Abstract
BackgroundThe epidermal growth factor receptor (EGFR) is pivotal for growth of epithelial cells and is overexpressed in several epithelial cancers like head and neck squamous cell carcinoma (HNSCC). EGFR signalling is also involved in diverse innate immune functions in epithelia. We previously found a role for EGFR in modulating the complement system in skin, this prompted an investigation into EGFR role in complement modulation in HNSCC.MethodsWe used patient derived HNSCC cell lines with varying sensitivities to EGFR inhibitors, and generated EGFR inhibition resistant cell lines to study the role of EGFR in modulating complement in HNSCC.ResultsWe found that HNSCC cell lines activate the complement system when incubated with human serum. This complement activation was increased in cell lines sensitive to EGFR inhibition following the use of the tyrosine kinase inhibitor Iressa. Sensitive cell line made resistant to EGFR-inhibitors displayed complement activation and a decrease in complement regulatory proteins even in the absence of EGFR-inhibitors. Complement activation did not cause lysis of HNSCC cells, and rather led to increased extracellular signal-regulated kinase (ERK) phosphorylation in one cell line.ConclusionThese data indicate that EGFR has a complement modulatory role in HNSCC, and that a prolonged EGFR-inhibition treatment in sensitive cancer cells increases complement activation. This has implications in understanding the response to EGFR inhibitors, in which resistance and inflammatory skin lesions are two major causes for treatment cessation.
Highlights
The epidermal growth factor receptor (EGFR) is pivotal for growth of epithelial cells and is overexpressed in several epithelial cancers like head and neck squamous cell carcinoma (HNSCC)
Head and neck squamous cell carcinoma (HNSCC) activate the complement system when incubated with human serum To investigate the role of the complement system in HNSCC, we first tested complement activation reflected by deposition of complement components C3 and terminal complement complex (TCC) in 4 patient-derived HNSCC cell lines, and compared the activation to primary human epidermal keratinocytes from adult donors
We found that incubation with normal human serum (NHS) as a source of complement but not Heatinactivated human serum (HIS) lacking complement activity, led to a significant increase in TCC deposition in HNSCC cells in comparison to primary keratinocytes (Fig. 1a)
Summary
The epidermal growth factor receptor (EGFR) is pivotal for growth of epithelial cells and is overexpressed in several epithelial cancers like head and neck squamous cell carcinoma (HNSCC). EGFR signalling is involved in diverse innate immune functions in epithelia. The complement system is a conserved cornerstone of innate immunity [1, 2]. More than 30 proteins comprising the complement system play a role in various immune and homeostatic functions, from killing of pathogens and clearance of apoptotic cells [3,4,5,6], to recently discovered roles in angiogenesis and tissue regeneration [7,8,9]. Activation of the complement system is tightly regulated both at the level of initiation and amplification [10,11,12]. Complement activation has been traditionally seen as an immune surveillance mechanism against cancer development [22]. Antibody therapies aim to promote complement dependent cytotoxicity [23], but malignant cells tend to upregulate the expression of complement regulatory proteins [24], highlighting a
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