title: Caveolin-1 modulates the ability of Ewing's sarcoma to metastasize.
abstract: Metastasis is the final stage of tumor progression and is thought to be responsible for up to 90% of deaths associated with solid tumors. Caveolin-1 (CAV1) regulates multiple cancer-associated processes related to malignant tumor progression. In the present study, we tested the hypothesis that CAV1 modulates the metastatic ability of cells from the Ewing's sarcoma family of tumors (ESFT). First, we analyzed the expression of CAV1 by immunostaining a tissue microarray containing 43 paraffin-embedded ESFT tumors with known EWS translocations. Even though no evidence was found for a significant association between CAV1 expression and stage, size or tumor site, all metastatic samples (10 of 10) had significantly high CAV1 expression, suggesting that high CAV1 content could positively contribute to enhance ESFT metastasis. To determine the effect of CAV1 on the migratory and invasive capabilities of ESFT cells, we knocked down CAV1 expression in TC252 and A673 cells by stably transfecting a previously validated shRNA construct. In vitro, migration and invasion assays showed that for both cell lines, CAV1 knocked-down cells migrated and invaded significantly less (P ≤ 0.01) than control cells. Moreover, control A673 cells introduced into BALB/c nude mice by tail vein injection strongly colonized the lungs. In contrast, animals injected with CAV1 knocked-down cells showed either no incidence of metastasis or developed lung metastases after a significant delay (P < 0.0001). Finally, we show that the molecular mechanisms by which CAV1 carries out its key role in regulating ESFT metastasis involve matrix metalloproteinase production and activation as well as the control of the expression of SPARC, a known determinant of lung colonization.
authors.affiliation: Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals-3 Planta Gran via s/n Km. 2, 7, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Sáinz-Jaspeado
authors.forename: Laura
authors.initials: L
authors.lastname: Lagares-Tena
authors.forename: Jaime
authors.initials: J
authors.lastname: Lasheras
authors.forename: Fariba
authors.initials: F
authors.lastname: Navid
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Galindo
authors.forename: Silvia
authors.initials: S
authors.lastname: Mateo-Lozano
authors.forename: Vicente
authors.initials: V
authors.lastname: Notario
authors.forename: Xavier
authors.initials: X
authors.lastname: Sanjuan
authors.forename: Xavier
authors.initials: X
authors.lastname: Garcia Del Muro
authors.forename: Angels
authors.initials: A
authors.lastname: Fabra
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Tirado
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051242:Caveolin 1 / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012512:Sarcoma, Ewing / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D051242:Caveolin 1; D020690:GTPase-Activating Proteins; C543508:Sipa1l1 protein, mouse; D045726:Metalloproteases; D053511:Matrix Metalloproteinase 14