Abstract
The therapeutic responses of many solid tumours to chemo- and radio-therapies are far from fully effective but therapies targeting malignancy-related cellular changes show promise for further control. In head and neck squamous cell carcinoma, the epidermal growth factor receptor (EGFR) is commonly overexpressed and investigation of agents that block this receptor indicate a limited response when used alone but an ability to enhance the actions of other drugs. The hierarchical stem cell patterns present in tumours generate cellular heterogeneity and this is further complicated by cancer stem cells (CSC) shifting between epithelial (Epi-CSC) and mesenchymal (EMT-CSC) states. To clarify how such heterogeneity influences responses to EGFR blocking, we examined the effects of Cetuximab and Erlotinib on the cell sub-populations in HNSCC cell lines. These agents reduced cell proliferation for all subpopulations but induced little cell death. They did however induce large shifts of cells between the EMT-CSC, Epi-CSC and differentiating cell compartments. Loss of EMT-CSCs reduced cell motility and is expected to reduce invasion and metastasis. EGFR blocking also induced shifts of Epi-CSCs into the differentiating cell compartment which typically has greater sensitivity to chemo/radiation, an effect expected to enhance the overall response of tumour cell populations to adjunctive therapies.
Highlights
Head and neck cancers are among the 10 most common cancers worldwide and the great majority of these cancers are squamous cell carcinomas and associated with severe mortality [1,2,3]
Treatment levels were initially determined by treating CA1 and Luc4 cell lines for 3 days with drug concentrations of Cetuximab and Erlotinib ranging from 0–500 μg/ml or 0–500 ng/ml respectively (Figure 1A, 1B)
Blocking epidermal growth factor receptor (EGFR) signaling has provided less therapeutic benefit than initially anticipated [39] and this may be largely related to the cellular heterogeneity of tumours and, to the presence of sub-populations of cancer stem cells (CSC) and differentiating cells [40]
Summary
Head and neck cancers are among the 10 most common cancers worldwide and the great majority of these cancers are squamous cell carcinomas and associated with severe mortality [1,2,3]. Despite therapeutic advances during the last decade, the 5-year-survival rate for HNSCC remains low with late diagnosis at advanced tumour stages typically associated with local and regional recurrences, and with development of lymph node and distant metastasis [7, 8]. Overexpression of the epidermal growth factor receptor (EGFR) is a frequent molecular alteration in HNSCC and increased activity of the EGF pathway has been associated with resistance to treatment and poor clinical outcome [5, 11, 12]. The EGFR is a member of the HER tyrosine kinase receptor family and binding of specific ligands, such as epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α), promotes homo- or hetero-dimerization of EGFR family members and activation of intracellular signaling pathways that control growth, differentiation, survival and invasion [13,14,15]. Various mechanisms for primary and acquired resistance to Cetuximab have been suggested and include www.impactjournals.com/oncotarget constitutive activation of EGFR-mediating signaling molecules and activation of alternative ErbB2 and ErbB3 pathways [16, 17]
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