Role of Notch signaling in tumorigenesis, stemness, and epithelial to mesenchymal transtion in colorectal cancer.

Abstract

Colorectal cancer is the third most commonly diagnosed cancer in both men and women in the United States. Surgical resection and combination chemotherapy are often used for treatment, but in later stages of the disease, these therapies are often unsuccessful. Previous studies have revealed that circulating cancer cells with stem-cell like properties are associated with disease progression and metastatic potential. The Notch signaling pathway has been found to be critical for proliferation and proper functioning in the stem cell compartment of the colon. Preliminary studies from our lab have shown a marked increase in Notch-1 levels from colon tumor tissue as compared to normal colon tissue. This study hypothesizes that overexpression of Notch-1 signaling in colon cancer results in enhanced Epithelial to Mesenchymal Transition (EMT) and stemness mediated by other Notch family members via the Jagged-1 ligand. Overexpression of Notch-1 resulted in a cell phenotype which resembles that of a cancer stem cell, with a slower dividing time, and enhanced aggressiveness. Furthermore, cells with constitutively active Notch-1 overexpressed proteins associated with stemness and EMT such as CD44 and Slug. The results which we obtained provide an indication that Notch signaling plays a significant role in the upregulation of EMT and stemness in colon cancer.