stroma (fibroblasts, inflammatory and immune cells) also plays a crucial role, by providing additional angiogenic factors. The angiogenic process through the VEGF-VEGFR axis can promote survival, proliferation and metastasis via autocrine mechanisms in cutaneous lymphomas. Microvascular density (MVD) measures the neo-vascularization of cutaneous lymphoma, generated by the response of tumor cells, proangiogenic stromal cells, and benign T/B lymphocytes within the tumor inflammatory infiltrate. Pro-angiogenic proteins have been found to indicate the evolution and prognosis in patients with CTCL. In conclusion, anti-angiogenic therapeutic protocols can target tumor vasculature or malignant tumor cells directly or through a large number of combinations with other drugs. The integration of proteomics into clinical practice based on high-throughput technologies leads to the development of personalized medicine, adapting the specific biomarkers to the application of cancer-type specific individual drug targets.

Clinical manifestations and pathogenesis of cutaneous lymphomas: current status and future directions.

The primary cutaneous lymphomas are a heterogeneous group of T-, Natural Killer- and B- cell neoplasms with a wide range of clinical and pathological presentations, and with very different prognoses compared to systemic lymphomas. Recent studies have shown that the skin microenvironment, which is composed of various immune cell subsets as well as their spatial distribution and T-cell interactions through different chemokines and cytokines, has an important role in the development and pathogenesis of cutaneous lymphomas and has assisted in the development of novel and more effective immunotherapies. The following review will focus on the major subtypes of primary cutaneous lymphomas, including the clinical and histological patterns, molecular hallmarks, and current and future treatment strategies.

Aurora Kinase A Is Upregulated in Cutaneous T-Cell Lymphoma and Represents a Potential Therapeutic Target

Cutaneous T-cell lymphomas (CTCLs) form a heterogeneous group of non-Hodgkin's lymphomas characterized by only poor prognosis in advanced stage. Despite significant progress made in the identification of novel genes and pathways involved in the pathogenesis of cutaneous lymphoma, the therapeutic value of these findings has still to be proven. Here, we demonstrate by gene expression arrays that Aurora kinase A is one of the highly overexpressed genes of the serine/threonine kinase in CTCL. The finding was confirmed by quantitative reverse transcriptase-PCR, western blotting, and immunohistochemistry in CTCL cell lines and primary patient samples. Moreover, treatment with a specific Aurora kinase A inhibitor blocks cell proliferation by inducing cell cycle arrest in G2 phase, as well as apoptosis in CTCL cell lines. These data provide a promising rationale for using Aurora kinase A inhibition as a therapeutic modality of CTCL.

C‐terminal deletions of Merkel cell polyomavirus large T‐antigen, a highly specific surrogate marker for virally induced malignancy

In 67-100% of cutaneous Merkel cell carcinomas (MCC) the Merkel cell polyomavirus (MCPyV) integrates into the host genome. Mutations and deletions truncating the C-terminal helicase domain of the T-antigen (TAg) protein have been detected in these MCCs, but not in healthy skin specimens. C-terminal deletions of the TAg nucleic acid sequences are characteristic for about 38% of these cases. While the association of MCPyV with MCC has been proven, it is unknown whether MCPyV may play a similar role in other tumor entities. We describe in detail the development and validation of a novel Merkel cell polyomavirus TAg C-terminus deletion assay (MCPyV ΔC-TAg). The triplex real-time PCR quantifies the N- and C-terminal part of the MCPyV TAg gene and the cellular β-globin gene. By comparing the copy numbers of the N- and C-terminal part, deletions of the MCPyV TAg C-terminus are rapidly identified. MCPyV ΔC-TAg was used to assess the physical state of MCPyV TAg in a large series of 55 MCCs, 15 cutaneous lymphomas and 47 forehead smears of healthy individuals. Neither DNA positivity nor viral load was able to discriminate MCCs from the other different types of samples. However, deleted TAg C-terminus sequences were detected only in MCPyV positive MCCs (39%). Consequently, detection of deleted C-terminal TAg sequences appears to be a highly specific surrogate marker for virally induced malignancy and should be used to support novel assumed MCPyV-tumor associations. The study further supports the notion that MCPyV does not play a role in cutaneous lymphoma pathogenesis.

Do Neoplastic Stem Cells Underlie the Pathogenesis of Cutaneous Lymphomas?

Do Neoplastic Stem Cells Underlie the Pathogenesis of Cutaneous Lymphomas?

From inflammation to neoplasia: new concepts in the pathogenesis of cutaneous lymphomas.

Mycosis fungoides is a clinicopathologic term which describes a neoplasm of cerebriform T lymphocytes that form plaques and tumors. We further suggest that mycosis fungoides arises in a background of chronic inflammation or as a response to chronic antigenic stimulation. Subsequently, a series of mutations results in the stepwise progression from eczematous patches, to plaques, tumors and eventual hematogenous dissemination. The pathogenetic process is driven by various, probably individually different, exogenous factors, e.g. environmental foreign antigens, bacterial superantigen, and/or endogenous factors, e.g. autocrine cytokine loops, CD40/CD40L and B7/CD28 interaction.

Molecular genetics of cutaneous lymphomas.

The underlying molecular basis of primary cutaneous lymphomas has not yet been clarified. However, abnormalities of cell cycle control genes and well-defined tumor suppressor genes such as p53 are common and may contribute to disease progression and treatment resistance. Biallelic inactivation of tumor suppressor genes usually occurs by a combination of deletion, point mutation, and/or promotor hypermethylation. The detection of UVB-specific mutations of p53 requires confirmation but may have important implications for the management of patients with mycosis fungoides. Molecular cytogenetic studies have identified common regions of chromosomal deletion and amplification, which suggests the presence and location of genes that are of critical importance in the pathogenesis of cutaneous lymphoma.

Pathogenesis of Cutaneous Lymphomas

Pathogenesis of Cutaneous Lymphomas

Pathogenesis of cutaneous lymphomas.

Cutaneous lymphomas are a heterogeneous group of lymphoproliferative disorders derived from T cells, B cells and, in rare cases, natural killer cells. The precise mechanisms of the lymphomagenesis are still obscure. However, there are various factors involved. These factors include environmental, especially infectious factors, translocations, mutations and genetic instability. The special microenvironment in the skin is responsible for the peculiar behavior of these neoplasms by providing various key factors, such as adhesion molecules and cytokines. Newly identified molecular disturbances in cutaneous lymphomas might be targeted by specific molecular or immunologic interventions in the future.

Cutaneous malignant lymphomas.

Abstract Progress in understanding the pathogenesis of cutaneous lymphomas was the focus of a recent meeting ∗ ∗The Clinically Oriented Symposium in Cutaneous Malignant Lymphomas of the European Society of Dermatological Research and the European Organization for Research and Treatment of Cancer was held at Charite, Berlin, Germany, on 24–28 October 1997.. Research in this area should improve diagnosis and treatment of these diseases, and aid the study of other T- and B-cell neoplasias