Gastrointestinal (GI) cancers ectopically express multiple splice variants of the cholecystokinin-2 (CCK2)/gastrin receptor; however, their relative contributions to the cancer phenotype are unknown. The aim of this study was to compare the effects of CCK2 receptor (CCK2R) and CCK2i4svR expression on cell growth both in vitro and in vivo using a human epithelial cell model, HEK239. In vitro, receptor variant expression did not affect cell proliferation either in the absence or presence of agonist. However, in vivo, the expression of CCK2i4svR, but not CCK2R, increases HEK293 tumor growth in a constitutive, Src-dependent manner. Enhanced tumorigenicity of CCK2i4svR is associated with an Src-dependent increase in the transcription factor, hypoxia-inducible factor-1α, its downstream target, vascular endothelial growth factor and tumor micro-vessel density, suggesting that CCK2i4svR may contribute to the growth and spread of GI cancers through agonist-independent mechanisms that enhance tumor angiogenesis.