Higher methylation subtype of malignant melanoma and its correlation with thicker progression and worse prognosis

Yamamoto, Yosuke; Matsusaka, Keisuke; Fukuyo, Masaki; Rahmutulla, Bahityar; Matsue, Hiroyuki; Kaneda, Atsushi

doi:10.1002/cam4.3127

Cited by 10 publications

(13 citation statements)

References 49 publications

(98 reference statements)

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“…However, its role in cancer has remained paradoxical. Previous work suggested that TFPI2 could cause decreased invasiveness and/or proliferation of gliomas, glioblastoma, breast cancer ( 44 , 45 , 56 ), and melanomas ( 46 , 57 ). Transcriptional silencing of TFPI2 by promoter methylation has been reported in a variety of tumors including melanoma ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

TFPI2 Promotes Perivascular Migration in an Angiotropism Model of Melanoma

Zhao

Wang

et al. 2021

Front. Oncol.

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PurposeAngiotropism is the process by which cancer cells attach to and migrate along blood vessels to acquire vasculature, disseminate, and metastasize. However, the molecular basis for such vessel–tumor interactions has not been fully elucidated, partly due to limited experimental models. In this study, we aimed to observe and explore the molecular mechanism underlying angiotropism in melanoma.MethodsTo monitor the interactions of human melanoma cells with the vasculature in vivo, a murine coxenograft model was employed by co-injecting highly and poorly invasive melanoma cells subcutaneously. To identify key pathways and genes involved in the angiotropic phenotype of melanoma, analysis of differentially expressed genes (DEGs) and gene set enrichment analysis (GSEA) were performed. The role of tissue factor pathway inhibitor 2 (TFPI2) in angiotropism was evaluated by immunostaining, adhesion assay, shRNA, and in vivo tumorigenicity. Angiotropism and TFPI2 expression were examined in surgical specimens of melanoma by immunohistochemical staining. Data from The Cancer Genome Atlas (TCGA) were analyzed to explore the expression and prognostic implications of TFPI2 in uveal and cutaneous melanoma.ResultsHighly invasive melanoma cells spread along the branches of intratumor blood vessels to the leading edge of invasion in the coxenograft model, resembling angiotropic migration. Mechanisms underlying angiotropism were primarily associated with molecular function regulators, regulation of cell population proliferation, developmental processes, cell differentiation, responses to cytokines and cell motility/locomotion. TFPI2 downregulation weakened the perivascular migration of highly invasive melanoma cells. High levels of TFPI2 were correlated with worse and better survival in uveal and cutaneous melanoma, respectively.ConclusionThese results provide a straightforward in vivo model for the observation of angiotropism and suggest that TFPI2 could inhibit the angiotropic phenotype of melanoma.

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Section: Discussionmentioning

confidence: 99%

TFPI2 Promotes Perivascular Migration in an Angiotropism Model of Melanoma

Zhao

Wang

et al. 2021

Front. Oncol.

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“…Koroknai et al ( 31 ) identified several methylation changes that can play a role in human melanoma progression, including hypermethylation of the promoter regions of the ARHGAP22 and NAV2 genes that are commonly altered in locally invasive primary melanomas as well as during metastasis. In addition, Yamamoto et al ( 32 ) investigated the role of epigenetic aberrations in human melanomas by genome-wide DNA methylation analysis of 51 clinical malignant melanoma samples. Hierarchical clustering analysis revealed two DNA methylation epigenotypes: high- and low-methylation subgroups.…”

Section: Discussionmentioning

confidence: 99%

Quantification of Global DNA Methylation in Canine Melanotic and Amelanotic Oral Mucosal Melanomas and Peripheral Blood Leukocytes From the Same Patients With OMM: First Study

et al. 2021

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Oral mucosal melanomas (OMMs) are aggressive and resistant cancers of high importance in veterinary oncology. Amelanotic OMM produces comparatively less melanin and is considered to be more aggressive than melanotic OMM. Global DNA methylation profiles with hypomethylated or hypermethylated patterns have both been associated with aggressive neoplasms; however, global DNA hypomethylation seems to correlate to higher aggressiveness. Accordingly, global DNA methylation in peripheral blood leukocytes has been investigated to understand the role of systemic or environmental factors in cancer development. This study aimed to quantify global DNA methylation in canine melanotic and amelanotic OMM samples and in the peripheral blood leukocytes of the same dogs. Tumor tissue samples were collected from 38 dogs, of which 19 were melanotic and 19 were amelanotic OMM. These were submitted to immunohistochemistry (IHC) with anti-5-methylcytosine (5mC) and anti-Ki67 primary antibodies. Ki67- and 5mC-positive nuclei were manually scored with the help of an image analysis system. Peripheral blood samples were collected from 18 among the 38 OMM-bearing dogs and from 7 additional healthy control dogs. Peripheral blood leukocytes were isolated from the 25 dogs, and DNA was extracted and analyzed by high-performance liquid chromatography (HPLC) for global DNA methylation. The pattern of global DNA methylation in both canine melanotic and amelanotic OMM indicated higher percentages of weakly or negatively stained nuclei in most of the OMM cells, presuming predominant global DNA hypomethylation. In addition, Ki67 counts in amelanotic OMM were significantly higher than those in melanotic OMM (p < 0.001). Global DNA methylation different immunostaining patterns (strong, weak or negative) correlated with Ki67 scores. Global DNA methylation in circulating leukocytes did not differ between the 9 melanotic and 9 amelanotic OMM or between the 18 OMM-bearing dogs and the 7 healthy dogs. This study provides new information on canine melanotic and amelanotic OMM based on global DNA methylation and cell proliferation.

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“…On the one hand, the tumors were shown to contain several thousand hypermethylated regions and according to a 2015 DNA methylation landscape study, 179 tumor-specific methylation sites were identified that could be melanoma biomarkers [ 96 ]. On the other hand, it seems that there is no correlation between the number of methylated sites and BRAF mutations [ 96 , 97 ]. The higher expression of DNMT3B was shown to correlate with melanoma progression [ 98 ] and a recent study also demonstrated a correlation between higher methylation and worse prognosis [ 97 ].…”

Section: Epigenetic Mechanisms Of Resistance To Braf Inhibitorsmentioning

confidence: 99%

“…On the other hand, it seems that there is no correlation between the number of methylated sites and BRAF mutations [ 96 , 97 ]. The higher expression of DNMT3B was shown to correlate with melanoma progression [ 98 ] and a recent study also demonstrated a correlation between higher methylation and worse prognosis [ 97 ].…”

Section: Epigenetic Mechanisms Of Resistance To Braf Inhibitorsmentioning

confidence: 99%

Targeted Therapy in Melanoma and Mechanisms of Resistance

Czarnecka

Bartnik

Fiedorowicz

et al. 2020

IJMS

124

101

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The common mutation BRAFV600 in primary melanomas activates the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway and the introduction of proto-oncogene B-Raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors (BRAFi and MEKi) was a breakthrough in the treatment of these cancers. However, 15–20% of tumors harbor primary resistance to this therapy, and moreover, patients develop acquired resistance to treatment. Understanding the molecular phenomena behind resistance to BRAFi/MEKis is indispensable in order to develop novel targeted therapies. Most often, resistance develops due to either the reactivation of the MAPK/ERK pathway or the activation of alternative kinase signaling pathways including phosphatase and tensin homolog (PTEN), neurofibromin 1 (NF-1) or RAS signaling. The hyperactivation of tyrosine kinase receptors, such as the receptor of the platelet-derived growth factor β (PDFRβ), insulin-like growth factor 1 receptor (IGF-1R) and the receptor for hepatocyte growth factor (HGF), lead to the induction of the AKT/3-phosphoinositol kinase (PI3K) pathway. Another pathway resulting in BRAFi/MEKi resistance is the hyperactivation of epidermal growth factor receptor (EGFR) signaling or the deregulation of microphthalmia-associated transcription factor (MITF).

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Higher methylation subtype of malignant melanoma and its correlation with thicker progression and worse prognosis

Cited by 10 publications

References 49 publications

TFPI2 Promotes Perivascular Migration in an Angiotropism Model of Melanoma

TFPI2 Promotes Perivascular Migration in an Angiotropism Model of Melanoma

Quantification of Global DNA Methylation in Canine Melanotic and Amelanotic Oral Mucosal Melanomas and Peripheral Blood Leukocytes From the Same Patients With OMM: First Study

Targeted Therapy in Melanoma and Mechanisms of Resistance

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