Downregulation of VEGF-C expression in lung and colon cancer cells decelerates tumor growth and inhibits metastasis via multiple mechanisms.

Experimental and clinical studies positively correlate expression of vascular endothelial growth factor (VEGF)-C in cancer cells with accelerated tumor progression and/or unfavorable clinical outcome. However, many aspects of tumor-promoting activity of VEGF-C and consequences of its downregulation for tumor progression remain poorly understood. To clarify these points, we created a set of VEGF receptor 3-positive lung carcinoma A549 and colon carcinoma HCT116 cell sublines with stable repression of VEGF-C synthesis. Analysis of the behavior of these cells revealed multiple effects of VEGF-C downregulation, which, in addition to deceleration of cell proliferation and invasion in vitro and inhibition of lymphangiogenesis in tumor and surrounding tissues observed earlier, included previously undescribed effects, in particular, partial restoration of epithelial phenotype, reduction in the percentage of tumor-initiating cells (cancer stem cells) in the cell population and inhibition of metastasis of orthotopic lung cancer xenografts to other lung lobes. These results are consistent with the idea of high potentiality of VEGF-C as a cancer drug target.