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

Abstract

Invasion and metastasis are the major cause of deaths in patients with esophageal cancer. In this study, we isolated cancer stem-like cells from an esophageal squamous cell carcinoma cell line EC109 based on aldehyde dehydrogenase 1A1 (ALDH1A1), and found that ALDH1A1 high cells possessed the capacities of self-renewal, differentiation and tumor initiation, indications of stem cell properties. To support their stemness, ALDH1A1 high cells exhibited increased potential of invasion and metastasis as compared with ALDH1A1 low cells. ALDH1A1 high esophageal squamous cell carcinoma cells expressed increased levels of mRNA for vimentin, matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9), but decreased the level of E-cadherin mRNA, suggesting that epithelial-mesenchymal transition and secretary MMPs may be attributed to the high invasive and metastatic capabilities of ALDH1A1 high cells. Furthermore, we examined esophageal squamous cell carcinoma specimens from 165 patients and found that ALDH1A1 high cells were associated with esophageal squamous dysplasia and the grades, differentiation and invasion depth, lymph node metastasis and UICC stage of esophageal squamous cell carcinoma, as well as poor prognosis of patients. Our results provide the strong evidence that ALDH1A1 high cancer stem-like cells contribute to the invasion, metastasis and poor outcome of human esophageal squamous cell carcinoma. Modern Pathology (2014) 27, 775-783; doi:10.1038/modpathol.2013.189; published online 8 November 2013Keywords: aldehyde dehydrogenase 1A1; cancer stem-like cells; esophageal squamous carcinoma; invasion; metastasis; prognosis Esophageal squamous cell carcinoma is one of the most frequent fatal malignancies in the area from northern Iran to north-central China ('Asian esophageal cancer belt'). 1,2 The 5-year survival rate of esophageal squamous cell carcinoma patients after surgery and chemotherapy remains low owing to highly invasive and metastatic nature of esophageal squamous cell carcinoma. Cancer stem-like cells are a small subpopulation within tumors with the capacities for self-renewal and generating heterogeneous tumor cell lineages. 3 Recent studies suggest that cancer stem-like cells are responsible for invasion and metastasis of many tumor types. We have reported that cancer stem-like cells possess higher capability of invasion and metastasis in solid tumors. [4][5][6] However, the biomarkers related to invasion and metastasis of cancer stem-like cells

Stemness-related markers in cancer

“…ALDH activity in CSCs has been attributed to ALDH1A1 expression, which can regulate stem cell self-protection, differentiation, and population expansion. ALDH has been reported to have prognostic significance in head and neck squamous cell [96] and esophageal squamous cell carcinomas [97]. It is also being pursued as a therapeutic target in ovarian [98, 99] and non-small cell lung cancers [100].…”

Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations

“…These mRNA expression patterns strongly suggest that all three ALDH1A enzymes contribute to at RA synthesis during postnatal life. In addition, ALDH1A1 expression has been proposed as a cancer stem cell marker and associated with poor prognosis in certain types of cancers, including clear cell renal, esophageal squamous cell, and papillary thyroid carcinomas (20)(21)(22). Conversely, ALDH1A2 has been identifi ed as a candidate tumor suppressor in a transgenic animal model of prostate cancer, and gene variants of ALDH1A2 have been found to be associated with osteoarthritis and increased newborn kidney size (23)(24)(25)(26).…”

Tumor-Initiating Cells: Emerging Biophysical Methods of Isolation

“…Studies dating more than a decade have described a correlation between high levels of ALDH and stemness and succeeded in isolating hematopoietic stem cells based on ALDH activity [68–70]. More recently, high ALDH levels have been associated with other stem cell types and with TICs [71–74]. Importantly, overexpression of some members of the ALDH family has been shown to be predictive of poor clinical outcome [75, 76].…”