DPP4 is a dipeptidyl peptidase that cleaves hormones/peptides that regulate glucose homeostasis and leucocyte chemotaxis and is a drug target for Type 2 diabetes. FAP is a close homolog that also has the ability to act as endopeptidase, but less is known about its in vivo substrates. This work aimed to examine their in vivo role in the development and progression of colorectal cancer. Wildtype (WT) and DPP4 and FAP knockout (KO) mice were given six weekly 10mg/kg injections of the carcinogen azoxymethane (AOM) and monitored for tumour development. A significant near three-fold increase (P<0.0001) in tumour number was observed in DPP4 KO (10.9±4.5, n=20) compared to WT (3.3±2.7, n=18) and FAP KO (2.4±2.2, n=19) mice treated with AOM. More tumours over 2 mm in size where observed in DPP4 and FAP KO, 68 % and 46% respectively compared to 13% in WT AOM treated mice. Tumours greater than 6mm in diameter were only observed in DPP4 KO mice treated with AOM. In contrast a significant reduction (P=0.0002) in aberrant cypt foci (ACF) an early marker of neoplastic changes was observed in DPP4 KO mice compared to WT and FAP KO AOM treated mice (5.1±5.1 ACF per colon compared to 12.7±6.8 and 13.3±7.6 ACF respectively). No ACF or tumours were observed in WT (n=15), DPP4 KO (n=13) or FAP KO (n=15) saline controls. We are now establishing whether differences in tumour initiation and progression are due to differences in cell proliferation and apoptosis in the different phenotypes, and/or differences in substrates controlling cell proliferation and tumour immunity. The beta-propeller domain of DPP4 functions as a protein binding domain that binds glypican-3 and fibronectin. Whether the mechanism of the increase in tumour load in mice that lack DPP4, relies upon the DPP4 enzymatic activity or protein binding, needs to be determined.