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

Chronic pancreatitis (CP) is one condition in which epidemiologic studies have 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 the codon 12 K-ras gene is one genetic aberration commonly associated with development of PAC. Tumor angiogenesis, or microvascular proliferation of new capillaries, is another pathophysiologic alteration associated with PAC. Although activated ras oncogenes modulate tumor angiogenesis/neovascularization 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 evaluated in resected specimens from 25 CP (23 CP plus two CP with PAC) and 16 PAC patients. Tumor angiogenesis was determined using immunohistochemistry of factor VIII-related antigen (FVIIIRAg) and ras mutations were identified by enriched-nested polymerase chain reaction. The mean number of FVIIIRAg-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 mutations were detected in three of 25 CP specimens (12%) and in 15 of 16 PAC specimens (94%). In CP patients with mutant K-ras in their genome, microvessel density was significantly (p < 0.01) elevated, compared to patients with a normal K-ras genome. Statistical analyses (Spearman rank-difference correlation coefficient, Student t test, and chi2 analysis) indicated a significant association between codon 12 K-ras mutations and tumor angiogenesis in both CP and PAC. This study demonstrates a significant association between 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 it may potentiate or promote tumor angiogenesis.