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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Fibroblasts Protect Melanoma Cells from the Cytotoxic Effects of Doxorubicin

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Tiago, Manoela [1] ; de Oliveira, Edson Mendes [1] ; Brohem, Carla Abdo [1] ; Pennacchi, Paula Comune [1] ; Paes, Rafael Duarte [1] ; Haga, Raquel Brandao [1] ; Campa, Ana [1] ; de Moraes Barros, Silvia Berlanga [1] ; Smalley, Keiran S. [2] ; Maria-Engler, Silvya Stuchi [1]
Número total de Autores: 10
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin Chem & Toxicol, BR-05508900 Sao Paulo - Brazil
[2] Univ S Florida, H Lee Moffitt Canc Ctr, Comprehens Melanoma Res Ctr, Dept Mol Oncol, Tampa, FL 33682 - USA
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: TISSUE ENGINEERING PART A; v. 20, n. 17-18, p. 2412-2421, SEP 2014.
Citações Web of Science: 15

Melanoma is the most aggressive form of skin cancer and until recently, it was extremely resistant to radio-, immuno-, and chemotherapy. Despite the latest success of BRAF V600E-targeted therapies, responses are typically short lived and relapse is all but certain. Furthermore, a percentage (40%) of melanoma cells is BRAF wild type. Emerging evidence suggests a role for normal host cells in the occurrence of drug resistance. In the current study, we compared a variety of cell culture models with an organotypic incomplete skin culture model (the ``dermal equivalent{''}) to investigate the role of the tissue microenvironment in the response of melanoma cells to the chemotherapeutic agent doxorubicin (Dox). In the dermal equivalent model, consisting of fibroblasts embedded in type I collagen matrix, melanoma cells showed a decreased cytotoxic response when compared with less complex culture conditions, such as seeding on plastic cell culture plate (as monolayers cultures) or on collagen gel. We further investigated the role of the microenvironment in p53 induction and caspase 3 and 9 cleavage. Melanoma cell lines cultured on dermal equivalent showed decreased expression of p53 after Dox treatment, and this outcome was accompanied by induction of interleukin IL-6, IL-8, and matrix metalloproteinases 2 and 9. Here, we show that the growth of melanoma cells in the dermal equivalent model inflects drug responses by recapitulating important pro-survival features of the tumor microenvironment. These studies indicate that the presence of stroma enhances the drug resistance of melanoma in vitro, more closely mirroring the in vivo phenotype. Our data, thus, demonstrate the utility of organotypic cell culture models in providing essential context-dependent information critical for the development of new therapeutic strategies for melanoma. We believe that the organotypic model represents an improved screening platform to investigate novel anti-cancer agents, as it provides important insights into tumor-stromal interactions, thus assisting in the elucidation of chemoresistance mechanisms. (AU)

Processo FAPESP: 10/15919-1 - Migração e invasão tumoral mediadas pelo gene RECK em modelo de melanoma
Beneficiário:Silvya Stuchi Maria-Engler
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 11/19045-9 - Metilação dos genes RECK e ALX3 em melanoma humano
Beneficiário:Manoela Tiago dos Santos
Linha de fomento: Bolsas no Brasil - Doutorado