Prognostic value of CD133⁺CD54⁺CD44⁺ circulating tumor cells in colorectal cancer with liver metastasis

Abstract

In the previous study, we had showed the expression of CD133+ CD54+ CD44+ cellular subpopulation of circulating tumor cells (CTCs) was significantly associated with liver metastasis of colorectal cancer (CRC). This study aimed to explore whether this subpopulation of CTCs have a prognostic value in CRC patients. Flow cytometry was used to detect the expression of cellular subpopulations of CTCs with CD133, CD54, and CD44 in 152 CRC patients, between December 2013 and October 2014. The impact of clinicopathological factors and the expression of cellular subpopulations of CTCs on overall survival were then analyzed. CRC patients with liver metastases who underwent resection of the primary tumor accompanied by surgical treatment for metastasis had a better survival than other patients (P < 0.001). The liver metastatic CRC patients with high expression of CD133+ CD54+ (P < 0.001), CD133− CD54+ (P = 0.004), and CD133+ CD44+ CD54+ (P = 0.003) cellular subpopulations of CTCs had a worse survival than those patients with low expression. Multivariable survival analyses identified carcinoembryonic antigen levels (hazard ratio [HR] = 3.056; 95% confidence interval [CI] = 1.354–6.897; P = 0.007), treatment strategy (HR = 0.212; 95% CI = 0.056–0.808; P = 0.023), and CD133+ CD44+ CD54+ cellular subpopulation of CTCs (HR = 6.459; 95% CI = 1.461–28.558; P = 0.014) as independent prognostic factors for CRC patients with liver metastasis. CD133+ CD44+ CD54+ cellular subpopulation of CTCs has a prognostic value in CRC patients with liver metastasis, especially in the survival of CRC patients with liver metastasis who did not undergo surgical treatment for metastasis.

Colorectal Cancer Stem Cells in the Progression to Liver Metastasis

“…Interestingly, the Warburg effect and the enhancement of the PPP in CSCs seem to be responsible for the enhanced production of antioxidant molecules and the overall reduction of reactive oxygen species (ROS) demonstrated in vivo and in vitro models (15,55,59). CD44 (CD44v) expression in CSCs suppresses PKM2 (mice model), thereby decreasing pyruvate dehydrogenase activity and promoting PPP; these are all consistent with the stabilization of the cysteine/glutamate antiporter and elevated GSH levels (58,(60)(61)(62). All these lead to higher survival rates of CSC even in hostile environments (15,57,58).…”

“…It is known that glutamine metabolism regulates the sensitivity of CSCs to metformin via the AMPK-mTOR pathway (76). Furthermore, glutamine can be hydrolyzed to glutamate which can be used to produce GSH (60)(61)(62).…”

Molecular and Immunohistochemical Markers with Prognostic and Predictive Significance in Liver Metastases from Colorectal Carcinoma

“…In a recent study, flow cytometry showed that the liver metastatic CRC patients with high expression of CD133 + CD54 + , CD133 − CD54 + , and CD133 + CD44 + CD54 + cellular subpopulations of circulating tumor cells had a worse survival than those patients with low expression. Moreover, the cellular subpopulation expressing CD133 + CD44 + CD54 + of CTCs showed its proficiency as independent prognostic factors for survival in CRC patients with liver metastasis not treated with surgical approach [ 65 ].…”

“…The study of MICs phenotype is particularly important for the understanding of the biological mechanism of metastasis and could also potentially harbor prognostic and predictive significance. In a recent study, the CD133 + CD44 + CD54 + subpopulation of CTCs has a prognostic value in metastatic colorectal cancer and shows a significant survival improvement in patients who did not undergo surgical treatment for metastasis [ 65 ]. Those studies are particularly promising, considering the feasibility of this test (a simple blood sampling) potentially able to add more prognostic information at subsequent moments during patient monitoring.…”

Sensitive and easy screening for circulating tumor cells by flow cytometry

“…The criteria for potential CTC detection were based on FSC (physical properties of the cells) and pan-cytokeratin (intracellular epithelial marker). Second, we also used DAPI as a marker to select nucleated cells and FSC and SSC to remove all possible contamination by debris as suggested by previous studies (32,33), thus improving the sensitivity and specificity of CTC detection. Last, we added VIM to the panel for CTC detection.…”