Chaotic neovascularization induced by aggressive fibrosarcoma cells overexpressing S-adenosylmethionine decarboxylase

Paasinen-Sohns, Aino; Kääriäinen, Essi; Yin, Miao; Järvinen, Kristiina; Nummela, Pirjo; Hölttä, Erkki

doi:10.1016/j.biocel.2010.11.018

Cited by 10 publications

(6 citation statements)

References 70 publications

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“…AdoMetDC is critical for embryonic stem cell self-renewal and differentiation to the neural lineage 7 . Its dysregulation is linked to tumorigenesis 8 , and its overexpression in rodent fibroblasts gives rise to aggressive transformants with extremely high invasive capacity in nude mice 9 . The synthesis of AdoMetDC is tightly controlled at the translational level allowing for quick adjustment in response to changes in polyamine concentrations.…”

Section: Adometdc Catalyses the Decarboxylation Of S-adenosylmethionimentioning

confidence: 99%

AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation

Yordanova

Loughran

Zhdanov

et al. 2018

Nature

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Section: Adometdc Catalyses the Decarboxylation Of S-adenosylmethionimentioning

confidence: 99%

AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation

Yordanova

Loughran

Zhdanov

et al. 2018

Nature

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“…More important, we and other researchers have previously found that this thick, two-layer Matrigel assay (measuring the invasive, migratory, and proliferative ability of the cells) correlates better with the tumor cell invasiveness/aggressiveness in vivo than the Matrigel-coated filter/Boyden chamber assays. 26,27 Corresponding invasion assays were also performed with cells embedded in a mixture of Matrigel (2 mg/mL) and collagen-I (2 or 4 mg/mL), 28,29 because collagen-I is the major matrix protein in dermis/connective tissues, acting as a barrier to cellular invasion. In testing the effects of various inhibitors, the experiments were performed with or without MMP inhibitors GM6001 (or its negative control), BB-2516, or BB-3103 (0.5, 5, 10, and 15 mol/L), cathepsin B inhibitors CA-074 or CA-074Me (1, 2, and 5 mol/L), cathepsin L inhibitors I and II (0.5, 5, and 15 mol/L), TGF-␤ receptor I (ALK5) inhibitor SB-505124 (1, 2.5, 5, and 10 mol/L), or the neutralizing antibodies to TGF-␤ (2.5, 5, and 10 g/mL), added into the Matrigel and the growth medium.…”

Section: Invasion Assaysmentioning

confidence: 99%

TGF-β Signaling, Activated Stromal Fibroblasts, and Cysteine Cathepsins B and L Drive the Invasive Growth of Human Melanoma Cells

Yin

Soikkeli

Jahkola

et al. 2012

The American Journal of Pathology

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Accumulating evidence indicates that interactions between cancer cells and stromal cells are important for the development/progression of many cancers. Herein, we found that the invasive growth of melanoma cells in three-dimensional-Matrigel/collagen-I matrices is dramatically increased on their co-culture with embryonic or adult skin fibroblasts. Studies with fluorescent-labeled cells revealed that the melanoma cells first activate the fibroblasts, which then take the lead in invasion. To identify the physiologically relevant invasion-related proteases involved, we performed genome-wide microarray analyses of invasive human melanomas and benign nevi; we found up-regulation of cysteine cathepsins B and L, matrix metalloproteinase (MMP)-1 and -9, and urokinase- and tissue-type plasminogen activators. The mRNA levels of cathepsins B/L and plasminogen activators, but not MMPs, correlated with metastasis. The invasiveness/growth of the melanoma cells with fibroblasts was inhibited by cell membrane-permeable inhibitors of cathepsins B/L, but not by wide-spectrum inhibitors of MMPs. The IHC analysis of primary melanomas and benign nevi revealed cathepsin B to be predominantly expressed by melanoma cells and cathepsin L to be predominantly expressed by the tumor-associated fibroblasts surrounding the invading melanoma cells. Finally, cathepsin B regulated TGF-β production/signaling, which was required for the activation of fibroblasts and their promotion of the invasive growth of melanoma cells. These data provide a basis for testing inhibitors of TGF-β signaling and cathepsins B/L in the therapy of invasive/metastatic melanomas.

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“…The overexpression of ODC, the other rate-limiting decarboxylase in polyamine biosynthesis, is sufficient to promote Ras or UV-initiated keratinocytes (29). Elevated AdoMetDC activity has been associated with proliferative stimuli and AdoMetDC transfection of rodent fibroblasts results in a highly invasive, pro-angiogenic transformed phenotype (12,13). These seemingly conflicting concepts can be reconciled by considering the context of each of the experiments.…”

Section: Cshi Et Almentioning

confidence: 99%

“…Thus, AdoMetDC activity determines the rate of conversion of putrescine to higher polyamines, and it is highly regulated at multiple levels including transcription, translation, proenzyme processing, catalytic activity, and degradation (1). AdoMetDC transfection of rodent fibroblasts yields a highly invasive and pro-angiogenic transformed phenotype (12,13), and this enzyme has also been proposed as a target for cancer prevention and therapy (5,14).…”

Section: Introductionmentioning

confidence: 99%

S -adenosylmethionine decarboxylase overexpression inhibits mouse skin tumor promotion

Shi¹,

Cooper²,

McCloskey³

et al. 2012

Carcinogenesis

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Neoplastic growth is associated with increased polyamine biosynthetic activity and content. Tumor promoter treatment induces the rate-limiting enzymes in polyamine biosynthesis, ornithine decarboxylase (ODC), and S-adenosylmethionine decarboxylase (AdoMetDC), and targeted ODC overexpression is sufficient for tumor promotion in initiated mouse skin. We generated a mouse model with doxycycline (Dox)-regulated AdoMetDC expression to determine the impact of this second rate-limiting enzyme on epithelial carcinogenesis. TetO-AdoMetDC (TAMD) transgenic founders were crossed with transgenic mice (K5-tTA) that express the tetracycline-regulated transcriptional activator within basal keratinocytes of the skin. Transgene expression in TAMD/K5-tTA mice was restricted to keratin 5 (K5) target tissues and silenced upon Dox treatment. AdoMetDC activity and its product, decarboxylated AdoMet, both increased approximately 8-fold in the skin. This enabled a redistribution of the polyamines that led to reduced putrescine, increased spermine, and an elevated spermine:spermidine ratio. Given the positive association between polyamine biosynthetic capacity and neoplastic growth, it was somewhat surprising to find that TAMD/K5-tTA mice developed significantly fewer tumors than controls in response to 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate chemical carcinogenesis. Importantly, tumor counts in TAMD/K5-tTA mice rebounded to nearly equal the levels in the control group upon Dox-mediated transgene silencing at a late stage of tumor promotion, which indicates that latent viable initiated cells remain in AdoMetDC-expressing skin. These results underscore the complexity of polyamine modulation of tumor development and emphasize the critical role of putrescine in tumor promotion. AdoMetDC-expressing mice will enable more refined spatial and temporal manipulation of polyamine biosynthesis during tumorigenesis and in other models of human disease.

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Chaotic neovascularization induced by aggressive fibrosarcoma cells overexpressing S-adenosylmethionine decarboxylase

Cited by 10 publications

References 70 publications

AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation

AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation

TGF-β Signaling, Activated Stromal Fibroblasts, and Cysteine Cathepsins B and L Drive the Invasive Growth of Human Melanoma Cells

S -adenosylmethionine decarboxylase overexpression inhibits mouse skin tumor promotion

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