Tumor angiogenesis in chronic pancreatitis and pancreatic adenocarcinoma: Impact of K-ras mutations

Chronic pancreatitis (CP) is one condition in which epidemiologic studies h ave demonstrated a definite association with pancreatic adenocarcinoma (PAC ). The pathophysiologic and molecular events that either predispose to the development of, or potentiate the growth of, PAC are unknown. Mutation of t he codon 12 K-ras gene is one genetic aberration commonly associated with d evelopment of PAC. Tumor angiogenesis, or microvascular proliferation of ne w capillaries, is another pathophysiologic alteration associated with PAC. Although activated ms oncogenes modulate tumor angiogenesis/neovascularizat ion in some tumors. the importance of tumor angiogenesis and the role of K- ras mutation in regulating angiogenesis in CP and PAC are unknown. The aim of this study was to elucidate the relationship between angiogenesis and K- ras mutations in CP and PAC. Tumor angiogenesis and K-ras mutations were ev aluated in resected specimens from 25 CP (23 CP plus two CP with PAC) and 1 6 PAC patients. Tumor angiogenesis was determined using immunohistochemistr y of factor VIII-related antigen (FVIIIRAg) and ras mutations were identifi ed by enriched-nested polymerase chain reaction. The mean number of FVIIIRA g-positive blood vessels was significantly (p < 0.005) higher in PAC (23.0 +/- 7.5), CP with a mutant K-ras genome (17.7 +/- 2.8) and CP with a normal K-ras genome (6.5 +/- 3.8), compared to unaffected areas. Codon 12 K-ras m utations were detected in three of 25 CP specimens (12%) and in 15 of 16 PA C specimens (94%). In CP patients with mutant K-ras in their genome, microv essel density was significantly (p < 0.01) elevated, compared to patients w ith a normal K-ras genome. Statistical analyses (Spearman rank-difference c orrelation coefficient, Student t test, and chi(2) analysis) indicated a si gnificant association between codon 12 K-ras mutations and turner angiogene sis in both CP and PAC. This study demonstrates a significant association b etween angiogenesis and K-ras mutation in both PAC and CP. At a minimum. K- ras mutation is associated with the events that increase angiogenesis and i t may potentiate or promote tumor angiogenesis.