The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells

Vascular endothelial growth factor (VEGF) production by stromal fibroblasts plays an important role in tumor angiogenesis. However, VEGF is also expressed by normal tissue fibroblasts, raising the question of how the VEGF activity of fibroblasts is regulated. Here we report that the latent VEGF angiogenic activity of fibroblasts is activated by cancer cells, resulting in tumor-selective utilization of fibroblast-derived VEGF. Through the production of VEGF, human VA-13 fibroblasts promote angiogenesis in and growth of human pancreas cancer Capan-1 xenograft tumors, whereas VA-13 fibroblasts alone do not show significant angiogenesis. Treatment of VA-13 fibroblast supernatant with matrix metalloproteinase-7 (MMP-7), an extracellular proteinase characteristically expressed by cancer cells, elicits endothelial tube formation. This effect is abrogated by anti-VEGF antibody or connective tissue growth factor (CTGF), which was previously reported to sequester VEGF and be degraded by MMP-7. Suppression of MMP-7 in Capan-1 cells abrogates the tumor angiogenic activity of VA-13 fibroblasts, which is restored by suppression of CTGF in VA-13 fibroblasts. We further show that these molecular mechanisms that trigger angiogenesis are effective in human primary fibroblasts and human colorectal tissue. These data suggest that fibroblasts may store VEGF in a latent state in the extracellular environment for urgent use in angiogenesis.