Tgfß1 secreted by cancer-associated fibroblasts as an inductor of resistance to photodynamic therapy in squamous cell carcinoma cells

Gallego Rentero M. ; Gutiérrez Pérez M. ; Fernández Guarino M. ; Mascaraque, M. (Universidad de Zaragoza) ; Portillo Esnaola M. ; Gilaberte, Y. ; Carrasco, E. ; Juarranz, Á.

Resumen: As an important component of tumor microenvironment, cancer-associated fibroblasts (CAFs) have lately gained prominence owing to their crucial role in the resistance to therapies. Photodynamic therapy (PDT) stands out as a successful therapeutic strategy to treat cutaneous squamous cell carcinoma. In this study, we demonstrate that the transforming growth factor ß1 (TGFß1) cytokine secreted by CAFs isolated from patients with SCC can drive resistance to PDT in epithelial SCC cells. To this end, CAFs obtained from patients with in situ cSCC were firstly characterized based on the expression levels of paramount markers as well as the levels of TGFß1 secreted to the extracellular environment. On a step forward, two established human cSCC cell lines (A431 and SCC13) were pre-treated with conditioned medium obtained from the selected CAF cultures. The CAF-derived conditioned medium effectively induced resistance to PDT in A431 cells through a reduction in the cell proliferation rate. This resistance effect was recapitulated by treating with recombinant TGFß1 and abolished by using the SB525334 TGFß1 receptor inhibitor, providing robust evidence of the role of TGFß1 secreted by CAFs in the development of resistance to PDT in this cell line. Conversely, higher levels of recombinant TGFß1 were needed to reduce cell proliferation in SCC13 cells, and no induction of resistance to PDT was observed in this cell line in response to CAF-derived conditioned medium. Interestingly, we probed that the comparatively higher intrinsic resistance to PDT of SCC13 cells was mediated by the elevated levels of TGFß1 secreted by this cell line. Our results point at this feature as a promising biomarker to predict both the suitability of PDT and the chances to optimize the treatment by targeting CAF-derived TGFß1 in the road to a more personalized treatment of particular cSCC tumors. © 2021 by the authors.

Idioma: Inglés

DOI: 10.3390/cancers13225613

Año: 2021

Publicado en: Cancers 13, 22 (2021), 5613 [24 pp.]
ISSN: 2072-6694

Factor impacto JCR: 6.575 (2021)

Categ. JCR: ONCOLOGY rank: 60 / 245 = 0.245 (2021) - Q1 - T1

Factor impacto CITESCORE: 5.8 - Medicine (Q1) - Biochemistry, Genetics and Molecular Biology (Q2)

Factor impacto SCIMAGO: 1.349 - Oncology (Q1) - Cancer Research (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MINECO-ISCIII-FEDER/FIS PI18-00708
Financiación: info:eu-repo/grantAgreement/ES/MINECO-ISCIII-FEDER/FIS PI18-00858

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Dermatología (Dpto. Medicina, Psiqu. y Derm.)