Abstract
Glial cell-derived neurotrophic factor (GDNF) is reported to promote the survival of neurons and salivary gland regeneration after radiation damage. This study investigated the effect of GDNF on cell migration, growth, and response to radiation in preclinical models of head and neck squamous cell carcinoma (HNSCC) and correlated GDNF expression to treatment outcomes in HNSCC patients. Our ultimate goal is to determine whether systemic administration of GDNF at high dose is safe for the management of hyposalivation or xerostomia in HNSCC patients. Three HPV-positive and three HPV-negative cell lines were examined for cell migration, growth, and clonogenic survival in vitro and tumor growth assay in vivo. Immunohistochemical staining of GDNF, its receptors GFRα1 and its co-receptor RET was performed on two independent HNSCC tissue microarrays (TMA) and correlated to treatment outcomes. Results showed that GDNF only enhanced cell migration in two HPV-positive cells at supra-physiologic doses, but not in HPV-negative cells. GDNF did not increase cell survival in the tested cell lines post-irradiation. Likewise, GDNF treatment affected neither tumor growth in vitro nor response to radiation in xenografts in two HPV-positive and two HPV-negative HNSCC models. High stromal expression of GDNF protein was associated with worse overall survival in HPV-negative HNSCC on multivariate analysis in a combined cohort of patients from Stanford University (n = 82) and Washington University (n = 189); however, the association between GDNF gene expression and worse survival was not confirmed in a separate group of HPV-negative HNSCC patients identified from the Cancer Genome Atlas (TCGA) database. Based on these data, we do not believe that GNDF is a safe systemic treatment to prevent or treat xerostomia in HNSCC and a local delivery approach such as intraglandular injection needs to be explored.
Highlights
Head and neck cancer is the 9th most common cancer globally [1, 2] and head and neck squamous cell carcinoma (HNSCC) accounts for most of these cases [3]
Glial Cell-Derived Neurotrophic Factor (GDNF) and GDNF Family Receptor-α1 (GFRα1) are expressed in HNSCC cell lines
Between the two human papillomavirus (HPV)-positive cell lines, SCC90 had higher level of both GDNF and GFRα1 compared to HMS001
Summary
Head and neck cancer is the 9th most common cancer globally [1, 2] and head and neck squamous cell carcinoma (HNSCC) accounts for most of these cases [3]. HNSCC could be related to alcohol and tobacco use and human papillomavirus (HPV) infection, with distinct prognosis [4,5,6,7]. Regardless of HNSCC type, most of these patients receive radiotherapy (RT) as part of their treatment, either in the definitive or adjuvant setting. A large percentage of HNSCC patients still suffer from xerostomia (severe dry mouth) and its related ramifications [8]. GDNF functions through binding to the GDNF Family Receptor-α1 (GFRα1) on the cell membrane, which further activates RET, a receptor tyrosine kinase. GDNF binds the Neural Cell Adhesion Molecule (NCAM) on the plasma membrane and does not require RET receptor for downstream signaling [11]
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