Tumor Initiating Cells in Esophageal Squamous Cell Carcinomas Express High Levels of CD44

Abstract

BackgroundEsophageal Squamous Cell Carcinoma (ESCC) is a major subtype of esophageal cancer causing significant morbility and mortality in Asia. Mechanism of initiation and progression of this disease is unclear. Tumor initiating cells (TICs) are the subpopulation of cells which have the ability to self-renew, as well as, to drive initiation and progression of cancer. Increasing evidence has shown that TICs exist in a variety of tumors. However, the identification and characterization of TICs in esophageal carcinoma has remained elusive.Methodology/Principal Findingsto identify TICs in ESCC, ESCC cell lines including two primary cells were used for screening suitable surface marker. Then colony formation assay, drug resistant assay and tumorigenicity assay in immune deficient mice were used to characterize TICs in ESCC. We found that just the CD44 expression correlated with tumorigenicity in ESCC cell lines. And then induced differentiation of ESCC cells by all-trans retinoic acid treatment led to decreased expression of CD44. The FACS isolated cell subpopulations with high CD44 expression showed increased colony formation and drug resistance in vitro, as well as significantly enhanced tumorigenicity in NOD/SICD mice, as compared to the low expressing CD44 ESCC cells.Conclusions/Significanceour study has discovered a novel TIC surface marker, CD44, which can be utilized to enrich efficiently the TICs in ESCC. These findings will be useful for further studies of these cells and exploring therapeutic approaches.

ALDH1A1 defines invasive cancer stem-like cells and predicts poor prognosis in patients with esophageal squamous cell carcinoma

“…CD44 has also been proposed as a marker for cancer stem-like cells in esophageal squamous cell carcinoma, although most of the esophageal squamous cell carcinoma cells express CD44. 25,26 Another molecule, CD90 as a cancer stem-like cell marker of esophageal squamous cell carcinoma cells, remains debatable. 25,27 Tumorsphere culture and pretreatment with radiation may be used for enrichment of cancer stem-like cells from esophageal squamous cell carcinoma; however, the cell heterogeneity limits Cancer stem-like cells are involved in the invasion and metastasis with yet to be defined mechanisms.…”

“…25,26 Another molecule, CD90 as a cancer stem-like cell marker of esophageal squamous cell carcinoma cells, remains debatable. 25,27 Tumorsphere culture and pretreatment with radiation may be used for enrichment of cancer stem-like cells from esophageal squamous cell carcinoma; however, the cell heterogeneity limits Cancer stem-like cells are involved in the invasion and metastasis with yet to be defined mechanisms. We found that ALDH1A1-positive cells were preferentially distributed in the invasion frontier of esophageal squamous cell carcinoma and metastatic lesions.…”

Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells

“…CSCs display greater resistance to radioand chemotherapy compared with more differentiated tumor cells, which indicates that the CSC subset can escape from conventional cancer therapy to initiate and perpetuate tumorigenesis (35). In multiple independent studies, the CSC population has been associated with poor patient prognosis in ESCC, which is the sixth leading cause of cancer deaths worldwide (28,36,37). Huang and colleagues reported that the CSC population in ESCC displays robust resistance to radio-and chemotherapy (38) and correlates with the risk of mortality in this disease.…”

“…Considering the ability of AGK to induce tumorigenesis in a very small number of cells, we suspected that AGK might be involved in the promotion of the CSC population in ESCC. We therefore conducted a tumor sphere formation assay to examine the effect of AGK on self-renewal of spherogenic ESCC It has been reported that the side population (SP) is a subpopulation of cells that may exhibit stem cell-like characteristics and that CD44 expression correlates with the tumorigenicity of ESCC cells (28)(29)(30). Consistent with previous reports, our analysis also shows that SP + cells sorted from ESCC cells had a higher proportion of CD44 + cells compared with SP -cells, and SP + cells and CD44 + cells sorted from ESCC cells exhibited a higher clonogenic ability and higher expression of pluripotency-associated markers, including ABCG2, SOX2, OCT4, NANOG, and BMI1 (Supplemental Figure 5, A-C).…”

A CD90+ Tumor-Initiating Cell Population with an Aggressive Signature and Metastatic Capacity in Esophageal Cancer

“…Thus, there is a need to identify and characterize the properties of these TICs to develop more efficient therapies against it. Thus far, studies have found TIC populations in ESCCs to be marked by a p75 neurotrophin receptor (p75 NTR or CD271) or CD44 surface phenotype (5)(6)(7). These cells were found to display classic TIC features including the ability to initiate tumor, self-renew, and resist standard chemotherapy.…”