title: The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis.
abstract: Melanoma is a highly metastatic and malignant skin cancer having poor rates of patient survival. Since the incidence of melanoma is steadily increasing in the population, finding prognostic and therapeutic targets are crucial tasks in cancer. The dioxin receptor (AhR) is required for xenobiotic-induced toxicity and carcinogenesis and for cell physiology and organ homeostasis. Yet, the mechanisms by which AhR affects tumor growth and dissemination are largely uncharacterized. We report here that AhR contributes to the tumor-stroma interaction, blocking melanoma growth and metastasis when expressed in the tumor cell but supporting melanoma when expressed in the stroma. B16F10 cells engineered to lack AhR (small hairpin RNA for AhR) exacerbated melanoma primary tumorigenesis and lung metastasis when injected in AhR+/+ recipient mice but not when injected in AhR- /- mice or when co-injected with AhR-/- fibroblasts in an AhR+/+ stroma. Contrary, B16F10 cells expressing a constitutively active AhR had reduced tumorigenicity and invasiveness in either AhR genetic background. The tumor suppressor role of AhR in melanoma cells correlated with reduced migration and invasion, with lower numbers of cancer stem-like cells and with altered levels of β1-integrin and caveolin1. Human melanoma cell lines with highest AHR expression also had lowest migration and invasion. Moreover, AHR expression was reduced in human melanomas with respect to nevi lesions. We conclude that AhR knockdown in melanoma cells requires stromal AhR for maximal tumor progression and metastasis. Thus, AhR can be a molecular marker in melanoma and its activity in both tumor and stromal compartments should be considered.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias and.
authors.forename: María
authors.initials: M
authors.lastname: Contador-Troca
authors.forename: Alberto
authors.initials: A
authors.lastname: Alvarez-Barrientos
authors.forename: Eva
authors.initials: E
authors.lastname: Barrasa
authors.forename: Eva M
authors.initials: EM
authors.lastname: Rico-Leo
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Catalina-Fernández
authors.forename: Mauricio
authors.initials: M
authors.lastname: Menacho-Márquez
authors.forename: Xosé R
authors.initials: XR
authors.lastname: Bustelo
authors.forename: José C
authors.initials: JC
authors.lastname: García-Borrón
authors.forename: Aurea
authors.initials: A
authors.lastname: Gómez-Durán
authors.forename: Javier
authors.initials: J
authors.lastname: Sáenz-Santamaría
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Fernández-Salguero
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D022461:Caveolins / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D022461:Caveolins; D019012:Integrin beta1; D018336:Receptors, Aryl Hydrocarbon; D025521:Tumor Suppressor Proteins