CD44 expression enhances chemoresistance and implies occult micrometastases after conversion hepatectomy for initially unresectable colorectal liver metastases.

Aim: The objective of this study was to examine the clinical and biological significance of CD44 expression in conversion hepatectomy for initially unresectable colorectal liver metastases.

Methods: Fifty-four patients who received chemotherapy followed by hepatectomy (conversion hepatectomy) for initially unresectable liver metastases were enrolled. CD44 expression and its clinical significance were examined in 52 resected specimens; two specimens revealed no residual cancer cells. The biological significance of CD44 expression in the chemoresistance response to fluorouracil, oxaliplatin or irinotecan, three major anti-cancer agents for colon cancer in the clinical setting, was examined using colon cancer cell lines.

Results: Membrane CD44 expression in the residual cancer cells after chemotherapy for colorectal liver metastases was detectable in 19 patients (37%), and was significantly associated with high proliferative activity represented by Ki-67 expression ( = 0.003). CD44 expression was also significantly associated with shorter disease-free survival and worse overall survival after hepatectomy (hazard ratio and -values were 2.570, 0.007 and 3.457, 0.026, respectively). In SW480 and HT29 colon cancer cells, siRNA-mediated knockdown attenuated cell growth. Additionally, knockdown overcame chemoresistance in response to fluorouracil and oxaliplatin with enhanced apoptosis and p27 upregulation, respectively. For irinotecan, knockdown showed no additional effect in chemoresistance.

Conclusions: CD44 enhances chemoresistance in response to anti-cancer drugs (fluorouracil and oxaliplatin) in colon cancer cells. CD44 expression in liver metastases after chemotherapy implies the presence of occult micrometastases and is a worse prognostic factor in patients with conversion hepatectomy for initially unresectable colorectal liver metastases.