| Full text | |
| Author(s): Show less - |
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]
Total Authors: 20
|
| Affiliation: | [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
Total Affiliations: 9
|
| Document type: | Journal article |
| Source: | Oncogene; v. 34, n. 10, p. 1270-1279, MAR 5 2015. |
| Web of Science Citations: | 8 |
| Abstract | |
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) | |