Developmental tumourigenesis: NCAM as a putative marker for the malignant renal stem/progenitor cell population

Pode‐Shakked, Naomi; Metsuyanim, Sally; Rom‐Gross, Eithan; Mor, Yoram; Fridman, Eduard; Goldstein, Itamar; Amariglio, Ninette; Rechavi, Gideon; Keshet, Gilmor I.; Dekel, Benjamin

doi:10.1111/j.1582-4934.2008.00607.x

Cited by 78 publications

(86 citation statements)

References 56 publications

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“…CSCs have been identified in many different types of solid tumors (32)(33)(34)(35)(36)(37). Recent evidence indicates that the Hh signaling pathway is recruited to stimulate CSC growth.…”

Section: Discussionmentioning

confidence: 99%

Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis

et al. 2012

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Abstract. Pancreatic cancer is one of the most aggressive and devastating malignancies. The Hedgehog (Hh) pathway has been reported to play an important role in pancreatic cancer development and progression. The aim of this study was to examine the activation of the Hh pathway in human pancreatic cancer tissue samples and pancreatic cancer cell lines, and the molecular mechanisms involved in the Hh pathway mediated effects on pancreatic cancer cell proliferation and invasion. The expression levels of Hh molecules in human pancreatic cancer tissue samples and pancreatic cancer cell lines were evaluated using RT-PCR. The role of the Hh pathway in cell proliferation and invasion was evaluated using flow cytometry, MTT, colony formation assays and Transwell invasion assays, and the expression of cancer stem cell markers and epithelial-mesenchymal transition (EMT) were evaluated using flow cytometry and RT-PCR. Tumorigenicity assays were used to further investigate the role of the Hh pathway in vivo. Hh molecules were highly expressed in human pancreatic cancer tissue samples and pancreatic cancer cell lines. Inhibition of the Hh pathway notably decreased cell proliferation and induced apoptosis through inhibition of the PI3K/AKT pathway and cancer stem cells. Furthermore, inhibition of the Hh signaling pathway significantly inhibited EMT by suppressing the activation of transcription factors Snail and Slug, which are correlated with significantly reduced pancreatic cancer cell invasion, suggesting that the Hh signaling pathway is involved in early metastasis. These results indicate that activation of the Hh pathway is a common event. Inhibition of the Hh pathway may be a potential molecular target of new therapeutic strategies for pancreatic cancer.

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“…CSCs have been identified in many different types of solid tumors (32)(33)(34)(35)(36)(37). Recent evidence indicates that the Hh signaling pathway is recruited to stimulate CSC growth.…”

Section: Discussionmentioning

confidence: 99%

Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis

et al. 2012

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“…Single tumorigenic WT cells could be robustly derived from these human WT xenografts and afforded the opportunity to perform in vitro and in vivo assays required to examine the CSC model in WT. Previous work aimed at deciphering the clonogenic and progenitor properties of primary WT cells in vitro suggested NCAM1 as a putative marker for WT CSCs [44]. The NCAM1+ cell population was shown to be highly clonogenic, over-expressing WT stemness and progenitor genes (e.g., WT1, SIX2, EZH2, BMI-1, FZD7, NANOG) and topoisomerase 2A (TOP2A), a WT bad prognostic marker.…”

Section: Cancer Stem Cells In Wilms' Tumorsmentioning

confidence: 99%

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

2013

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Wilms' tumor (WT), a common renal pediatric solid tumor, serves as a model for a malignancy formed by renal precursor cells that have failed to differentiate properly. Here we review recent evidence showing that the tumors' heterogeneous cell population contains a small fraction of cancer stem cells (CSC) identified by two markers: Neural Cell Adhesion Molecule 1 (NCAM1) expression and Aldehyde dehydrogenase 1 (ALDH1) enzymatic activity. In vivo studies show these CSCs to both self-renew and differentiate to give rise to all tumor components. Similar to other malignancies, the identification of a specific CSC fraction has allowed the examination of a novel targeted therapy, aimed at eradicating the CSC population. The loss of CSCs abolishes the tumor's ability to sustain and propagate, hence, causing tumor degradation with minimal damage to normal tissue.

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“…Immunohistochemical staining of WT As previously described (Dekel et al, 2006b;Pode-Shakked et al, 2008). See Supplementary Information.…”

Section: Facs Sortingmentioning

confidence: 99%

Resistance or sensitivity of Wilms’ tumor to anti-FZD7 antibody highlights the Wnt pathway as a possible therapeutic target

et al. 2011

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Wilms' tumor (WT), the most frequent renal solid tumor in children, has been linked to aberrant Wnt signaling. Herein, we demonstrate that different WTs can be grouped according to either sensitivity or resistance to an antibody (Ab) specific to frizzled7 (FZD7), a Wnt receptor. In the FZD7-sensitive WT phenotype, the Ab induced cell death of the FZD7 þ fraction, which in turn depleted primary WT cultures of their clonogenic and sphere-forming cells and decreased in vivo proliferation and survival on xenografting to the chick chorio-allantoic-membrane. In contrast, FZD7-resistant WT in which no cell death was induced showed a different intracellular route of the Ab-FZD7 complex compared with sensitive tumors and accumulation of b-catenin. This coincided with a low sFRP1 and DKK1 (Wnt inhibitors) expression pattern, restored epigenetically with de-methylating agents, and lack of b-catenin or WTX mutations. The addition of exogenous DKK1 and sFRP1 to the tumor cells enabled the sensitization of FZD7-resistant WT to the FZD7 Ab. Finally, although extremely difficult to achieve because of dynamic cellular localization of FZD7, sorting of FZD7 þ cells from resistant WT, showed them to be highly clonogenic/proliferative, overexpressing WT 'stemness' genes, emphasizing the importance of targeting this fraction. FZD7 Ab therapy alone or in combination with Wnt pathway antagonists may have a significant role in the treatment of WT via targeting of a tumor progenitor population.

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Developmental tumourigenesis: NCAM as a putative marker for the malignant renal stem/progenitor cell population

Cited by 78 publications

References 56 publications

Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis

Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

Resistance or sensitivity of Wilms’ tumor to anti-FZD7 antibody highlights the Wnt pathway as a possible therapeutic target

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