BMP6-induced modulation of the tumor micro-milieu

Stieglitz, David; Lamm, Susanne; Braig, Simone; Feuerer, Lena; Kuphal, Silke; Dietrich, Péter; Arndt, Stephanie; Echtenacher, Bernd; Hellerbrand, Claus; Karrer, Sigrid; Boßerhoff, Anja-Katrin

doi:10.1038/s41388-018-0475-x

Cited by 28 publications

(26 citation statements)

References 48 publications

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“…administration (Grujic et al, ). Moreover, our findings are consistent with clinical evidence in support of a correlation between MC protease expression and protection against melanoma (Crincoli et al, ; Siiskonen et al, ; Stieglitz et al, ). A protective role of MCs is also supported by a study where secreted MC mediators showed anti‐proliferative effects on cultured melanoma cells, although the nature of the active MC mediator(s) was not revealed (Stieglitz et al, ).…”

Section: Discussionsupporting

confidence: 92%

Protective role of mouse mast cell tryptase Mcpt6 in melanoma

Grujić

Hellman

Gustafson

et al. 2020

Pigment Cell Melanoma Res

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Tryptase‐positive mast cells populate melanomas, but it is not known whether tryptase impacts on melanoma progression. Here we addressed this and show that melanoma growth is significantly higher in tryptase‐deficient (Mcpt6−/−) versus wild‐type mice. Histochemical analysis showed that mast cells were frequent in the tumor stroma of both wild‐type and Mcpt6−/− mice, and also revealed their presence within the tumor parenchyma. Confocal microscopy analysis revealed that tryptase was taken up by the tumor cells. Further, tryptase‐positive granules were released from mast cells and were widely distributed within the tumor tissue, suggesting that tryptase could impact on the tumor microenvironment. Indeed, gene expression analysis showed that the absence of Mcpt6 caused decreased expression of numerous genes, including Cxcl9, Tgtp2, and Gbp10, while the expression of 5p‐miR3098 was enhanced. The levels of CXCL9 were lower in serum from Mcpt6−/− versus wild‐type mice. In further support of a functional impact of tryptase on melanoma, recombinant tryptase (Mcpt6) was taken up by cultured melanoma cells and caused reduced proliferation. Altogether, our results indicate a protective role of mast cell tryptase in melanoma growth.

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Section: Discussionsupporting

confidence: 92%

Protective role of mouse mast cell tryptase Mcpt6 in melanoma

Grujić

Hellman

Gustafson

et al. 2020

Pigment Cell Melanoma Res

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“…After direct and indirect CAP treatment, followed an incubation of one hour at 37 °C and 8% CO 2 . The radioimmunoprecipitation assay (RIPA) buffer was used to produce total protein lysates, as described previously [72]. The RIPA protein lysates were separated via sodium dodecyl sulphate polyacrylamide gel electrophoresis on a 10% gel and blotted on a poly-vinylidene difluoride (PVDF) membrane.…”

Section: Methodsmentioning

confidence: 99%

Acidification is an Essential Process of Cold Atmospheric Plasma and Promotes the Anti-Cancer Effect on Malignant Melanoma Cells

Schneider

Gebhardt

Arndt

et al. 2019

Cancers

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(1) Background: Cold atmospheric plasma (CAP) is ionized gas near room temperature. The anti-cancer effects of CAP were confirmed for several cancer types and were attributed to CAP-induced reactive species. However, the mode of action of CAP is still not well understood. (2) Methods: Changes in cytoplasmic Ca2+ level after CAP treatment of malignant melanoma cells were analyzed via the intracellular Ca2+ indicator fura-2 AM. CAP-produced reactive species were determined by fluorescence spectroscopic and protein nitration by Western Blot analysis. (3) Results: CAP caused a strong acidification of water and solutions that were buffered with the so-called Good buffers, while phosphate-buffered solutions with higher buffer capacity showed minor pH reductions. The CAP-induced Ca2+ influx in melanoma cells was stronger in acidic pH than in physiological conditions. NO formation that is induced by CAP was dose- and pH-dependent and CAP-treated solutions only caused protein nitration in cells under acidic conditions. (4) Conclusions: We describe the impact of CAP-induced acidification on the anti-cancer effects of CAP. A synergistic effect of CAP-induced ROS, RNS, and acidic conditions affected the intracellular Ca2+ level of melanoma cells. As the microenvironment of tumors is often acidic, further acidification might be one reason for the specific anti-cancer effects of CAP.

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“…In a previous study we approached this issue and showed that the combined absence of tryptase, chymase, and CPA3 can lead to increased tumor progression in a melanoma model 16 . There is also clinical evidence suggesting a correlation between the presence of MC proteases and good outcome in melanoma 17,18 . However, there is no mechanistic insight into how MC proteases could exert such anti-tumor effects.…”

Section: Introductionmentioning

confidence: 99%

Exosome-mediated uptake of mast cell tryptase into the nucleus of melanoma cells: a novel axis for regulating tumor cell proliferation and gene expression

et al. 2019

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It is well established that mast cell accumulation accompanies most malignancies. However, the knowledge of how mast cells functionally impact on tumors is still rudimentary. Here we addressed this issue and show that mast cells have anti-proliferative activity on melanoma cells and that this effect is dependent on tryptase, a tetrameric protease stored in mast cell granules. Mechanistically, tryptase was found to be endocytosed by melanoma cells as cargo of DNA-coated exosomes released from melanoma cells, followed by transport to the nucleus. In the nucleus, tryptase executed clipping of histone 3 and degradation of Lamin B1, accompanied by extensive nuclear remodeling. Moreover, tryptase degraded hnRNP A2/B1, a protein involved in mRNA stabilization and interaction with non-coding RNAs. This was followed by downregulated expression of the oncogene EGR1 and of multiple non-coding RNAs, including oncogenic species. Altogether, these findings establish a new principle for regulation of tumor cell proliferation.

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BMP6-induced modulation of the tumor micro-milieu

Cited by 28 publications

References 48 publications

Protective role of mouse mast cell tryptase Mcpt6 in melanoma

Protective role of mouse mast cell tryptase Mcpt6 in melanoma

Acidification is an Essential Process of Cold Atmospheric Plasma and Promotes the Anti-Cancer Effect on Malignant Melanoma Cells

Exosome-mediated uptake of mast cell tryptase into the nucleus of melanoma cells: a novel axis for regulating tumor cell proliferation and gene expression

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