Transforming growth factor β1 enhances stemness of head and neck squamous cell carcinoma cells through activation of Wnt signaling

Abstract

Abstract. Transforming growth factor β (TGFβ) ligands, including TGFβ1, are multifunctional cytokines known as key regulators of cell growth, differentiation and inflammation. Dysregulated TGFβ signaling is common in numerous solid tumors, including head and neck squamous cell carcinoma (HNSCC). Previously, TGFβ ligands were also reported to be associated with an enhancement of stemness in glioma stem-like cells. However, their role in HNSCC cancer stem cells (CSCs) has not been explored. The present study demonstrated that TGFβ1 enriches the properties of HNSCC CSCs. TGFβ1 promoted sphere formation and increased stemness-associated gene expression (Oct4 and Sox2) of primary HNSCC CSCs. Additionally, the population of aldehyde dehydrogenase (ALDH)-positive cells was increased subsequent to exogenous treatment of cells with TGFβ1. In addition, following stimulation with TGFβ1, the cells exhibited more resistance to cisplatin and elevated expression of Twist, Snail and Slug. Mechanistically, TGFβ1 acts as an upstream stimulator of Wnt/β-catenin signaling. Collectively, the present findings provide insights toward the development of TGFβ1 signaling inhibition strategies for treating HNSCC CSCs.

The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer

“…What we are discovering is that chemoresistance is much more than the overexpression of drug efflux transporters or the modulation of the cell’s DNA damage response, but rather many signaling pathways related to the stem-like phenotypes of CSCs are also intimately linked to CSC chemoresistance. Such is the case for Hedgehog (Hh), NF-κB, Notch, AKT1, Tumor growth factor-beta (TGF-β) or Wnt/β-catenin signaling pathways, all of which are both signaling pathways upregulated in CSCs and pathways that can promote chemoresistance [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ] ( Figure 3 ). Along these lines, CSCs overexpress or silence numerous pathways and/or factors in order to enhance their inherent resistance to different chemotherapeutics.…”

Cancer: the dark side of wound healing

“…The tumour‐suppressive role of miR‐198 has been demonstrated in several other cancers such as pancreatic, colorectal, liver and lung cancer . FSTL1 promotes cell survival, invasion and metastasis in glioma, liver, oesophageal SCC and lung cancer . Given the wide range of miR‐198 targets being distinct in different tissues and the modulation of various signalling pathways by FSTL1 in different cancers, miR‐198/FSTL1 molecular switch may be a master controller in physiological wound healing and cancer.…”

Transforming growth factor‑β signaling in head and neck squamous cell carcinoma: Insights into cellular responses (Review)

“…A series of therapies have been applied in the treatment of HNSCC, including surgery, radiotherapy, neoadjuvant chemotherapy and a combination of these methods (16). However, the 5-year survival rate of this disease has not evidently increased in last 30 years and remains at ≤50% (17)(18)(19)(20)(21). Accumulating evidence suggested that deregulation of TGF-β signaling is of great importance in HNSCC and may be the result of defected TGF-β signaling (22)(23)(24).…”