The first study revealed that genetic ablation of cystatin C, major extracellular cathepsin inhibitor, in the pancreatic neurocrine tumor model (Rip-Tag2) resulted in an increased size of islet cell carcinomas and angiogenic islets, which was linked to deregulated cathepsin S activity leading to increased endostatin generation [91]. This evidence concerns the gene CTSS and pancreatic endocrine carcinoma.