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

Abstract

BackgroundMelanoma aggressiveness determines its growth and metastatic potential. This study aimed at identifying new molecular pathways controlling melanoma cell malignancy.MethodsTen 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.ResultsAn 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).ConclusionsInflammatory 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.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0982-1) contains supplementary material, which is available to authorized users.

ElevatedMCOLN1Expression in p53-Deficient Bladder Cancer is Necessary for Oncogene-Induced Cell proliferation, Inflammation, and Invasion

“…elevated cell-cell association ( Figure 6D). Given the established roles for TNFα in metastases (Rossi et al, 2018;Wu and Zhou, 2010;Zhu et al, 2014), our data are consistent with TRPML1 regulating the invasiveness of bladder cancer cells via the regulation of TNF expression.…”

“…Indeed, Etanercept-induced decline in T24 cell number was enhanced by ML-SI1. Since TNFα also promotes cancer cell invasion (Rossi et al, 2018;Wu and Zhou, 2010;Zhu et al, 2014), T24 cells were significantly more invasive than were RT4 or HT1197 cells. MCOLN1 knockdown mitigated the invasiveness of T24 cells, which agrees with TRPML1 being needed for TNF expression.…”

IL22 drives cutaneous melanoma cell proliferation, migration and invasion through activation of miR-181/STAT3/AKT axis

“…Consistently, we observed increased expression of p-β-catenin and MMP-4 in CM cells under IL22 treatment, revealing the underlying mechanism of IL22-induced CM progression. Interestingly, although many studies have linked diverse subset of MMP to invasion of CM [40][41][42] , to our knowledge, this is the first report for the role of MMP-4 in CM progression; however, the exact molecular mechanisms implicated in it require additional mechanistic studies.…”

Inhibition of Melanoma Cell Migration and Invasion Targeting the Hypoxic Tumor Associated CAXII

“…Melanoma is one of the most aggressive skin cancers and represents the fifth most common cancer type in men and the sixth in women [ 1 ]. Its incidence has enhanced in recent decades [ 2 , 3 , 4 ] but unfortunately, the prognosis is quite good only for localized melanoma after surgery [ 5 ]. Indeed melanoma often metastasizes and the prognosis remains poor, along with a low free-disease survival rate [ 6 , 7 ].…”

“…Indeed melanoma often metastasizes and the prognosis remains poor, along with a low free-disease survival rate [ 6 , 7 ]. The key role in the metastatic transition is due to increased cell motility caused by cytoskeletal changes and altered interactions with extra-cellular matrix (ECM) components [ 2 , 8 ].…”