TNF-alpha and metalloproteases as key players in melanoma cells aggressiveness

S. Rossi, M. Cordella, C. Tabolacci, G. Nassa, D. D'Arcangelo, C. Senatore, P. Pagnotto, R. Magliozzi, A. Salvati, A. Weisz, A. Facchiano, F. Facchiano

Research output: Contribution to journalArticle

Abstract

Background: Melanoma aggressiveness determines its growth and metastatic potential. This study aimed at identifying new molecular pathways controlling melanoma cell malignancy. Methods: Ten metastatic melanoma cell lines were characterized by their proliferation, migration and invasion capabilities. The most representative cells were also characterized by spheroid formation assay, gene- and protein- expression profiling as well as cytokines secretion and the most relevant pathways identified through bioinformatic analysis were tested by in silico transcriptomic validation on datasets generated from biopsies specimens of melanoma patients. Further, matrix metalloproteases (MMPs) activity was tested by zymography assays and TNF-alpha role was validated by anti-TNF cell-treatment. Results: An aggressiveness score (here named Melanoma AGgressiveness Score: MAGS) was calculated by measuring proliferation, migration, invasion and cell-doubling time in10human melanoma cell lines which were clustered in two distinct groups, according to the corresponding MAGS. SK-MEL-28 and A375 cell lines were selected as representative models for the less and the most aggressive phenotype, respectively. Gene-expression and protein expression data were collected for SK-MEL-28 and A375 cells by Illumina-, multiplex x-MAP-and mass-spectrometry technology. The collected data were subjected to an integrated Ingenuity Pathway Analysis, which highlighted that cytokine/chemokine secretion, as well as Cell-To-Cell Signaling and Interaction functions as well as matrix metalloproteases activity were significantly different in these two cell types. The key role of these pathways was then confirmed by functional validation. TNF role was confirmed by exposing cells to the anti-TNF Infliximab antibody. Upon such treatment melanoma cells aggressiveness was strongly reduced. Metalloproteases activity was assayed, and their role was confirmed by comparing transcriptomic data from cutaneous melanoma patients (n = 45) and benign nevi (n = 18). Conclusions: Inflammatory signals such as TNF and MMP-2 activity are key intrinsic players to determine melanoma cells aggressiveness suggesting new venue sin the identification of novel molecular targets with potential therapeutic relevance. © 2018 The Author(s).
Original languageEnglish
JournalJournal of Experimental and Clinical Cancer Research
Volume37
Issue number1
DOIs
Publication statusPublished - 2018

Fingerprint

Metalloproteases
Melanoma
Tumor Necrosis Factor-alpha
Cell Line
Cytokines
Nevus
Gene Expression Profiling
Computational Biology
Chemokines
Cell Communication
Computer Simulation
Cell Movement
Mass Spectrometry
Proteins
Therapeutics
Technology
Phenotype
Biopsy
Gene Expression
Skin

Keywords

  • Cancer
  • Cutaneous melanoma
  • Cytokines
  • Inflammation
  • Malignancy
  • Metalloproteases
  • Proteomics
  • TNF
  • Uveal melanoma
  • eotaxin
  • gamma interferon
  • gelatinase A
  • granulocyte colony stimulating factor
  • infliximab
  • interleukin 1 receptor blocking agent
  • interleukin 10
  • interleukin 12
  • interleukin 1beta
  • interleukin 6
  • interleukin 8
  • interleukin 9
  • matrix metalloproteinase
  • platelet derived growth factor BB
  • RANTES
  • tumor necrosis factor
  • vasculotropin
  • cytokine
  • metalloproteinase
  • A-375 cell line
  • Article
  • assay
  • bioinformatics
  • cell interaction
  • cell invasion
  • cell migration
  • cell proliferation
  • computer model
  • controlled study
  • cytokine release
  • enzyme activity
  • gene expression
  • human
  • human cell
  • intracellular signaling
  • major clinical study
  • mass spectrometry
  • melanoma
  • Melanoma Aggressiveness Score
  • priority journal
  • protein expression
  • scoring system
  • SK-MEL-28 cell line
  • spheroid formation assay
  • transcriptomics
  • zymography
  • genetics
  • metabolism
  • pathology
  • physiology
  • proteomics
  • skin tumor
  • tumor cell line
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Melanoma
  • Skin Neoplasms
  • Tumor Necrosis Factor-alpha

Cite this

TNF-alpha and metalloproteases as key players in melanoma cells aggressiveness. / Rossi, S.; Cordella, M.; Tabolacci, C.; Nassa, G.; D'Arcangelo, D.; Senatore, C.; Pagnotto, P.; Magliozzi, R.; Salvati, A.; Weisz, A.; Facchiano, A.; Facchiano, F.

In: Journal of Experimental and Clinical Cancer Research, Vol. 37, No. 1, 2018.

Research output: Contribution to journalArticle

Rossi, S, Cordella, M, Tabolacci, C, Nassa, G, D'Arcangelo, D, Senatore, C, Pagnotto, P, Magliozzi, R, Salvati, A, Weisz, A, Facchiano, A & Facchiano, F 2018, 'TNF-alpha and metalloproteases as key players in melanoma cells aggressiveness', Journal of Experimental and Clinical Cancer Research, vol. 37, no. 1. https://doi.org/10.1186/s13046-018-0982-1
Rossi, S. ; Cordella, M. ; Tabolacci, C. ; Nassa, G. ; D'Arcangelo, D. ; Senatore, C. ; Pagnotto, P. ; Magliozzi, R. ; Salvati, A. ; Weisz, A. ; Facchiano, A. ; Facchiano, F. / TNF-alpha and metalloproteases as key players in melanoma cells aggressiveness. In: Journal of Experimental and Clinical Cancer Research. 2018 ; Vol. 37, No. 1.
@article{29de3c49e90748b884ccfb7fbc2df26c,
title = "TNF-alpha and metalloproteases as key players in melanoma cells aggressiveness",
abstract = "Background: Melanoma aggressiveness determines its growth and metastatic potential. This study aimed at identifying new molecular pathways controlling melanoma cell malignancy. Methods: Ten metastatic melanoma cell lines were characterized by their proliferation, migration and invasion capabilities. The most representative cells were also characterized by spheroid formation assay, gene- and protein- expression profiling as well as cytokines secretion and the most relevant pathways identified through bioinformatic analysis were tested by in silico transcriptomic validation on datasets generated from biopsies specimens of melanoma patients. Further, matrix metalloproteases (MMPs) activity was tested by zymography assays and TNF-alpha role was validated by anti-TNF cell-treatment. Results: An aggressiveness score (here named Melanoma AGgressiveness Score: MAGS) was calculated by measuring proliferation, migration, invasion and cell-doubling time in10human melanoma cell lines which were clustered in two distinct groups, according to the corresponding MAGS. SK-MEL-28 and A375 cell lines were selected as representative models for the less and the most aggressive phenotype, respectively. Gene-expression and protein expression data were collected for SK-MEL-28 and A375 cells by Illumina-, multiplex x-MAP-and mass-spectrometry technology. The collected data were subjected to an integrated Ingenuity Pathway Analysis, which highlighted that cytokine/chemokine secretion, as well as Cell-To-Cell Signaling and Interaction functions as well as matrix metalloproteases activity were significantly different in these two cell types. The key role of these pathways was then confirmed by functional validation. TNF role was confirmed by exposing cells to the anti-TNF Infliximab antibody. Upon such treatment melanoma cells aggressiveness was strongly reduced. Metalloproteases activity was assayed, and their role was confirmed by comparing transcriptomic data from cutaneous melanoma patients (n = 45) and benign nevi (n = 18). Conclusions: Inflammatory signals such as TNF and MMP-2 activity are key intrinsic players to determine melanoma cells aggressiveness suggesting new venue sin the identification of novel molecular targets with potential therapeutic relevance. {\circledC} 2018 The Author(s).",
keywords = "Cancer, Cutaneous melanoma, Cytokines, Inflammation, Malignancy, Metalloproteases, Proteomics, TNF, Uveal melanoma, eotaxin, gamma interferon, gelatinase A, granulocyte colony stimulating factor, infliximab, interleukin 1 receptor blocking agent, interleukin 10, interleukin 12, interleukin 1beta, interleukin 6, interleukin 8, interleukin 9, matrix metalloproteinase, platelet derived growth factor BB, RANTES, tumor necrosis factor, vasculotropin, cytokine, metalloproteinase, A-375 cell line, Article, assay, bioinformatics, cell interaction, cell invasion, cell migration, cell proliferation, computer model, controlled study, cytokine release, enzyme activity, gene expression, human, human cell, intracellular signaling, major clinical study, mass spectrometry, melanoma, Melanoma Aggressiveness Score, priority journal, protein expression, scoring system, SK-MEL-28 cell line, spheroid formation assay, transcriptomics, zymography, genetics, metabolism, pathology, physiology, proteomics, skin tumor, tumor cell line, Cell Line, Tumor, Cell Proliferation, Humans, Melanoma, Skin Neoplasms, Tumor Necrosis Factor-alpha",
author = "S. Rossi and M. Cordella and C. Tabolacci and G. Nassa and D. D'Arcangelo and C. Senatore and P. Pagnotto and R. Magliozzi and A. Salvati and A. Weisz and A. Facchiano and F. Facchiano",
note = "Export Date: 11 April 2019 CODEN: JECRD Correspondence Address: Facchiano, A.; Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata, IDI-IRCCSItaly; email: a.facchiano@idi.it Chemicals/CAS: gamma interferon, 82115-62-6; gelatinase A, 146480-35-5; infliximab, 170277-31-3; interleukin 12, 138415-13-1; interleukin 8, 114308-91-7; vasculotropin, 127464-60-2; metalloproteinase, 81669-70-7; Cytokines; Metalloproteases; Tumor Necrosis Factor-alpha Funding details: Ministero della Salute Funding details: FARB 2017 Funding details: Ministero dell’Istruzione, dell’Universit{\`a} e della Ricerca Funding details: Associazione Italiana per la Ricerca sul Cancro, IG-17426 Funding text 1: The following grants gave a financial support for collection, analysis, and interpretation of data and in writing the manuscript: University of Salerno (FARB 2017) to AW; Ministero della Salute (Programma Italia-USA, Progetto Sieroproteomica; Progetto Oncotecnologico) to FF; Ministero della Salute (Ricerca Corrente) to DD and AF RC-2017_3.4; AIRC (IG-17426) to AW; MIUR (CNR Flagship Project InterOmics) to AW. 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year = "2018",
doi = "10.1186/s13046-018-0982-1",
language = "English",
volume = "37",
journal = "Journal of Experimental and Clinical Cancer Research",
issn = "0392-9078",
publisher = "BioMed Central Ltd.",
number = "1",

}

TY - JOUR

T1 - TNF-alpha and metalloproteases as key players in melanoma cells aggressiveness

AU - Rossi, S.

AU - Cordella, M.

AU - Tabolacci, C.

AU - Nassa, G.

AU - D'Arcangelo, D.

AU - Senatore, C.

AU - Pagnotto, P.

AU - Magliozzi, R.

AU - Salvati, A.

AU - Weisz, A.

AU - Facchiano, A.

AU - Facchiano, F.

N1 - Export Date: 11 April 2019 CODEN: JECRD Correspondence Address: Facchiano, A.; Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata, IDI-IRCCSItaly; email: a.facchiano@idi.it Chemicals/CAS: gamma interferon, 82115-62-6; gelatinase A, 146480-35-5; infliximab, 170277-31-3; interleukin 12, 138415-13-1; interleukin 8, 114308-91-7; vasculotropin, 127464-60-2; metalloproteinase, 81669-70-7; Cytokines; Metalloproteases; Tumor Necrosis Factor-alpha Funding details: Ministero della Salute Funding details: FARB 2017 Funding details: Ministero dell’Istruzione, dell’Università e della Ricerca Funding details: Associazione Italiana per la Ricerca sul Cancro, IG-17426 Funding text 1: The following grants gave a financial support for collection, analysis, and interpretation of data and in writing the manuscript: University of Salerno (FARB 2017) to AW; Ministero della Salute (Programma Italia-USA, Progetto Sieroproteomica; Progetto Oncotecnologico) to FF; Ministero della Salute (Ricerca Corrente) to DD and AF RC-2017_3.4; AIRC (IG-17426) to AW; MIUR (CNR Flagship Project InterOmics) to AW. 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PY - 2018

Y1 - 2018

N2 - Background: Melanoma aggressiveness determines its growth and metastatic potential. This study aimed at identifying new molecular pathways controlling melanoma cell malignancy. Methods: Ten metastatic melanoma cell lines were characterized by their proliferation, migration and invasion capabilities. The most representative cells were also characterized by spheroid formation assay, gene- and protein- expression profiling as well as cytokines secretion and the most relevant pathways identified through bioinformatic analysis were tested by in silico transcriptomic validation on datasets generated from biopsies specimens of melanoma patients. Further, matrix metalloproteases (MMPs) activity was tested by zymography assays and TNF-alpha role was validated by anti-TNF cell-treatment. Results: An aggressiveness score (here named Melanoma AGgressiveness Score: MAGS) was calculated by measuring proliferation, migration, invasion and cell-doubling time in10human melanoma cell lines which were clustered in two distinct groups, according to the corresponding MAGS. SK-MEL-28 and A375 cell lines were selected as representative models for the less and the most aggressive phenotype, respectively. Gene-expression and protein expression data were collected for SK-MEL-28 and A375 cells by Illumina-, multiplex x-MAP-and mass-spectrometry technology. The collected data were subjected to an integrated Ingenuity Pathway Analysis, which highlighted that cytokine/chemokine secretion, as well as Cell-To-Cell Signaling and Interaction functions as well as matrix metalloproteases activity were significantly different in these two cell types. The key role of these pathways was then confirmed by functional validation. TNF role was confirmed by exposing cells to the anti-TNF Infliximab antibody. Upon such treatment melanoma cells aggressiveness was strongly reduced. Metalloproteases activity was assayed, and their role was confirmed by comparing transcriptomic data from cutaneous melanoma patients (n = 45) and benign nevi (n = 18). Conclusions: Inflammatory signals such as TNF and MMP-2 activity are key intrinsic players to determine melanoma cells aggressiveness suggesting new venue sin the identification of novel molecular targets with potential therapeutic relevance. © 2018 The Author(s).

AB - Background: Melanoma aggressiveness determines its growth and metastatic potential. This study aimed at identifying new molecular pathways controlling melanoma cell malignancy. Methods: Ten metastatic melanoma cell lines were characterized by their proliferation, migration and invasion capabilities. The most representative cells were also characterized by spheroid formation assay, gene- and protein- expression profiling as well as cytokines secretion and the most relevant pathways identified through bioinformatic analysis were tested by in silico transcriptomic validation on datasets generated from biopsies specimens of melanoma patients. Further, matrix metalloproteases (MMPs) activity was tested by zymography assays and TNF-alpha role was validated by anti-TNF cell-treatment. Results: An aggressiveness score (here named Melanoma AGgressiveness Score: MAGS) was calculated by measuring proliferation, migration, invasion and cell-doubling time in10human melanoma cell lines which were clustered in two distinct groups, according to the corresponding MAGS. SK-MEL-28 and A375 cell lines were selected as representative models for the less and the most aggressive phenotype, respectively. Gene-expression and protein expression data were collected for SK-MEL-28 and A375 cells by Illumina-, multiplex x-MAP-and mass-spectrometry technology. The collected data were subjected to an integrated Ingenuity Pathway Analysis, which highlighted that cytokine/chemokine secretion, as well as Cell-To-Cell Signaling and Interaction functions as well as matrix metalloproteases activity were significantly different in these two cell types. The key role of these pathways was then confirmed by functional validation. TNF role was confirmed by exposing cells to the anti-TNF Infliximab antibody. Upon such treatment melanoma cells aggressiveness was strongly reduced. Metalloproteases activity was assayed, and their role was confirmed by comparing transcriptomic data from cutaneous melanoma patients (n = 45) and benign nevi (n = 18). Conclusions: Inflammatory signals such as TNF and MMP-2 activity are key intrinsic players to determine melanoma cells aggressiveness suggesting new venue sin the identification of novel molecular targets with potential therapeutic relevance. © 2018 The Author(s).

KW - Cancer

KW - Cutaneous melanoma

KW - Cytokines

KW - Inflammation

KW - Malignancy

KW - Metalloproteases

KW - Proteomics

KW - TNF

KW - Uveal melanoma

KW - eotaxin

KW - gamma interferon

KW - gelatinase A

KW - granulocyte colony stimulating factor

KW - infliximab

KW - interleukin 1 receptor blocking agent

KW - interleukin 10

KW - interleukin 12

KW - interleukin 1beta

KW - interleukin 6

KW - interleukin 8

KW - interleukin 9

KW - matrix metalloproteinase

KW - platelet derived growth factor BB

KW - RANTES

KW - tumor necrosis factor

KW - vasculotropin

KW - cytokine

KW - metalloproteinase

KW - A-375 cell line

KW - Article

KW - assay

KW - bioinformatics

KW - cell interaction

KW - cell invasion

KW - cell migration

KW - cell proliferation

KW - computer model

KW - controlled study

KW - cytokine release

KW - enzyme activity

KW - gene expression

KW - human

KW - human cell

KW - intracellular signaling

KW - major clinical study

KW - mass spectrometry

KW - melanoma

KW - Melanoma Aggressiveness Score

KW - priority journal

KW - protein expression

KW - scoring system

KW - SK-MEL-28 cell line

KW - spheroid formation assay

KW - transcriptomics

KW - zymography

KW - genetics

KW - metabolism

KW - pathology

KW - physiology

KW - proteomics

KW - skin tumor

KW - tumor cell line

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Humans

KW - Melanoma

KW - Skin Neoplasms

KW - Tumor Necrosis Factor-alpha

U2 - 10.1186/s13046-018-0982-1

DO - 10.1186/s13046-018-0982-1

M3 - Article

VL - 37

JO - Journal of Experimental and Clinical Cancer Research

JF - Journal of Experimental and Clinical Cancer Research

SN - 0392-9078

IS - 1

ER -