Abstract
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.
Highlights
Mounting evidence indicates that tumors are highly complex heterogeneous structures in which growth is supported by the cancer cells themselves, and the surrounding microenvironment
This study investigated for the first time the crosstalk between stromal fibroblasts and cancer stem cell (CSC) in the context of head and neck squamous cell carcinomas (HNSCC)
Fibroblast-Secreted Factors Sustain Cancer Stem Properties of HNSCC Cells yet been explored. This prompted us to investigate the effect of conditioned media (CM) from cancer-associated fibroblasts (CAFs) or normal fibroblasts (NFs) on cancer stem
Summary
Mounting evidence indicates that tumors are highly complex heterogeneous structures in which growth is supported by the cancer cells themselves, and the surrounding microenvironment. The tumor stroma is constituted by various types of stromal cells and the extracellular matrix (ECM), collectively denominated as tumor microenvironment (TME) [1]. It is well established that tumor cells can stimulate stromal cells to release paracrine factors that facilitate cancer growth and dissemination. CAFs emerge as critical players in this process, stimulating cancer progression toward aggressive phenotypes through cell–cell communication with cancer cells or other stromal cells, remodeling the ECM and releasing a plethora of growth factors, chemokines, cytokines, and matrix metalloproteinases (MMPs) in the TME [4]. The presence of CAFs has been widely associated with poor prognosis in numerous tumor types, including among others, gastric, colorectal, breast, and prostate cancers [5,6]
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