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Downregulation of VEGF-C expression in lung and colon cancer cells decelerates tumor growth and inhibits metastasis via multiple mechanisms N Khromova, P Kopnin, V Rybko and BP Kopnin Oncogene (2011) 1–9 Presenter: Ting-chia Chang Date/Time: 2011/12/08 16:10 -17:00 Commentator: Dr. Nan-Haw Chow Location: Room 601,Med College Building Background : Vascular endothelial growth factor C (VEGF-C) plays an important role in lymphangiogenesis. VEGF-C binds to Flt4/VEGF receptor 3 (VEGFR3), a receptor tyrosine kinase that is expressed in the progression of several malignant tumors, including non-small cell lung cancer, colorectal cancer, and breast carcinoma. In terms of biological effects, VEGF-C involves in (1) metastasis promotion through lymphangionenesis induction in tumor tissues and sentinel lymph node spreading and (2) cancer cells migration. Recent study reported that stimulation of cancer cell motility is partly mediated by activation of VEGFR3-Src-p38MAPK-C/EBP-contactin-1 pathway. However, both tumor-promoting mechanism of VEGF-C and the effects of its down-regulation remain undisclosed. Therefore, both VEGF-C receptor 3-positive A549 lung carcinoma and HCT116 colon carcinoma cell line with stable repression of VEGF-C expression were chosen to address these issues in the lung and colon cancer cells. Objective: To investigate the biological effects of VEGF-C down-regulation on cell proliferation and invasion in vitro and inhibition of lymphangiogenesis in vivo. Results: Down-regulation of VEGF-C were successfully established in A549 and HCT116 cancer cell lines by lentiviral constructs pLKO.1-shVEGFC (shVEGF-C3 or C-5) as examined at mRNA and protein levels. The growth of A549 and HCT116 xenografts in vivo were suppressed after transfection with shVEGF C-3 or C-5. In addition to inhibition of cell proliferation, migration and tumor lymphangiogenesis, these sublines also exhibited complex effects of VEGF-C down-regulation. The novel effects observed included partial reversion of epithelial–mesenchymal transition and a decrease in the percentage of tumor-initiating cells, also known as ‘cancer stem cells’. Conclusion: These results support the potential of VEGF-C as an important drug target in the design of cancer therapy. References : 1. Jen-Liang Su et al. The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. CANCER CELL 9, 209–223 (2006)