title: Inhibition of uPAR-TGFβ crosstalk blocks MSC-dependent EMT in melanoma cells.
abstract: The capacity of cancer cells to undergo epithelial-to-mesenchymal transition (EMT) is now considered a hallmark of tumor progression, and it is known that interactions between cancer cells and mesenchymal stem cells (MSCs) of tumor microenvironment may promote this program. Herein, we demonstrate that MSC-conditioned medium (MSC-CM) is a potent inducer of EMT in melanoma cells. The EMT profile acquired by MSC-CM-exposed melanoma cells is characterized by an enhanced level of mesenchymal markers, including TGFβ/TGFβ-receptors system upregulation, by increased invasiveness and uPAR expression, and in vivo tumor growth. Silencing TGFβ in MSC is found to abrogate ability of MSC to promote EMT characteristics in melanoma cells, together with uPAR expression, and this finding is strengthened using an antagonist peptide of TGFβRIII, the so-called P17. Finally, we demonstrate that the uPAR antisense oligonucleotide (uPAR aODN) may inhibit EMT of melanoma cells either stimulated by exogenous TGFβ or MSC-CM. Thus, uPAR upregulation in melanoma cells exposed to MSC-medium drives TGFβ-mediated EMT. On the whole, TGFβ/uPAR dangerous liaison in cancer cell/MSC interactions may disclose a new strategy to abrogate melanoma progression.
  
  
  CONCLUSIONS
  Mesenchymal stem cell (MSC)-conditioned medium induces EMT-like profile in melanoma. MSC-derived TGFβ promotes uPAR and TGFβ/TGFβ-receptor upregulation in melanoma. TGFβ gene silencing in MSCs downregulates uPAR expression and EMT in melanoma. uPAR downregulation prevents MSC-induced EMT-like profile in melanoma cells. Inhibition of the dangerous TGFβ/uPAR relationship might abrogate melanoma progression.
authors.affiliation: Department of Experimental and Clinical Biomedical Science, University of Florence, Viale G.B. Morgagni, 50, 50134, Florence, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Laurenzana
authors.forename: Alessio
authors.initials: A
authors.lastname: Biagioni
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchini
authors.forename: Silvia
authors.initials: S
authors.lastname: Peppicelli
authors.forename: Anastasia
authors.initials: A
authors.lastname: Chillà
authors.forename: Francesca
authors.initials: F
authors.lastname: Margheri
authors.forename: Cristina
authors.initials: C
authors.lastname: Luciani
authors.forename: Nicola
authors.initials: N
authors.lastname: Pimpinelli
authors.forename: Mario
authors.initials: M
authors.lastname: Del Rosso
authors.forename: Lido
authors.initials: L
authors.lastname: Calorini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fibbi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D055293:Receptors, Urokinase Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment
chemical_list: D017077:Culture Media, Conditioned; D018125:Receptors, Transforming Growth Factor beta; D055293:Receptors, Urokinase Plasminogen Activator; D016212:Transforming Growth Factor beta