Identification of Drivers of Tumor Lymphangiogenesis in Non-Small Cell Lung Carcinoma (NSCLC)
Sibley, Robert Carson
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BACKGROUND: Non-small Cell Lung Carcinomas (NSCLCs) frequently spread to regional lymph nodes before they colonize other regions of the body, and the status of regional lymph nodes is an important prognostic factor for predicting the outcome of patients with lung cancer. It has recently been demonstrated that lymphangiogenesis, the sprouting of new lymphatic vessels from pre-existing vessels, facilitates the lymphogenous dissemination of NSCLC. However, the molecular mechanisms driving lymphangiogenesis in NSCLC are poorly understood. Objective: Our aim was to identify novel lymphangiogenic genes by identifying lymphangiogenic lung tumor cell lines, and then to use microarray data to generate a "lymphangiogenic" gene signature. METHODS: Tumors from 13 lung tumor cell lines were stained with antibodies against LYVE-1 and Podoplanin. Lymphatic vessels were counted in 5 representative 20X fields per tumor. Average lymphatic vessel densities were then calculated. Cell lines were grouped into lymphangiogenic, non-lymphangiogenic, and intermediate categories. Microarray data from the two extreme groups were then compared to generate a "lymphangiogenic" signature. RESULTS: Four cell lines, (Calu-1, H1993, HCC461, and HCC827) displayed high intratumoral lymphatic density, and five cell lines (Calu-3, H1155, H1395, H1975, and H2073) displayed no intratumoral lymphatic vessels. The "lymphangiogenic" signature obtained from the microarray data from these groups contained 146 genes, including the lymphatic growth factor VEGF-C. CONCLUSIONS: Our preliminary findings suggest that VEGF-C is an important driver of tumor lymphangiogenesis in NSCLC. The other 145 genes in the signature may also serve novel functions in regulating tumor lymphangiogenesis. Together, the results from this project provide mechanistic insight into the process of tumor lymphangiogenesis and metastasis. We believe that this information will lead to the development of new prognostic or predictive markers and therapeutic strategies to improve the outcome of patients with lung cancer.