Targeted Inhibition of Vav1 Activity Does Not Favour Development of Colitis-Associated Colon Cancer

To the Editors: Azathioprine and 6-mercaptopurine represent effective drugs for the maintenance of remission in inflammatory bowel disease (IBD),1 although there is an ongoing and controversial discussion about the carcinogenic potential of thiopurine drugs.2,3 Recent studies by Poppe et al4 identified the guanine nucleotide exchange factor Vav1 and its substrate Rac1 as the key intracellular targets of thiopurines in IBD. The azathioprine metabolite 6-thio-GTP is able to bind to Rac1 and thereby block guanine nucleotide exchange factor activity of Vav1, resulting in a subsequent induction of T-cell apoptosis and finally in an efficient inhibition of overwhelming immune responses.4 To investigate whether this molecular process might also underlie the carcinogenic potential of azathioprine, we endoscopically monitored the development of inflammation-associated colonic tumors in Vav1-deficient mice (kindly provided by Victor Tybulewicz, National Institute of Medical Research, London, United Kingdom).5 Using the experimental model of azoxymethane/dextran sulfate sodium–induced colon cancer6 and a validated endoscopic tumor score,7 we determined the number and size of tumors, which developed in the chronically inflamed distal colon of Vav1-deficient and wild-type BALB/c mice. Interestingly, colonic tumor formation turned out to occur independently from the presence or absence of Vav1 activity: Mean tumor size and tumor number per mouse was 2.0 and 4.4, respectively, in the group of Vav1-deficient animals, whereas wild-type control mice developed 4.9 distal tumors in average and showed a mean tumor size of 1.8. The overall tumor score of Vav1-deficient and proficient mice did not differ significantly (Fig. 1). Because of the fact that dextran sulfate sodium treatment alone resulted in comparable levels of intestinal inflammation in both the groups (data not shown), we were able to exclude that the above-described findings were relevantly impacted by Vav1-mediated effects on the severity of colitis in our experimental setting. Tumor development was analyzed endoscopically in Vav1-deficient and wild-type BALB/c mice after azoxymethane injection and repeated cycles of dextran sulfate sodium treatment. Number of tumors within the distal part of the colon was determined, and tumor size was graded. To calculate the overall tumor score, all tumor size scores of the individual animal were summed up. Thus, our data strongly implicate that azathioprine-mediated blockade of Vav1/Rac1 interaction successfully dampens the proinflammatory T-cell response in IBD without increasing the risk of colorectal cancer development. This conclusion is well in line with a prospective observational cohort study presented by Beaugerie et al8 at Digestive Disease Week 2012 in San Diego, showing no impact of immunosuppressive treatment in IBD on cancer development or tumor recurrence in patients with a personal history of cancer.