Lars Ekblad1, Charlotte Welinder2, Elisabeth Kjellén2, Eva Brun2, Johan Wennerberg3. 1. Division of Oncology and Pathology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden. Electronic address: Lars.Ekblad@med.lu.se. 2. Division of Oncology and Pathology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden. 3. Division of Otorhinolaryngology/Head and Neck Surgery, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
Abstract
OBJECTIVES: Cetuximab is an epidermal growth factor receptor (EGFR)-targeting drug that has shown effects in head and neck squamous cell carcinoma (HNSCC). The effects are, however, small and have mainly been proven in a subset of patients, and the cost-effectiveness has been questioned. For this reason, we need to know more about the basic mechanisms controlling the effect of EGFR signalling on tumour growth. MATERIALS AND METHODS: We investigated the effect of the EGFR ligand transforming growth factor alpha (TGF-α) and cetuximab, alone and in combination, on HNSCC cell lines, measuring proliferation and the activity of intracellular signalling pathways. RESULTS: In line with previous reports we found the majority of the cell lines to be growth-inhibited by TGF-α. Surprisingly, two of the cell lines, which were more thoroughly investigated, were either growth-inhibited or stimulated by both cetuximab and TGF-α, depending on the presence or absence of the other substance. We also present data indicating the existence of two different receptor activities emanating from the EGFR protein. CONCLUSION: We therefore show that TGF-α can have both growth-stimulating and growth-inhibiting effects in the same cell line and that EGFR-targeting drugs can be similarly double-edged. The implication for such drugs is that the micro-environment within a tumour, and possibly within portions of a tumour, may influence the growth-inhibiting effect of the drug. There may also be important implications for our understanding of EGFR signalling and its influence on growth and development.
OBJECTIVES:Cetuximab is an epidermal growth factor receptor (EGFR)-targeting drug that has shown effects in head and neck squamous cell carcinoma (HNSCC). The effects are, however, small and have mainly been proven in a subset of patients, and the cost-effectiveness has been questioned. For this reason, we need to know more about the basic mechanisms controlling the effect of EGFR signalling on tumour growth. MATERIALS AND METHODS: We investigated the effect of the EGFR ligand transforming growth factor alpha (TGF-α) and cetuximab, alone and in combination, on HNSCC cell lines, measuring proliferation and the activity of intracellular signalling pathways. RESULTS: In line with previous reports we found the majority of the cell lines to be growth-inhibited by TGF-α. Surprisingly, two of the cell lines, which were more thoroughly investigated, were either growth-inhibited or stimulated by both cetuximab and TGF-α, depending on the presence or absence of the other substance. We also present data indicating the existence of two different receptor activities emanating from the EGFR protein. CONCLUSION: We therefore show that TGF-α can have both growth-stimulating and growth-inhibiting effects in the same cell line and that EGFR-targeting drugs can be similarly double-edged. The implication for such drugs is that the micro-environment within a tumour, and possibly within portions of a tumour, may influence the growth-inhibiting effect of the drug. There may also be important implications for our understanding of EGFR signalling and its influence on growth and development.
Keywords:
Cetuximab; Epidermal growth factor receptor; Molecular-targeted therapy; Squamous cell carcinoma of the head and neck; Transforming growth factor alpha