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Background: Notch pathway is involved in regulating colon cancer stem cells (CSCs), which play an important role in angiogenesis and resistance to conventional therapies. CD44 and CD133 are transmembrane glycoproteins reported as putative markers for isolating CSCs. High expression of Notch Intracellular Cleaved Domain (NICD) has been associated with resistance to anti-vascular endothelial growth factor therapy. Based on these reports, we evaluated NICD, CD44 and CD133 expression in a series of consecutive metastatic colon cancer patients treated with bevacizumab-based chemotherapy within first-line clinical trials. Methods: Histological samples obtained from 45 primary adenocarcinomas were tested by immunohistochemistry for NICD, CD44 and CD133. A scoring system based on staining intensity and percentage of stained cells was used. Vessels density was measured in hot-spot areas by CD31 antibody. Results: CD44 levels were higher in high NICD cases than in low NICD cases (63% vs. 16%, respectively, p=0.014). High NICD and CD44 levels predicted shorter progression-free (p<0.001) and overall survival (p=0.012). No significant association was found between CD133 or CD31 and NICD or CD44 expression. Conclusion: Our data suggest that colon cancer patient with high NICD and CD44 levels have a reduced likelihood of response to bevacizumab-based therapy.

Notch Activation Modulates Bevacizumab Activity by CD44 Positive Cancer Stem Cells in Advanced Colon Cancer