IntroductionCutaneous T-cell lymphomas (CTCL) are the most frequent primary lymphomas of the skin, with mycosis fungoides (MF) being the most prevalent clinical form. 1 In early disease stages, which can last several years, MF presents as flat erythematous skin patches resembling inflammatory diseases such as allergic contact dermatitis, eczema, or psoriasis. In later stages, MF lesions gradually form plaques and overt tumors and may disseminate to lymph nodes and internal organs. The early skin lesions contain numerous inflammatory cells, including a large quantity of T cells with a normal phenotype as well as a small population of T cells with abnormal morphology and a malignant phenotype. T cells with a malignant phenotype are characterized by epidermotropism and are preferentially present in the upper parts of the skin, whereas T cells with a normal phenotype primarily are detected in the lower portions of the dermis. The epidermal T cells are sometimes found in patterns of Pautrier microabscesses, which are collections of T cells adherent to dendritic processes of Langerhans cells. During disease development, the epidermotropism is gradually lost concomitant with an increase in malignant, and a decrease in nonmalignant, infiltrating T cells. The etiology of CTCL remains poorly understood, and occupational exposures, infectious agents, and genetic mutations have been proposed as etiological factors, but no evidence of causation has been provided. [2][3][4][5][6] However, already in early disease stages, the transcription factor nuclear factor-kappa B (NF-B) has been shown to be constitutively active in the malignant T cells of patients with CTCL where it promotes proliferation and cell survival. [7][8][9] The malignant T cells also show aberrant hyperactivation of the Janus kinase 3 (Jak3)/signal transducer and activator of transcription 3 (Stat3) pathway, which protects them from apoptosis and is a marker of resistance to therapy. [10][11][12][13] It has been hypothesized that the aberrant activation of NF-B and the Jak3/Stat3 pathway are key events in the development of CTCL. [7][8][9][10] Early diagnosis of CTCL has important consequences concerning therapeutic options and determination of prognosis. 14 Currently, it is primarily based on clinical observations and histologic examinations of cutaneous biopsies as well as additional laboratory tests such as analysis of T-cell receptor (TCR) clonality by polymerase chain reaction (PCR). Unfortunately, early diagnosis of CTCL has proven difficult because of the great clinical, pathologic, and histologic resemblance to benign inflammatory skin diseases and because inflammatory skin disorders can be associated with clonal TCR rearrangements. [15][16][17][18] In humans, the Src family kinases (SFKs) of nonreceptor protein tyrosine kinases classically consists of 8 members: c-Src, Fyn, Lck, c-Yes, Fgr, Hck, Lyn, and B-lymphoid kinase (Blk). 19 Blk is exclusively expressed in B cells and thymocytes but not in mature T cells. [20][21][22] Besides a role of Blk in B...
Mutated BRAF and NRAS are suspected to contribute to melanomagenesis by activation of extracellular signal-regulated kinase (ERK). To test this notion, we analyzed the presence of phosphorylated ERK1/2 in 170 melanomas with established NRAS/BRAF mutational status and well-documented clinical follow-up by immunohistochemistry. Several notable observations were obtained: (i) phospho-ERK staining was very heterogeneous within the tumor; (ii) in most cases, ERK was phosphorylated in only a minority of tumor cells; (iii) the percentage of phospho-ERK-positive cells was not correlated with the mutational status of NRAS and/or BRAF; (iv) the Raf kinase inhibitor protein (RKIP) was expressed homogeneously in virtually all melanoma samples not reflecting the inhomogeneity of phospho-ERK; and, finally, (v) neither the portion of phospho-ERK-positive tumor cells nor the RKIP staining intensity showed any correlation to the clinical course of the patients. Furthermore, the ability of BRAF mutant melanoma cells to downregulate mitogen-activated protein kinase activation was shown in melanoma cell lines cultured at high densities or under nonadherent conditions. Our findings suggest that mitogen-activated protein kinase (MAPK) activity is subject to regulation even in BRAF/NRAS mutant melanoma cells and that high MAPK pathway signaling may be important only in distinct subsets of tumor cells.
Merkel cell carcinoma (MCC) is a highly metastatic skin tumor. To assess the relevance of the Ras/Raf/MEK/MAP kinase pathway, we analyzed for activating B-Raf mutations and we elucidated the presence of the Raf Kinase Inhibitor Protein (RKIP) and extracellular signal-regulated kinase (ERK) as well as the phosphorylation status of ERK. All MCC samples were negative for the B-Raf(V600E) mutation. Remarkably, RKIP, which was shown to interfere with the activation of MEK by Raf, was highly expressed in primary as well as in metastatic MCC. Immunohistochemical analysis of the phosphorylation status of ERK revealed in 42 out of 44 samples a complete lack of activated ERK in the tumor cells although ERK is expressed; in the two positive cases phosphorylated ERK was restricted to a minor fraction of the tumor cells. Western blot analysis of three MCC-derived cell lines revealed in one case the pattern present in situ (i.e. high RKIP expression and complete absence of phosphorylated ERK). In summary, our data demonstrate the inactivity of the classical MAP kinase signal transduction pathway in MCC, which seems to be because of lack of activation as well as active deactivation. These findings should be accounted for in future therapeutic approaches for this tumor.
CD147 is highly expressed on many tumor cells; its role for tumor invasiveness and metastasis has been deduced from its capacity to induce MMPs, i.e., MMP-1, -2, -3, and -9. However, in the murine B16 melanoma model, MMP-2/-9 expression occurs independent of CD147. To scrutinize the impact of CD147 on metastasis formation and angiogenesis in this model, CD147 was stably knocked down in B16 cells. This silencing of CD147 expression resulted in a reduced capability of the tumor cells to metastasize to the draining lymph nodes. Notably, the CD147 knock down caused a decreased VEGF expression in vivo accompanied by reduced blood vessel formation. Thus, in the B16 melanoma model, CD147 promotes metastasis formation by induction of angiogenesis in an MMP independent manner.
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