NEW WORK ON CANCER-ASSOCIATED FIBROBLASTS -OPEN ACCESS-

Led by the Head and Neck Group of the Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo.

In Cancers

http://www.mdpi.com/2072-6694/10/9/334,  https://www.ncbi.nlm.nih.gov/pubmed/30227608

Cancers (Basel). 2018 Sep 17;10(9). pii: E334. doi: 10.3390/cancers10090334.

Factors Secreted by Cancer-Associated Fibroblasts that Sustain Cancer Stem Properties in Head and Neck Squamous Carcinoma Cells as Potential Therapeutic Targets.

Álvarez-Teijeiro S^1,2, García-Inclán C³, Villaronga MÁ^4,5, Casado P⁶, Hermida-Prado F⁷, Granda-Díaz R⁸, Rodrigo JP^9,10, Calvo F¹¹, Del-Río-Ibisate N¹², Gandarillas A¹³, Morís F¹⁴, Hermsen M^15,16, Cutillas P¹⁷, García-Pedrero JM^18,19.

This study investigates for the first time the crosstalk between stromal fibroblasts and cancer stem cell (CSC) biology in head and neck squamous cell carcinomas (HNSCC), with the ultimate goal of identifying effective therapeutic targets. The effects of conditioned media from cancer-associated fibroblasts (CAFs) and normal fibroblasts (NFs) on the CSC phenotype were assessed by combining functional and expression analyses in HNSCC-derived cell lines. Further characterization of CAFs and NFs secretomes by mass spectrometry was followed by pharmacologic target inhibition. We demonstrate that factors secreted by CAFs but not NFs, in the absence of serum/supplements, robustly increased anchorage-independent growth, tumorsphere formation, and CSC-marker expression. Modulators of epidermal growth factor receptor (EGFR), insulin-like growth factor receptor (IGFR), and platelet-derived growth factor receptor (PDGFR) activity were identified as paracrine cytokines/factors differentially secreted between CAFs and NFs, in a mass spectrometry analysis. Furthermore, pharmacologic inhibition of EGFR, IGFR, and PDGFR significantly reduced CAF-induced tumorsphere formation and anchorage-independent growth suggesting a role of these receptor tyrosine kinases in sustaining the CSC phenotype. These findings provide novel insights into tumor stroma–CSC communication, and potential therapeutic targets to effectively block the CAF-enhanced CSC niche signaling circuit.