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

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.

Multi-omics analysis of DNA replication-associated primase polymerase (PRIMPOL) in pan-cancer: a potential target for prognosis and immune response

“…Recent studies have the important regulatory roles of CAFs in tumor immune response, which could affect the anti-tumor activity of tumor-infiltrating immune cells [ 32 , 33 ]. In solid tumors, CAFs could recruit and stimulate immunosuppressive cells, and induce the formation of dense extracellular matrix (ECM), consequently affecting the anti-tumor immunity [ 34 ].…”

Introduction to the Special Issue on “Keratinocyte Carcinomas: Biology and Evolving Non-Invasive Management Paradigms”

“…Gallego-Rentero, M. et al [ 1 ] conducted research focused on the role of the tumor microenvironment (TIME) in the resistance to Photodynamic therapy (PDT). In particular, the authors evaluated the role of TGFβ1 produced by cancer-associated fibroblasts (CAFs).…”

The Distinctive Features behind the Aggressiveness of Oral and Cutaneous Squamous Cell Carcinomas

“…As a major secreted factor of CAFs, TGFβ predominantly mediates the crosstalk between CAFs and cancer cells. Several in vitro studies have demonstrated that, in OSCC and CSCC, the TGFβ secreted by CAFs induces EMT and resistance to different therapies [ 71 , 72 , 73 , 74 , 75 ].…”