transforming-growth-factor-beta and Melanoma--Amelanotic

Melanoma is an aggressive type of cancer that can metastasize to numerous other organs. TGFβ is one of the key signaling pathways in melanoma progression. Previous studies on various types of cancer have shown that both: polyphenols and a static magnetic field (SMF) can be potential chemopreventive/therapeutic agents. Therefore, the aim of the study was to evaluate the effect of a SMF and selected polyphenols on the transcriptional activity of TGFβ genes in melanoma cells.. Experiments were performed on the C32 cell line treated with caffeic or chlorogenic acids, and with simultaneous exposure to a moderate-strength SMF. The RT-qPCR method was used to determine the mRNA level of genes encoding the TGFβ isoforms and their receptors. The concentration of the TGFβ1 and TGFβ2 proteins were also measured in the cell culture supernates. The first response of C32 melanoma cells to both factors is the reduction of TGFβ levels. Then, mRNA level of these molecules returned to values close to pre-treatment level by the end of experiment.. Our study results demonstrate the potential of polyphenols and a moderate-strength SMF to support cancer therapy by altering TGFβ expression, which is a very promising topic for the diagnosis and treatment of melanoma.

Topics: Humans; Melanoma, Amelanotic; Melanoma, Cutaneous Malignant; Protein Isoforms; Receptors, Transforming Growth Factor beta; RNA, Messenger; Skin Neoplasms; Transforming Growth Factor beta; Transforming Growth Factor beta1

We compared gene expression signatures of aggressive amelanotic (Amela) melanomas with those of slowly growing pigmented melanomas (Mela), identifying pathways potentially responsible for the aggressive Amela phenotype. Both tumors develop in mice upon conditional deletion in melanocytes of Ink4a/Arf tumor suppressor genes with concomitant expression of oncogene H-Ras(G12V) and a known tumor antigen. We previously showed that only the aggressive Amela tumors were highly infiltrated by leukocytes concomitant with local and systemic inflammation. We report that Amela tumors present a pattern of de-differentiation with reduced expression of genes involved in pigmentation. This correlates with reduced and enhanced expression, respectively, of microphthalmia-associated (Mitf) and Pou3f2/Brn-2 transcription factors. The reduced expression of Mitf-controlled melanocyte differentiation antigens also observed in some human cutaneous melanoma has important implications for immunotherapy protocols that generally target such antigens. Induced Amela tumors also express Epithelial-Mesenchymal-Transition (EMT)-like and TGFβ-pathway signatures. These are correlated with constitutive Smad3 signaling in Amela tumors and melanoma cell lines. Signatures of infiltrating leukocytes and some chemokines such as chemotactic cytokine ligand 2 (Ccl2) that contribute to leukocyte recruitment further characterize Amela tumors. Inhibition of the mitogen-activated protein kinase (MAPK) activation pathway in Amela tumor lines leads to reduced expression of EMT hallmark genes and inhibits both proinflammatory cytokine Ccl2 gene expression and Ccl2 production by the melanoma cells. These results indicate a link between EMT-like processes and alterations of immune functions, both being controlled by the MAPK pathway. They further suggest that targeting the MAPK pathway within tumor cells will impact tumor-intrinsic oncogenic properties as well as the nature of the tumor microenvironment.

Topics: Animals; Cell Differentiation; Cell Line, Tumor; Chemokine CCL2; Down-Regulation; Enzyme Activation; Epithelial-Mesenchymal Transition; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Melanocytes; Melanoma, Amelanotic; Melanoma, Experimental; Mice; Mitogen-Activated Protein Kinases; Nerve Tissue Proteins; POU Domain Factors; Signal Transduction; Skin Neoplasms; Smad3 Protein; Transforming Growth Factor beta; Up-Regulation