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TGFβ1 Secreted by Cancer-Associated Fibroblasts as an Inductor of Resistance to Photodynamic Therapy in Squamous Cell Carcinoma Cells

Authors :
María Gallego-Rentero
Mikel Portillo-Esnaola
Yolanda Gilaberte
María Gutiérrez-Pérez
Elisa Carrasco
Marta Mascaraque
Montserrat Fernández-Guarino
Angeles Juarranz
UAM. Departamento de Biología
UAM. Departamento de Medicina
Source :
Cancers; Volume 13; Issue 22; Pages: 5613, Biblos-e Archivo. Repositorio Institucional de la UAM, instname, Cancers, Cancers, Vol 13, Iss 5613, p 5613 (2021), Zaguán. Repositorio Digital de la Universidad de Zaragoza
Publication Year :
2021
Publisher :
Multidisciplinary Digital Publishing Institute, 2021.

Abstract

Simple Summary Photodynamic therapy (PDT) is used for the treatment of in situ cutaneous squamous cell carcinoma (cSCC), the second most common form of skin cancer, as well as for its precancerous form, actinic keratosis. However, relapses after the treatment can occur. Transforming growth factor β1 (TGFβ1) produced by cancer-associated fibroblasts (CAFs) in the tumor microenvironment has been pointed as a key player in the development of cSCC resistance to other therapies, such as chemotherapy. Here, we demonstrate that TGFβ1 produced by CAFs isolated from patients with cSCC can drive resistance to PDT in SCC cells. This finding opens up novel possibilities for strategy optimization in the field of cSCC resistance to PDT and highlights CAF-derived TGFβ1 as a potential target to improve the efficacy of PDT. Abstract 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 β1 (TGFβ1) 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 TGFβ1 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 TGFβ1 and abolished by using the SB525334 TGFβ1 receptor inhibitor, providing robust evidence of the role of TGFβ1 secreted by CAFs in the development of resistance to PDT in this cell line. Conversely, higher levels of recombinant TGFβ1 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 TGFβ1 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 TGFβ1 in the road to a more personalized treatment of particular cSCC tumors.

Details

Language :
English
ISSN :
20726694
Database :
OpenAIRE
Journal :
Cancers; Volume 13; Issue 22; Pages: 5613
Accession number :
edsair.doi.dedup.....16873c2ba15e068ab9995d5b489dbaed
Full Text :
https://doi.org/10.3390/cancers13225613