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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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]
Total Authors: 10
[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
Total Affiliations: 2
Document type: Journal article
Source: TISSUE ENGINEERING PART A; v. 20, n. 17-18, p. 2412-2421, SEP 2014.
Web of Science Citations: 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)

FAPESP's process: 10/15919-1 - Tumoral migration and invasion RECK-mediated: melanoma as a model
Grantee:Silvya Stuchi Maria-Engler
Support type: Regular Research Grants
FAPESP's process: 11/19045-9 - Methylation of RECK and ALX3 genes in human melanoma
Grantee:Manoela Tiago dos Santos
Support type: Scholarships in Brazil - Doctorate