Prognostic value of VEGFC, HER2 and HER3 gene expression in recurrent squamous cell head and neck tumors

Abstract

5538 Background: The main prognostic variables of head and neck squamous cell carcinoma (HNSCC) are the location and size of the tumor and the presence of cervical lymph node metastases. Differential gene expression of members of the HER and VEGF families is a common feature in HNSCC. To elucidate the prognostic value and the interrelation of these factors we performed a detailed gene expression analysis within HNSCC tissue samples Methods: We analyzed fresh frozen tissue from 48 recurrent HNSCC tumors stored at -80oC. RNA was isolated with the RNeasy kit (Qiagen, Inc.), followed by kinetic one-step RT-PCR for the expression of 8 candidate genes (EGFR, HER2, HER3, HER4, VEGFA, VEGFB, VEGFC and VEGFD). Raw data (Ct values) were normalized to RPL37A expression (housekeeper gene) and candidate gene expression between patient groups with differential clinical outcomes was analyzed by using Genedata Expressionist and GraphPad Prism 4 software packages. Median patient follow-up from initial diagnosis was 27 months. Results: Overexpression of VEGFA and EGFR was prominent in most tumors, but did not appear to have any prognostic value. However, VEGFC expression was significantly higher (p = 0.0002) in the tumors of patients with poor overall survival (< 27 months). Interestingly, these tumors were further characterized by significantly lower expression levels of HER2 and HER3. Median survival of patients with tumor VEGFC expression levels of >600 was calculated to be 42 months from initial diagnosis (Kaplan-Meier Survival Analysis), compared to 182 months in the rest of the patients. Conclusions: We have found that elevated VEGFC expression and low expression of HER2 and HER3 correlate with poor outcome in recurrent HNSCC patients. VEGFC preferably binds to the VEGFR3, which is predominantly expressed on lymphatic vessels. Overexpression of VEGFC may therefore result in the establishment of intratumoral lymphatic vessels, which have been shown to facilitate the dissemination of tumor cells into lymph nodes and the formation of distant metastases. We conclude that the determination of VEGFC, HER2 and HER3 expression may be of high prognostic value in HNSCC patients and that it may serve in the early identification of aggressive HNSCC subtypes. No significant financial relationships to disclose.