Abstract B80: Deletion of Smad4 results in enhancement of lymphangiogenesis and node metastasis in head and neck squamous cell carcinoma

Abstract

Abstract Lymph node metastasis is the single most important clinical prognostic factor in human head and neck squamous cell carcinoma (HNSCC). The 5-year overall survival is reduced by approximately 50% in HNSCC patients with node metastasis. Understanding the molecular mechanisms of lymph node metastasis in HNSCC is thus of pivotal importance for improving patient's survival. It has been shown that increased lymphatic vessel density in HNSCC tumors correlates with high metastasis rate to lymph nodes, suggesting a connection of enhancement of lymphangiogenesis and node metastasis in HNSCC. We have recently shown that deletion of Smad4, a tumor suppressor commonly inactivated in human HNSCC patients, in a genetically engineer mouse model developed head and neck squamous cell carcinomas with metastasis to cervical lymph nodes. Moreover, examining Smad4 expression and lymphangiogenesis marker podoplanin by immunohistochemistry in human HNSCC patients with node metastasis revealed a negative correlation between Smad4 and podoplanin, validating our initial findings from the Smad4 knockout mouse model. To further investigate the functional role of Smad4 in lymphangiogenesis and node metastasis, we restored Smad4 expression in a Smad4-deficient HNSCC cell line, Cal27. We then orthotopically injected both cell lines on the floor of mouth of nude mice, and observed tumor formation and cervical lymph node metastasis around 7 weeks. Analysis of tumor tissues showed that Smad4 restoration reduced lymphangiogenesis, as revealed by LYVE1, a lymphangiogenesis marker immunostaining. Furthermore, the rate of cervical lymph node metastasis is decreased upon the Smad4 restoration. The potential molecular mechanism of Smad4 in regulating lymphangiogenesis is currently undergoing. In conclusion, our studies have shown the deletion of Smad4 increases lymphangiogenesis and node metastasis from both HNSCC mouse models and human patient samples. Further investigation of the underneath molecular mechanism will be ultimately translated into novel therapeutical approaches for controlling lymph node metastasis and improving survival for human HNSCC patients. Citation Format: Masako Oka, Xi Chen, Xiao-Jing Wang, Shi-Long Lu. Deletion of Smad4 results in enhancement of lymphangiogenesis and node metastasis in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B80.