Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals

Autor(es):Mostrar menos -

Costa, E. T. ^{[1, 2]} ; Barnabe, G. F. ^{[1, 2]} ; Li, M. ^[3] ; Dias, A. A. M. ^[4] ; Machado, T. R. ^[2] ; Asprino, P. F. ^{[1, 2]} ; Cavalher, F. P. ^[2] ; Ferreira, E. N. ^[5] ; Inda, M. del Mar ^[3] ; Nagai, M. H. ^[6] ; Malnic, B. ^[6] ; Duarte, M. L. ^{[1, 2]} ; Leite, K. R. M. ^[7] ; de Barros, A. C. S. D. ^[8] ; Carraro, D. M. ^[5] ; Chammas, R. ^[7] ; Armelin, H. A. ^{[9, 6]} ; Cavenee, W. ^[3] ; Furnari, F. ^[3] ; Camargo, A. A. ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Hosp Sirio Libanes, Ctr Mol Oncol, BR-01308060 Sao Paulo - Brazil

^[2] LICR, Sao Paulo - Brazil

^[3] Univ Calif San Diego, LICR, San Diego, CA 92103 - USA

^[4] Univ Fed Minas Gerais, Dept Biol Geral ICB, Belo Horizonte, MG - Brazil

^[5] Hosp AC Camargo Fund Antonio Prudente, Ctr Internacl Pesquisa, Sao Paulo - Brazil

^[6] Univ Sao Paulo, Dept Bioquim IQ, Sao Paulo - Brazil

^[7] Univ Sao Paulo, Fac Med, Dept Urol, Sao Paulo - Brazil

^[8] Hosp Sirio Libanes, Dept Mastol, BR-01308060 Sao Paulo - Brazil

^[9] Inst Butantan, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Oncogene; v. 34, n. 10, p. 1270-1279, MAR 5 2015.
• Citações Web of Science: 8

Resumo

Intratumoral heterogeneity (ITH) represents an obstacle for cancer diagnosis and treatment, but little is known about its functional role in cancer progression. The A Desintegrin And Metalloproteinase 23 (ADAM23) gene is epigenetically silenced in different types of tumors, and silencing is often associated with advanced disease and metastasis. Here, we show that invasive breast tumors exhibit significant ADAM23-ITH and that this heterogeneity is critical for tumor growth and metastasis. We demonstrate that while loss of ADAM23 expression enhances invasion, it causes a severe proliferative deficiency and is not itself sufficient to trigger metastasis. Rather, we observed that, in ADAM23-heterotypic environments, ADAM23-negative cells promote tumor growth and metastasis by enhancing the proliferation and invasion of adjacent A23-positive cells through the production of LGI4 (Leucine-rich Glioma Inactivated 4) and nitric oxide (NO). Ablation of LGI4 and NO in A23-negative cells significantly attenuates A23-positive cell proliferation and invasion. Our work denotes a driving role of ADAM23-ITH during disease progression, shifting the malignant phenotype from the cellular to the tissue level. Our findings also provide insights for therapeutic intervention, enforcing the need to ascertain ITH to improve cancer diagnosis and therapy. (AU)

• Processo FAPESP: 07/52920-5 - Analise de expressao do gene adam23 em tumores do sistema nervoso cen tral (snc) e estudo de sua funcao de gliomas e em melanomas.
• Beneficiário: Tamara da Rocha Machado Ferreira
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 07/51194-9 - Caracterizacao funcional das isoformas de splicing do gene adam23.
• Beneficiário: Felicia Peterson Cavalher
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 06/60219-2 - Mecanismo de ação de ADAM23: estudo das vias de sinalização de uma nova proteína supressora de metástase
• Beneficiário: Erico Tosoni Costa
• Modalidade de apoio: Auxílio à Pesquisa - Programa Primeiros Projetos
• Processo FAPESP: 11/50541-2 - Analise global da expressao genica em subpopulacoes tumorais envolvida em processos de cooperacao metastatica.
• Beneficiário: Gabriela Filoso Barnabé
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado