Matrix metalloproteinase-9 (MMP-9) is a key component of the angiogenic switch during carcinogenesis. In transgenic mice, the angiogenic switch activates the quiescent vasculature, enabling tumor growth. Despite constitutive expression of vascular endothelial growth factor (VEGF) and its receptors, synthetic VEGF inhibitors like SU5416 impair angiogenic switching and tumor growth. MMP-9 is upregulated in angiogenic lesions and can render normal islets angiogenic by releasing VEGF. MMP inhibitors reduce angiogenic switching and tumor growth, while genetic ablation of MMP-9 decreases angiogenic islets and tumor burden. MMP-2, though also upregulated, has a lesser role in the angiogenic switch. The study shows that MMP-9 is essential for the angiogenic switch, as its absence reduces tumor progression and angiogenesis. MMP-9 is not expressed in tumor cells but in cells near the vasculature. The availability of VEGF is increased by MMP-9, which mobilizes it from an extracellular reservoir. This process is critical for angiogenesis in normal islets and tumors. The findings suggest that MMP-9 and VEGF are functionally linked, with MMP-9 facilitating VEGF release and availability. The study also highlights the importance of MMP-9 in tumor progression and the potential of MMP-9 inhibitors as therapeutic agents. The results indicate that MMP-9 is a key regulator of angiogenesis during carcinogenesis, with implications for cancer treatment and understanding the molecular mechanisms of tumor angiogenesis.Matrix metalloproteinase-9 (MMP-9) is a key component of the angiogenic switch during carcinogenesis. In transgenic mice, the angiogenic switch activates the quiescent vasculature, enabling tumor growth. Despite constitutive expression of vascular endothelial growth factor (VEGF) and its receptors, synthetic VEGF inhibitors like SU5416 impair angiogenic switching and tumor growth. MMP-9 is upregulated in angiogenic lesions and can render normal islets angiogenic by releasing VEGF. MMP inhibitors reduce angiogenic switching and tumor growth, while genetic ablation of MMP-9 decreases angiogenic islets and tumor burden. MMP-2, though also upregulated, has a lesser role in the angiogenic switch. The study shows that MMP-9 is essential for the angiogenic switch, as its absence reduces tumor progression and angiogenesis. MMP-9 is not expressed in tumor cells but in cells near the vasculature. The availability of VEGF is increased by MMP-9, which mobilizes it from an extracellular reservoir. This process is critical for angiogenesis in normal islets and tumors. The findings suggest that MMP-9 and VEGF are functionally linked, with MMP-9 facilitating VEGF release and availability. The study also highlights the importance of MMP-9 in tumor progression and the potential of MMP-9 inhibitors as therapeutic agents. The results indicate that MMP-9 is a key regulator of angiogenesis during carcinogenesis, with implications for cancer treatment and understanding the molecular mechanisms of tumor angiogenesis.