Cripto-1 acts as a functional marker of cancer stem-like cells and predicts prognosis of the patients in esophageal squamous cell carcinoma

Apr 23, 2017Molecular cancer

Cripto-1 marks cancer stem-like cells and may predict outcomes in esophageal squamous cell carcinoma

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Abstract

CR-1 expression in cancerous tissues is positively correlated to TNM stage, invasive depth, and lymph node metastasis in esophageal squamous cell carcinoma (ESCC).

The CR-1 subpopulation of ESCC cells shows high levels of genes associated with stemness and the process where cells gain migratory and invasive properties.
These CR-1 positive cells exhibit enhanced self-renewal, tumor formation, invasion, and metastasis capabilities.
Reducing CR-1 expression leads to decreased activity of stemness and invasive genes, along with diminished tumorigenic and metastatic potential.
Cox regression analysis reveals that CR-1 serves as an independent prognostic factor for ESCC outcomes.
CR-1 expression overlaps with that of ALDH1A1, another marker for esophageal cancer stem-like cells.

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BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is highly malignant with highly invasive and metastatic capabilities and poor prognosis. It is believed that the ESCC cancer stem-like cells (ECSLCs) are critical for tumorigenicity, invasion and metastasis of ESCC. However, the properties of ECSLCs vary with different markers used in isolation, so that new and more effective markers of ECSLCs need to be identified. This study aimed to estimate the potentiality of Cripto-1 (CR-1) as an ECSLC surface marker and investigate the clinical significance of CR-1 expression in ESCC.

METHODS: ESCC cells with CR-1or CR-1were obtained by flow cytometry then their self-renewal capability and tumorigenicity were compared by colony and limiting dilution sphere formation analysis in vitro and xenograft in nude mice in vivo, respectively. Knockdown of CR-1 expression in ESCC cells was conducted with short hairpin RNA. Cell migration and invasion were examined by scratch test and matrigel transwell assay, respectively. Metastatic capability of ESCC cells was assayed by a mouse tail vein metastasis model. The levels of CR-1 expression in cancerous and paired adjacent normal tissues were assessed by IHC and qRT-RCR. high low

RESULTS: CR-1subpopulation of ESCC cells isolated by FACS expressed high level of genes related to stemness and epithelial-mesenchymal transition (EMT), and possessed high capacities of self-renewal, tumorigenesis, invasion and metastasis. Suppression of CR-1 expression significantly reduced the expression of stemness- and EMT-related genes and the capabilities of self-renewal in vitro, tumorigenicity and metastasis in vivo in ESCC cells. In the clinical ESCC specimens, the expression levels of CR-1 in cancerous tissues were positively correlated to TNM stage, invasive depth, and lymph node metastasis. Cox regression analysis indicated that CR-1 was an independent indicator of prognosis. The expression of CR-1 was found overlapping with aldehyde dehydrogenase 1A1 (ALDH1A1), an intracellular marker for ESCLCs, in ESCC cell lines and specimens. high

CONCLUSIONS: CR-1 is a functional and cell surface ECSLC marker, and an independent prognostic indicator as well as a potential therapeutic target for ESCC.

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Cripto-1 acts as a functional marker of cancer stem-like cells and predicts prognosis of the patients in esophageal squamous cell carcinoma

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