Imatinib targets PDGF signaling in melanoma and host smooth muscle neighboring cells.
In previous in vitro studies, we showed that imatinib abrogated platelet-derived growth factor receptor α (PDGFRα) signaling, disrupting both breast cancer and smooth muscle cells (SMC). PDGF is also a powerful mitogen for neural crest origin cells like melanocytes. The purpose of the present study was to evaluate the effect of imatinib on melanoma growth and in angiogenesis, with emphasis to the involvement in PDGF signaling. B16 melanoma cells incubation with 5 µM (IC50) imatinib resulted in a significant reduction in cell proliferation and migration. Apoptosis, however, was not significantly affected. Phosphorylated-PDGFRα expression was decreased in B16 lysates. In a mouse model of B16 melanoma, intraperitoneal administration of imatinib at early day light significantly decreased tumor growth. These findings were corroborated by a highly significant reduction in cell proliferation and increase in apoptosis in melanoma tumors. This was accompanied by a decrease in microvessel density and in the number of SMC-presenting vessels. Imatinib further inhibited PDGFRα expression and activity, as confirmed by the down-regulation of downstream Erk signaling pathway. Altogether, this study demonstrates that besides targeting tumor cells, imatinib also prevents vascular integrity. The current study provides evidence that the paracrine crosstalk between tumor cells and host neighboring cells is crucial for the elucidation of imatinib effects. In addition, the fact that this molecule targets vascular support cells further enlarges its therapeutic purpose to a wide range of vasculoproliferative pathologies.
Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.
Ana
A
Pirraco
Pedro
P
Coelho
Ana
A
Rocha
Raquel
R
Costa
Luísa
L
Vasques
Raquel
R
Soares
D000818:Animals; D001549:Benzamides; D000068877:Imatinib Mesylate; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*
D001549:Benzamides; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D000068877:Imatinib Mesylate