Although all KRas (protein that in humans is encoded by the KRas gene) point 
mutants are considered to have a similar prognostic capacity, their 
transformation and tumorigenic capacities vary widely. We compared the 
metastatic efficiency of KRas G12V (Kirsten rat sarcoma viral oncogene homolog 
with valine mutation at codon 12) and KRas G13D (Kirsten rat sarcoma viral 
oncogene homolog with aspartic mutation at codon 13) oncogenes in an orthotopic 
colorectal cancer (CRC) model. Following subcutaneous preconditioning, 
recombinant clones of the SW48 CRC cell line [Kras wild-type (Kras WT)] 
expressing the KRas G12V or KRas G13D allele were microinjected in the mouse 
cecum. The percentage of animals developing lymph node metastasis was higher in 
KRas G12V than in KRas G13D mice. Microscopic, macroscopic, and visible 
lymphatic foci were 1.5- to 3.0-fold larger in KRas G12V than in KRas G13D mice 
(P < 0.05). In the lung, only microfoci were developed in both groups. KRas G12V 
primary tumors had lower apoptosis (7.0 ± 1.2 vs. 7.4 ± 1.0 per field, P = 
0.02), higher tumor budding at the invasion front (1.2 ± 0.2 vs. 0.6 ± 0.1, P = 
0.04), and a higher percentage of C-X-C chemokine receptor type 4 
(CXCR4)-overexpressing intravasated tumor emboli (49.8 ± 9.4% vs. 12.8 ± 4.4%, P 
< 0.001) than KRas G13D tumors. KRas G12V primary tumors showed Akt activation, 
and β5 integrin, vascular endothelial growth factor A (VEGFA), and Serpine-1 
overexpression, whereas KRas G13D tumors showed integrin β1 and angiopoietin 2 
(Angpt2) overexpression. The increased cell survival, invasion, intravasation, 
and specific molecular regulation observed in KRas G12V tumors is consistent 
with the higher aggressiveness observed in patients with CRC expressing this 
oncogene.