title: CCL27-CCR10 and CXCL12-CXCR4 chemokine ligand-receptor mRNA expression ratio: new predictive factors of tumor progression in cutaneous malignant melanoma.
abstract: CXCR4, CCR7 and CCR10 chemokine receptors are known to be involved in melanoma metastasis. Our goal was to compare the relative intratumoral mRNA expression of these receptors with that of their corresponding chemokine ligands, CXCL12, CCL19, CCL21, and CCL27 across the full spectrum of human melanoma progression: thin and thick primary melanomas, as well as "in transit", lymph node, and distant metastases. Expression was quantified by real-time RT-PCR in 103 melanoma samples: 51 primary tumors and 52 metastases. Particular emphasis was focused on chemokine ligand-receptor expression ratios. Immunohistochemistry was performed to identify the cell types expressing these molecules. CXCL12-CXCR4 and CCL27-CCR10 ratios were higher in thin than in thick primary melanomas, and all four chemokine-receptor ratios were higher in primary tumors than in melanoma metastases. CCL27-CCR10 and CXCL12-CXCR4 expression ratios in primary tumors were inversely associated with the development of distant metastases, and improved the predictive value of tumor thickness for distant metastasis, which is important since chemokine ligand-receptor ratios are not affected by the endogenous gene employed for normalizing mRNA expression. Both receptor and ligand immunolabeling were detected in neoplastic cells suggesting autocrine mechanisms. Our results support the concept that low CCL27/CCR10 and CXCL12/CXCR4 intratumoral mRNA ratios are associated with melanoma progression, and in combination with Breslow thickness, are the best predictive factors for the development of distant metastases in primary cutaneous melanoma.
authors.affiliation: Department of Pathology, Facultad de Medicina, University of Valencia, Avda. Blasco Ibañez 15, 46010, Valencia, Spain. Carlos.Monteagudo@uv.es
authors.forename: Carlos
authors.initials: C
authors.lastname: Monteagudo
authors.forename: David
authors.initials: D
authors.lastname: Ramos
authors.forename: Ana
authors.initials: A
authors.lastname: Pellín-Carcelén
authors.forename: Rosario
authors.initials: R
authors.lastname: Gil
authors.forename: Robert C
authors.initials: RC
authors.lastname: Callaghan
authors.forename: José M
authors.initials: JM
authors.lastname: Martín
authors.forename: Vicent
authors.initials: V
authors.lastname: Alonso
authors.forename: Amelia
authors.initials: A
authors.lastname: Murgui
authors.forename: Lara
authors.initials: L
authors.lastname: Navarro
authors.forename: Silvia
authors.initials: S
authors.lastname: Calabuig
authors.forename: José Antonio
authors.initials: JA
authors.lastname: López-Guerrero
authors.forename: Esperanza
authors.initials: E
authors.lastname: Jordá
authors.forename: Antonio
authors.initials: A
authors.lastname: Pellín
mesh_terms: D000368:Aged; D054425:Chemokine CCL27 / Q000096:biosynthesis*; D054377:Chemokine CXCL12 / Q000096:biosynthesis*; D018925:Chemokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008024:Ligands; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D054447:Receptors, CCR10 / Q000096:biosynthesis*; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D012878:Skin Neoplasms / Q000378:metabolism*
chemical_list: C492276:CCL27 protein, human; C515706:CCR10 protein, human; C527276:CXCR4 protein, human; D054425:Chemokine CCL27; D054377:Chemokine CXCL12; D018925:Chemokines; D008024:Ligands; D012333:RNA, Messenger; D054447:Receptors, CCR10; D019718:Receptors, CXCR4