L. Thai1,2, J. DeVecchio2, G. Karagkounis1,2, L. C. Duraes1,2, A. Mace1,2, G. Gantt1,2, K. F. Matthew1,2 1Cleveland Clinic,Colorectal Surgery, Digestive Disease Institute,Cleveland, OH, USA 2Cleveland Clinic,Department Of Stem Cell And Regenerative Medicine,Cleveland, OH, USA
Introduction:
Response to neoadjuvant chemoradiation (CRT) improves oncologic outcomes in rectal cancer, however, a subset of patients still develop recurrence. Colorectal cancer stem cells (CSCs) are relatively resistant to CRT, and could contribute to poor response or recurrent disease. We have previously shown in vitro that the proportion of CD44+ (marker for colorectal CSCS) cells is increased after chemoradiation. As an extension to study of human tissues, we hypothesized that rectal cancers with high CD44+ cells would be most resistant to chemoradiation.
Methods:
Thirty-five patients with rectal cancer underwent standard neoadjuvant CRT, and post-treatment responses were evaluated pathologically based on the American Joint Committee on Cancer (AJCC) criteria. Total tumor mRNAs were isolated from pretreatment specimens. CD44 mRNA expression was measured using real-time reverse-transcription polymerase chain reaction (RT-PCR) and protein expression was examined by immunofluorescence. Gene expressions were compared between responders (AJCC 0) and non-responders (AJCC 1-3). Associations between gene expression with nodal status and tumor recurrence were also evaluated.
Results:
Pretreatment CD44 mRNA expression was significantly lower in responders (AJCC 0) compared to non-responders (AJCC 1-3) (p=0.02). CD44 protein expression was also significantly lower in AJCC 0 patients as measured by immunofluorescence. Conversely, CD44 was significantly higher in nonresponders (AJCC 3) (p=0.018). When evaluating mRNA expression with stage and outcome, lower levels of CD44 expression significantly correlated with pathologic N0 nodal status, whereas higher levels of CD44 were associated with N1 and N2 nodal status (p=0.008). There was no significant correlation between CD44 levels and tumor recurrence.
Conclusion:
Low pretreatment CD44 expression levels in rectal cancers correlate with better response to neoadjuvant chemoradiation and are associated with pathologic N0 nodal status. CD44, as a marker for CSC, may be a predictive biomarker for identifying rectal cancer patients who may derive the most or least benefit from neoadjuvant chemoradiation. Further characterization may potentially lead towards more individualized treatment decisions.