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Open AccessArticle

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

1
Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias; Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain
2
CIBERONC, 28029 Madrid, Spain
3
Cell Signalling & Proteomics Group, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
4
Tumour Microenvironment Team, Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
5
Cell Cycle, Stem Cell Fate and Cancer Lab Instituto de Investigación Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
6
EntreChem SL, Vivero Ciencias de la Salud, 33011 Oviedo, Spain
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2018, 10(9), 334; https://doi.org/10.3390/cancers10090334
Received: 22 August 2018 / Revised: 9 September 2018 / Accepted: 12 September 2018 / Published: 17 September 2018
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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. View Full-Text
Keywords: head and neck squamous cell carcinoma; cancer-associated fibroblasts; cancer stem cells; tumor microenvironment; secretome; therapeutic target head and neck squamous cell carcinoma; cancer-associated fibroblasts; cancer stem cells; tumor microenvironment; secretome; therapeutic target
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Álvarez-Teijeiro, S.; García-Inclán, C.; Villaronga, M.Á.; Casado, P.; Hermida-Prado, F.; Granda-Díaz, R.; Rodrigo, J.P.; Calvo, F.; Del-Río-Ibisate, N.; Gandarillas, A.; Morís, F.; Hermsen, M.; Cutillas, P.; García-Pedrero, J.M. Factors Secreted by Cancer-Associated Fibroblasts that Sustain Cancer Stem Properties in Head and Neck Squamous Carcinoma Cells as Potential Therapeutic Targets. Cancers 2018, 10, 334.

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