Overexpression of a panel of cancer stem cell markers enhances the predictive capability of the progression and recurrence in the early stage cholangiocarcinoma

Abstract

Background Cancer recurrence is the important problem of cholangiocarcinoma (CCA) patients, lead to a very high mortality rate. Therefore, the identification of candidate markers to predict CCA recurrence is needed in order to effectively manage the disease. This study aims to examine the predictive value of cancer stem cell (CSC) markers on the progression and recurrence of CCA patients. Methods The expression of 6 putative CSC markers, cluster of differentiation 44 (CD44), CD44 variant 6 (CD44v6), CD44 variants 8-10 (CD44v8-10), cluster of differentiation 133 (CD133), epithelial cell adhesion molecule (EpCAM), and aldehyde dehydrogenase 1A1 (ALDH1A1), was investigated in 178 CCA tissue samples using immunohistochemistry (IHC) and analyzed with respect to clinicopathological data and patient outcome including recurrence-free survival (RFS) and overall survival (OS). The candidate CSC markers were also investigated in serum from CCA patients, and explored for their predictive ability on CCA recurrence. Results Elevated protein level of CD44 and positive expression of CD44v6 and CD44v8-10 were significantly associated with short RFS and OS, while high levels of ALDH1A1 were correlated with a favorable prognosis patient. The elevated CD44v6 level was also correlated with higher tumor staging, whereas a decreasing level of ALDH1A1 was correlated with lower tumor staging. The levels of CD44, CD44v6 and CD44v8-10 were also correlated and were associated with a poor outcome. Furthermore, soluble CD44, CD44v6, CD44v8-10 and EpCAM were significantly increased in the recurrence group for early stage CCA; they also correlated with high levels of the tumor marker CA19-9. Elevated levels of CD44, CD44v6, CD44v8-10 or EpCAM alone or in combination has the potential to predict CCA recurrence. Conclusions The overexpression of CD44, CD44v6, CD44v8-10 and EpCAM increases predictability of post-operative CCA recurrence. Moreover, the overexpression of the panel of CSC markers combined with CA19-9 could improve our predictive ability for tumor recurrence in early stage CCA patients. This result may be beneficial for the patients in order to predict the outcome after treatment and may be useful for clinical intervention in order to improve patient survival.

Integration of global metabolomics and lipidomics approaches reveals the molecular mechanisms and the potential biomarkers for postoperative recurrence in early-stage cholangiocarcinoma

“…Recently, we reported the association of CSCs and recurrence with the overexpression of putative cancer stem-like cell (CSC) markers. These have the potential to predict CCA recurrence [ 7 ]. However, the mechanism involved in CCA recurrence is not well understood.…”

High Levels of Serum IgG for Opisthorchis viverrini and CD44 Expression Predict Worse Prognosis for Cholangiocarcinoma Patients after Curative Resection

“…Moreover, our result also supports a previous study that found a high expression of cancer stem cell markers, CD44s, CD44v6 and CD44v8-10, associated with poor prognosis in early stage CCA patients. 36 CD44v8-10 is a variant isoform of CD44 that plays a role in the regulation of oxidative stress in tumors by stabilizing the cystine–glutamate transporter and promoting glutathione synthesis. 37 In OV induced hamster CCA tissues, the expression of CD44v8-10 was induced during bile duct transformation, and it was associated with a poor prognosis.…”

Proteomic analysis identifies deregulated metabolic and oxidative-associated proteins in Italian intrahepatic cholangiocarcinoma patients

“…HIST1H4A resulted highly up-regulated in exosomes released by NSCLC [ 47 ]. A recent study conducted on CCA patients showed that high expression of ALDH1A1 correlated with a more favorable prognosis [ 48 ]; in many studies, ALDH1A1 is a cancer stem cell marker and a suitable target for therapy and only its activity is associated to worse prognosis [ 49 , 50 ].…”