Our data indicate that TNFSF15, a cytokine mainly produced by blood endothelial cells, facilitates tumor lymphangiogenesis by upregulating VEGFC expression in A549 cells, contributing to lymphatic metastasis in tumor-bearing mice.
These findings support the view that tumor-infiltrating NK and CD4(+) T cells under the influence of cancer cells significantly increase the production of IFNγ, which in turn inhibits TNFSF15 expression in vascular endothelial cells, shifting the balance of pro- and anti-angiogenic factors toward escalated angiogenesis potential in the tumor.
Using the NIRF imaging technique, we visualized and quantified the specific delivery of Cy5.5-NGR-VEGI protein to subcutaneous HT-1080 fibrosarcoma tumors in mouse xenografts.
VEGI protein expression was observed in normal renal tubular epithelial cells, but was decreased or absent in RCC specimens, particularly in tumors with high grade.
Our findings indicate that downregulation of TNFSF15 by cancer cells and tumor infiltrating macrophages and lymphocytes is a pre-requisite for tumor neovascularization.
Therefore, our studies for the first time establish the regulatory axis of AMPK-LITAF-TNFSF15 and also suggest that LITAF may function as a tumor suppressor.
VEGI-251-transfected cancer cells form xenograft tumors of reduced growth rate and microvessel density compared with tumors of empty vector transfectants.