Cell competition, a defense system orchestrated by epithelial cells to suppress cancer formation, is altered in epithelial cells with sequential mutations. Activated Ras mutant epithelial cells, which would normally be eliminated into the lumen, instead infiltrate into the tissue to form invasive tumors. The underlying mechanisms were found to be increased MMP21 expression, via activation of NF-?B signaling. Analysis using human samples suggests that the NF-?B-MMP21 pathway contributes to early colorectal cancer progression.