Aldehyde Dehydrogenase 1 Protein Expression Research Articles

Phenotypic and microRNA characterization of the neglected CD24+ cell population in MCF-7 breast cancer 3-dimensional spheroid culture.

In vitro 3-dimensional (3D) spheroid culture has been widely used as model to enrich CD44CD24 cancer stem cells (CSC) with high aldehyde dehydrogenase 1 (ALDH1) activity. Although CD24 subpopulation was known to be present in 3D spheroids and may influence cancer drug therapies, its characteristics and CSC properties were not well defined. In this study, CD24 population from the Michigan Cancer Foundation-7 (MCF-7) spheroid was sorted and subjected to spheroid formation test, stem cell markers immunofluorescence, invasion and migration test, as well as microRNA expression profiling. Sorted MCF-7 CD24 cells from primary spheroids were able to reform its 3D spheroid shape after 7 days in nonadherent culture conditions. In contrast to the primary spheroids, the expression of SOX-2, CD44, CD49f, and Nanog was dim in MCF-7 CD24 cells. Remarkably, MCF-7 CD24 cells were found to show high expression of ALDH1 protein which may have resulted in these cells exhibiting higher resistance against doxorubicin and cisplatin when compared with that of the parental cells. Moreover, microRNA profiling has shown that the absence of CSC properties was consistent with the downregulation of major CSCs-related pathways including Hedgehog, wingless-related integration site (Wnt), and microtubule associated protein kinase (MAPK) signaling pathways. However, the upregulated pathways such as adherens junctions, focal adhesion, and tight junction suggest that CD24 cells were probably at an epithelial-like state of cell transition. In conclusion, neglected CD24 cells in MCF-7 spheroid did not exhibit typical breast CSCs properties. The presence of miRNAs and their analyzed pathways suggested that these cells could be a distinct intermediate cell state in breast CSCs.

Expressions and clinical significances of aldehyde dehydrogenase 1 and transforming growth factor-β2 in triple negative breast cancer

Objective To investigate the expressions and clinical significances of breast cancer stem cell markers such as aldehyde dehydrogenase 1 (ALDH1) and transforming growth factor-β2 (TGF-β2) in patients with triple negative breast cancer. Methods Samples of 60 triple negative breast cancer tissues were investigated for the expressions of ALDH1 and TGF-β2 proteins by immunohistochemical staining. The correlation analysis, disease-free survival analysis and overall survival analysis were performed. Results The positive expressions of ALDH1 protein and TGF-β2 protein in the 60 breast cancer primary lesions were 23 cases (38.33%) and 38 cases (63.33%) respectively. The expression of ALDH1 protein was not correlated with tumor size (χ2=0.307, P=0.580), histological grade (χ2=4.244, P=0.120), clinical stage (χ2=0.982, P=0.612) or lymph node metastasis (χ2=1.111, P=0.292). The expression of TGF-β2 protein was not correlated with histological grade (χ2=4.651, P=0.098), lymph node metastasis (χ2=3.513, P=0.061), clinical stage (χ2=1.310, P=0.519) or tumor size (χ2=0.629, P=0.428). The disease-free survival time [(38.43±3.86) months vs. (53.38±2.58) months] and the overall survival time [(42.00±3.11) months vs. (53.84±2.19) months] of ALDH1-positive patients were significantly shorter than those of ALDH1-negative patients, and the differences were statistically significant (χ2=8.490, P=0.004; χ2=11.270, P=0.001). The disease-free survival time [(42.81±3.32) months vs. (54.72±2.50) months] and the overall survival time [(44.74±2.68) months vs. (57.18±1.55) months] of TGF-β2 positive patients were significantly shorter than those of TGF-β2-negative patients, and the differences were statistically significant (χ2=4.300, P=0.038; χ2=8.900, P=0.003). The expression of ALDH1 protein was positively correlated with the expression of TGF-β2 protein (r=0.360, P=0.005). Conclusion The ALDH1 phenotype is an indepen-dent predictor of poor prognosis. The activation of TGF-β2 signaling pathway may be involved in the regulation of triple-negative breast cancer stem cells. Key words: Breast neoplasms; Neoplastic stem cells; Transforming growth factor beta 2; Aldehyde dehydrogenase 1

Clinical significance of ALDH1 combined with DAPI expression in patients with esophageal carcinoma.

Esophageal carcinoma is the most common type of tumor, with the incidence in China accounting for 50% of cases worldwide and the majority of patients not surviving due to tumor recurrence. According to the cancer stem cell theory, tumor development and recurrence is due to the excitation of a cancer stem cell. Aldehyde dehydrogenase 1 (ALDH1) is an appropriate marker for cancer stem cells and the present study aimed at determining the function of ALDH1 in human esophageal carcinoma. Indirect fluorescence antibody staining was used to investigate the association between the level of ALDH1 protein expression and clinicopathological parameters, including sex, age, vein invasion, degree of tumor cell differentiation and clinical stage. DAPI was used to stain the nuclei of tumor cells and exclude non-tumor cells. The results of the present study revealed that ALDH1 expression was associated with the level of tumor cell differentiation, tumor-node-metastasis stage and lymphatic invasion. In addition, increased expression of ALDH1 was identified in esophageal carcinoma tissues compared with in healthy esophageal tissues. Therefore, ALDH1 may be used as a parameter for the pathology of esophageal carcinoma.

Aldehyde dehydrogenase 1 (ALDH1) expression is associated with a poor prognosis of bladder cancer

Aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, has been reported to be altered in human carcinogenesis. This study assessed the expression of ALDH1 protein in invasive vs. noninvasive bladder cancer tissues for association with clinicopathological factors and bladder cancer prognosis. Tissue samples were collected from 227 bladder cancer patients, including 118 with noninvasive and 109 with invasive bladder cancer for immunostaining of ALDH1 expression. ALDH1 expression in tumor tissues was significantly greater than that in adjacent normal tissues. ALDH1 protein was highly expressed in 29.07% (66/227) of bladder tumor tissues (i.e., 24.58% of noninvasive bladder cancer tissues vs. 33.94% of invasive bladder cancer tissues). In patients with noninvasive bladder cancer, ALDH1 protein expression was significantly associated with an advanced tumor grade and frequent tumor recurrence (P≤0.05). In patients with invasive bladder cancer, ALDH1 protein expression was significantly associated with an advanced tumor grade, stage, as well as lymph node and distant metastases (P≤0.05). After adjusting for the confounding factors, ALDH1 protein expression was significantly associated with relapse-free survival in noninvasive bladder cancer patients [HR (95% CI)=4.45 (1.32–15.04); P=0.027] and overall survival in invasive bladder cancer patients [HR (5% CI)=2.86 (1.72–8.83); P=0.020]. These data indicate that ALDH1 expression plays an important role in bladder cancer development and prognosis. Further validation of our results is warranted in a larger sample cohort, and further investigation of ALDH1 signaling and function will increase our understanding of ALDH1 in bladder cancer progression.

Aldehyde dehydrogenase 1: a specific cancer stem cell marker for human colorectal carcinoma.

Since the identification of cancer stem cells (CSCs) a new understanding of tumor occurrence and development has evolved. According to the stem cell (SC) theory, colorectal carcinoma (CRC) SCs may be derived from mutations in normal intestinal cells. CSCs can be defined by their cell of origin (SCs or early progenitor cells). Thus, through a shared stem cell marker between CSCs and SCs, it is possible to investigate the association between its expression and the various clinicopathological features in patients with CRC. Aldehyde dehydrogenase 1 (ALDH1) is an appropriate marker. The present study was performed to examine the role of ALDH1 in CRC. Through indirect fluorescence antibody staining, the association between ALDH1 protein expression and various clinicopathological parameters was investigated. Furthermore, enzyme‑linked immunosorbent assay (ELISA) was used to investigate the differing content of ALDH1 between CRC tissues and normal colorectal tissues. The results revealed that ALDH1 expression was markedly associated with tumor stage, Dukes' stage and the level of tumor cell differentiation. Using ELISA, it was demonstrated that there was a greater level of ALDH1 in CRC tissue than in normal colorectal tissue. Therefore, ALDH1 levels can be used as a useful parameter for pathological evaluation of tissue histology and to predict disease prognosis.

7-difluoromethoxyl-5,4'-di-n-octyl genistein inhibits ovarian cancer stem cell characteristics through the downregulation of FOXM1.

7-Difluoromethoxyl-5,4′-di-n-octylgenistein (DFOG) is a novel synthetic genistein analogue that possesses anti-cancer activity in a variety of cancers, including ovarian cancer. The objective of the present study was to investigate whether DFOG inhibits the self-renewal capacity of ovarian cancer stem-like cells (OCSLCs) and to identify its potential mechanism of action. It was found that the sphere-forming cells (SFCs) of the SKOV3 cell line exhibited a self-renewal capacity and high tumorigenicity, indicating that they possessed the properties of ovarian cancer stem cells (OCSCs). It was also shown for the first time that DFOG preferentially inhibited proliferation, self-renewal capacity and expression of stem cell markers [cluster of differentiation (CD)133, CD44 and aldehyde dehydrogenase 1 (ALDH1)] in the SFCs derived from the SKOV3 cells. These effects were accompanied by the downregulation of forkhead box M1 (FOXM1) expression. Overexpression of FOXM1 rescued the DFOG-induced downregulation of FOXM1, CD133, CD44 and ALDH1 protein expression. It also inhibited the self-renewal capacity of the SFCs derived from the SKOV3 cells. Thus, DFOG appears to inhibit the characteristics of OCSLCs by downregulating FOXM1 expression.

Casticin suppresses self-renewal and invasion of lung cancer stem-like cells from A549 cells through down-regulation of pAkt

A subpopulation of cancer stem cells is recognized as the cause of tumorigenesis and spreading. To investigate the effects of casticin (5,3'-dihydroxy-3,6,7,4'-tetramethoxyflavone), derived from Fructus Viticis Simplicifoliae, on lung cancer stem cells, we isolated and identified a subpopulation of lung cancer stem-like cells (LCSLCs) from non-small-cell lung carcinoma A549 cells with the features including self-renewal capacity and high invasiveness in vitro, elevated tumorigenic activity in vivo, and high expression of stemness markers CD133, CD44, and aldehyde dehydrogenase 1 (ALDH1), using serum-free suspension sphere-forming culture method. We then found that casticin could suppress the proliferation of LCSLCs in a concentration-dependent manner with an IC50 value of 0.4 μmol/L, being much stronger than that in parental A549 cells. In addition, casticin could suppress the self-renewal and invasion of LCSLCs concomitant with decreased CD133, CD44, and ALDH1 protein expression and reduced MMP-9 activity. Further experiments showed that casticin suppressed self-renewal and invasion at least partly through down-regulation of Akt phosphorylation. In conclusion, casticin suppressed the characteristics of LCSLCs, suggesting that casticin may be a candidate compound for curing lung cancer via eliminating cancer stem cells.

Aldehyde dehydrogenase 1/epidermal growth factor receptor coexpression is characteristic of a highly aggressive, poor-prognosis subgroup of high-grade serous ovarian carcinoma

In models of triple-negative breast cancer (TNBC), it has recently been shown that the epidermal growth factor receptor (EGFR) pathway is up-regulated in the aldehyde dehydrogenase 1 (ALDH1)-positive cancer stem cell fraction. Because high-grade serous ovarian carcinoma (HGSC) reveals strong molecular similarities to TNBC, we aimed to investigate the potential link between ALDH1 and EGFR in this entity. Expression of ALDH1 was investigated in 131 primary HGSCs using immunohistochemistry. Expression data were correlated with EGFR expression as well as with clinicopathologic parameters and survival. Forty-two carcinomas (32.1%) were positive for ALDH1 protein expression. Data on EGFR expression were available for 112 tumors. In these cases ALDH1 was significantly linked to EGFR expression (P < .0001). ALDH1 positivity was a significant negative prognostic factor for overall survival both in univariate (P = .010) and in multivariate survival analyses (P = .041). Tumors that were positive for both ALDH1 and EGFR had an exceptionally bad prognosis as compared with carcinomas with 1 or both markers negative in univariate analysis (P < .0001) and in the multivariate setting (P = .004). Our study suggests that similar to TNBC, there is a link between ALDH1 and EGFR expression in HGSC. Double positivity for both markers identifies a subgroup of highly aggressive, poor-prognosis cancers for which alternative treatment options-potentially EGFR-targeting drugs-should be evaluated.

Cancer stem cell marker ALDH1 expression is associated with lymph node metastasis and poor survival in esophageal squamous cell carcinoma: a study from high incidence area of northern China

Tumor recurrence and metastasis is the leading cause of death in esophageal squamous cell carcinoma (ESCC). Cancer stem cell (CSC) may be responsible for tumor growth and maintenance of aggressive behavior. Aldehyde dehydrogenase 1 (ALDH1) has been proposed as one of the possible candidates for a CSC marker. The expression of ALDH1 may be correlated with the clinicopathologic factor and clinical outcome of patients with ESCC. The purpose of this study was to investigate the expression of ALDH1 protein in human ESCC tissues, and evaluated the clinical implication of ALDH1 expression for these patients. All 79 patients who underwent esophagectomy for ESCC between January 2005 and June 2006 were enrolled in this study. The expression of ALDH1 in ESCC and adjacent noncancerous tissues was analyzed by immunohistochemistry. ALDH1 was mainly expressed in ESCC cell nucleus. For the 79 ESCC patients, increased nuclear accumulation of ALDH1 was found in 12 (15.2%) specimens. ALDH1 expression was correlated with poor histological differentiation (P= 0.003), lymph node metastasis (P= 0.011), and late pathologic TNM classification (pTNM) staging (P= 0.003). Patients in ALDH1 positive group had a significantly poor 5-year overall survival than those in the negative group (8.3% vs. 52.2%, P= 0.025). We have demonstrated for the first time that the CSC marker, ALDH1, is expressed in human ESCC. The expression of ALDH1 protein in nucleus of the ESCC is significantly associated with lymph node metastasis and poor survival. Our results highly indicate the involvement of ALDH1 in the aggressive behavior of ESCC.