ALDH1 expression correlates with favorable prognosis in ovarian cancers

Chang, Bin; Liu, Guangzhi; Xue, Fengxia; Rosen, Daniel; Xiao, Lianchun; Wang, Xuemei; Liu, Jinsong

doi:10.1038/modpathol.2009.35

Cited by 135 publications

(133 citation statements)

References 35 publications

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“…In the present study, we investigated potential alterations in the RA pathway and analyzed their clinical relevance. In contrast to findings in other tumor entities, [7][8][9][10][11][12][13][14] we observed a marked up-regulation of key molecules associated with increased RA availability and alternative, prosurvival RA usage in gliomas. This was accompanied by increased intratumoral levels of RA precursors and activated RA.…”

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confidence: 99%

“…[7][8][9][10][11][12][13][14] In particular, epithelial tumors, which originate from tissues that depend on a closely orchestrated balance between cellular proliferation and subsequent differentiation, show loss of RA signaling components involved in RA availability. This frequently includes altered expression of cellular retinolbinding protein 1 (CRBP1), an intracellular transport protein in charge of facilitating the uptake of RA precursor molecules, [7][8][9] and of aldehyde dehydrogenase 1A1 (ALDH1A1), which is capable of activating RA precursors into the active RA metabolite, 10,11 as well as of cellular retinoic acid binding protein 2 (CRABP2) and cellular retinoic acid binding protein 1 (CRABP1), two chaperone proteins that shuttle between different cellular compartments channeling RA to designated nuclear RA receptors or to endosomal degradation by cytochrome P450, family 26 members (CYP26), respectively. [12][13][14] In addition, recent studies on breast tumor cells revealed a pathological involvement of the intracellular transport protein fatty acid binding protein 5 (FABP5) in neoplastic RA signaling.…”

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confidence: 99%

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Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

Campos

Centner

Bermejo

et al. 2011

The American Journal of Pathology

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Undifferentiated cell populations may influence tumor growth in malignant glioma. We investigated potential disruptions in the retinoic acid (RA) differentiation pathway that could lead to a loss of differentiation capacity, influencing patient prognosis. Expression of key molecules belonging to the RA differentiation pathway was analyzed in 283 astrocytic gliomas and was correlated with tumor proliferation, tumor differentiation, and patient survival. In addition, in situ concentrations of retinoids were measured in tumors, and RA signaling events were studied in vitro. Unlike other tumors, in gliomas expression of most RA signaling molecules increased with malignancy and was associated with augmented intratumoral retinoid levels in high-grade gliomas. Aberrantly expressed RA signaling molecules included i) the retinol-binding protein CRBP1, which facilitates cellular retinoid uptake; ii) ALDH1A1, capable of activating RA precursors; iii) the RA-degrading enzyme CYP26B1; and iv) the RA-binding protein FABP5, which can inhibit RA-induced differentiation. In contrast, expression of the RA-binding protein CRABP2, which fosters differentiation, was decreased in high-grade tumors. Moreover, expression of CRBP1 correlated with tumor proliferation, and FABP5 expression correlated with an undifferentiated tumor phenotype. CRBP1 and ALDH1A1 were independent prognostic markers for adverse patient survival. Our data indicate a complex and clinically relevant deregulation of RA signaling, which seems to be a central event in glioma pathogenesis.

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confidence: 99%

Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

Campos

Centner

Bermejo

et al. 2011

The American Journal of Pathology

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“…Beyond alcohol metabolism, the role of ALDH1A1 is not yet understood. There are studies that report ALDH1A1 expression as a favorable prognostic factor in ovarian (11) and pancreatic cancer (12). However, contradicting data also show that positive cells have increased invasive and metastatic capabilities (13) and that ALDH1A1 expression is correlated with poor survival in breast cancer (14).…”

Section: Resultsmentioning

confidence: 99%

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Danielsson

Skogs

Huss

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The transformation of normal cells to malignant, metastatic tumor cells is a multistep process caused by the sequential acquirement of genetic changes. To identify these changes, we compared the transcriptomes and levels and distribution of proteins in a fourstage cell model of isogenically matched normal, immortalized, transformed, and metastatic human cells, using deep transcriptome sequencing and immunofluorescence microscopy. The data show that ∼6% (n = 1,357) of the human protein-coding genes are differentially expressed across the stages in the model. Interestingly, the majority of these genes are down-regulated, linking malignant transformation to dedifferentiation. The up-regulated genes are mainly components that control cellular proliferation, whereas the down-regulated genes consist of proteins exposed on or secreted from the cell surface. As many of the identified gene products control basic cellular functions that are defective in cancers, the data provide candidates for follow-up studies to investigate their functional roles in tumor formation. When we further compared the expression levels of four of the identified proteins in clinical cancer cohorts, similar differences were observed between benign and cancer cells, as in the cell model. This shows that this comprehensive demonstration of the molecular changes underlying malignant transformation is a relevant model to study the process of tumor formation.C ancer development is a multistep process where genetic changes are accumulated, thus progressively transforming cells into a cancerous phenotype (1, 2). Over the last decades, numerous investigators have studied the underlying molecular mechanisms for malignant transformation. This has resulted in many models that explain the development of a malignant phenotype of human cells, for instance the "hallmarks of cancer" by Hanahan and Weinberg (3,4).With new technologies for deep sequencing, novel opportunities to study the underlying molecular events leading to cancers have emerged. A large number of investigations have analyzed mutations occurring in tumors, such as the analysis of mRNA expression, microRNA expression, and DNA copy number in a large number of tumors in the Cancer Genome Atlas (5). Similarly, the Human Protein Atlas project (6) studies human cancers using a proteome-wide collection of antibodies, resulting in publicly available immunohistochemistry images covering 20 different human cancer types.An interesting approach to studying the molecular mechanisms underlying cancer is to use an isogenically matched cell model in which normal cells are progressively transformed into malignant cells. There are several studies where genetic elements such as oncogenes have been introduced to different types of cells in an accumulative order as an attempt to mimic the natural steps of transformation (7,8). One such cell model is the fourstage model based on BJ fibroblasts developed by the Weinberg group, in which primary fibroblast cells were immortalized with telomerase reverse transcriptase (...

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“…However, we detected that ALDH1A1 protein mainly in the cytoplasm of precancerous and cancer cells of esophagus, consistent with reports on breast and ovarian tumors. 7,20 Our data showed that in the low-grade esophageal squamous dysplasia, ALDH1A1-positive cells were distributed in the basal layer of the mucosa, suggesting normal mucosal stem cells as one of the sources for cancer stem-like cells. 21 Further, ALDH1A1 expression was positively correlated with the UICC stages, invasion depth and lymph node metastasis of esophageal squamous cell carcinoma and was associated with shorter survival of the patients.…”

Section: Discussionmentioning

confidence: 71%

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

et al. 2014

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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

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ALDH1 expression correlates with favorable prognosis in ovarian cancers

Cited by 135 publications

References 35 publications

Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

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

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