title: Activation of the A2B adenosine receptor in B16 melanomas induces CXCL12 expression in FAP-positive tumor stromal cells, enhancing tumor progression.
abstract: The A2B receptor (A2BR) can mediate adenosine-induced tumor proliferation, immunosuppression and angiogenesis. Targeting the A2BR has proved to be therapeutically effective in some murine tumor models, but the mechanisms of these effects are still incompletely understood. Here, we report that pharmacologic inhibition of A2BR with PSB1115, which inhibits tumor growth, decreased the number of fibroblast activation protein (FAP)-expressing cells in tumors in a mouse model of melanoma. This effect was associated with reduced expression of fibroblast growth factor (FGF)-2. Treatment of melanoma-associated fibroblasts with the A2BR agonist Bay60-6583 enhanced CXCL12 and FGF2 expression. This effect was abrogated by PSB1115. The A2AR agonist CGS21680 did not induce CXCL12 or FGF2 expression in tumor associated fibroblasts. Similar results were obtained under hypoxic conditions in skin-derived fibroblasts, which responded to Bay60-6583 in an A2BR-dependent manner, by stimulating pERK1/2. FGF2 produced by Bay60-6583-treated fibroblasts directly enhanced the proliferation of melanoma cells. This effect could be reversed by PSB1115 or an anti-FGF2 antibody. Interestingly, melanoma growth in mice receiving Bay60-6583 was attenuated by inhibition of the CXCL12/CXCR4 pathway with AMD3100. CXCL12 and its receptor CXCR4 are involved in angiogenesis and immune-suppression. Treatment of mice with AMD3100 reduced the number of CD31+ cells induced by Bay60-6583. Conversely, CXCR4 blockade did not affect the accumulation of tumor-infiltrating MDSCs or Tregs. Together, our data reveal an important role for A2BR in stimulating FGF2 and CXCL12 expression in melanoma-associated fibroblasts. These factors contribute to create a tumor-promoting microenvironment. Our findings support the therapeutic potential of PSB1115 for melanoma.
authors: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.|PhD Program in Drug Discovery and Development, Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors: Claudia
authors: C
authors: Sorrentino
authors: Department of Genetics, Louisiana State University Health Sciences Center and Stanley S. Scott Cancer Center, New Orleans, LA, USA.
authors: Lucio
authors: L
authors: Miele
authors: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors: Amalia
authors: A
authors: Porta
authors: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors: Aldo
authors: A
authors: Pinto
authors: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors: Silvana
authors: S
authors: Morello
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism*; D018450:Disease Progression; D010450:Endopeptidases; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019899:Paracrine Communication; D010766:Phosphorylation; D043704:Receptor, Adenosine A2B / Q000187:drug effects / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D054377:Chemokine CXCL12; D010450:Endopeptidases; D048049:Extracellular Signal-Regulated MAP Kinases; D016222:Fibroblast Growth Factor 2; D018093:Gelatinases; D008565:Membrane Proteins; D043704:Receptor, Adenosine A2B; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C515256:Cxcl12 protein, mouse
keywords: A2BR; CXCL12; fibroblasts; mouse melanoma model; tumor