Abstract
During melanoma progression, malignant melanocytes are reprogrammed into mesenchymal-like cells through to an epithelial-mesenchymal transition (EMT) process associated with the acquisition of an invasive, prometastatic phenotype. The fibroblast growth factor-2 (FGF2)/FGF receptor (FGFR) system plays a pivotal role in melanoma, leading to autocrine/paracrine induction of tumor cell proliferation and angiogenesis. Long pentraxin-3 (PTX3) interacts with FGF2, and other FGF family members, inhibiting FGF-dependent neovascularization and tumor growth. Here, PTX3 protein and the PTX3-derived acetylated pentapeptide Ac-ARPCA-NH2 inhibit FGF2-driven proliferation and downstream FGFR signaling in murine melanoma B16-F10 cells. Moreover, human PTX3-overexpressing hPTX_B16-F10 cells are characterized by the reversed transition from a mesenchymal to an epithelial-like appearance, inhibition of cell proliferation, loss of clonogenic potential, reduced motility and invasive capacity, downregulation of various mesenchymal markers, and upregulation of the epithelial marker E-cadherin. Accordingly, PTX3 affects cell proliferation and EMT transition in human A375 and A2058 melanoma cells. Also, hPTX_B16-F10 cells showed a reduced tumorigenic and metastatic activity in syngeneic C57BL/6 mice. In conclusion, PTX3 inhibits FGF/FGFR-driven EMT in melanoma cells, hampering their tumorigenic and metastatic potential. These data represent the first experimental evidence about a nonredundant role of the FGF/FGFR system in the modulation of the EMT process in melanoma and indicate that PTX3 or its derivatives may represent the basis for the design of novel therapeutic approaches in FGF/FGFR-dependent tumors, including melanoma.
Highlights
Melanoma is an aggressive skin cancer that arises from neural crest-derived melanocytes [1]
Invasion plays a critical role in melanoma progression during which the conversion from the radial growth phase to the vertical growth phase is the direct precursor to metastasis [1]
Melanoma progression is paralleled by the upregulation of epithelial-mesenchymal transition (EMT)-driving transcription factors, including Snai1 and Snai2 [6], and downregulation of E-cadherin [7], a potent suppressor of tumor cell invasion and metastasis [4, 5]
Summary
Melanoma is an aggressive skin cancer that arises from neural crest-derived melanocytes [1]. Resistant to both chemotherapy and radiotherapy, metastatic melanoma represents the most lethal form of skin cancer. The dissemination of malignant cells from primary epithelial tumors is the result of an epithelial-mesenchymal transition (EMT) process, a highly conserved developmental program activated during mesoderm formation and neural crest cell migration [3]. EMT is mediated by the upregulation of several transcription repressors, including Snai1/Snail, Snai2/Slug, Twist and ZEB1, and is characterized by increased expression of the mesenchymal markers Vimentin and Ncadherin and downregulation of the E-cadherin gene, an epithelial marker and potent suppressor of tumor cell invasion and metastasis [4, 5]. Snai and Snai drive EMT in melanoma [6] and the transition from the radial growth phase to the vertical growth phase during melanoma progression is associated with a more motile and invasive phenotype characterized by E-cadherin downregulation [7]
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