Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells

Dontu, Gabriela; Jackson, Kyle W.; McNicholas, Erin; Kawamura, Marenori; Abdallah, Wissam M.; Wicha, Max S.

doi:10.1186/bcr920

Cited by 699 publications

(620 citation statements)

References 40 publications

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“…Several studies have also identified Notch1 and ALDH1 as markers in both normal and malignant stem and progenitor cells (Dontu et al, 2004;Matsui et al, 2004;Ginestier et al, 2007). Yang et al (2008) first suggested CD90 to be a potential marker for liver CSCs.…”

Section: Discussionmentioning

confidence: 99%

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

et al. 2011

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Identification and characterization of cancer stem cells (CSCs) in gastric cancer are difficult owing to the lack of specific markers and consensus methods. In this study, we show that cells with the CD90 surface marker in gastric tumors could be enriched under non-adherent, serumfree and sphere-forming conditions. These CD90 þ cells possess a higher ability to initiate tumor in vivo and could re-establish the cellular hierarchy of tumors from singlecell implantation, demonstrating their self-renewal properties. Interestingly, higher proportion of CD90 þ cells correlates with higher in vivo tumorigenicity of gastric primary tumor models. In addition, it was found that ERBB2 was overexpressed in about 25% of the gastric primary tumor models, which correlates with the higher level of CD90 expression in these tumors. Trastuzumab (humanized anti-ERBB2 antibody) treatment of hightumorigenic gastric primary tumor models could reduce the CD90 þ population in tumor mass and suppress tumor growth when combined with traditional chemotherapy. Moreover, tumorigenicity of tumor cells could also be suppressed when trastuzumab treatment starts at the same time as cell implantation. Therefore, we have identified a CSC population in gastric primary tumors characterized by their CD90 phenotype. The finding that trastuzumab targets the CSC population in gastric tumors suggests that ERBB2 signaling has a role in maintaining CSC populations, thus contributing to carcinogenesis and tumor invasion. In conclusion, the results from this study provide new insights into the gastric tumorigenic process and offer potential implications for the development of anticancer drugs as well as therapeutic treatment of gastric cancers.

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Section: Discussionmentioning

confidence: 99%

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

et al. 2011

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“…Hey1 transcripts were reduced by about sixfold in two independent tumors of mice that were administered MRK-003 compared with tumors from the vehicletreated mice suggesting that MRK-003 attenuated Notch signaling in tumor-resident cells (Figure 5c). mammosphere-forming cells, but the reversibility of these inhibitors was not addressed in a previous study (Dontu et al, 2004).…”

Section: Mrk-003 Shrinks and Eliminates Tumors In Micementioning

confidence: 98%

“…Although the nature of the cells that form spheres is not known, mouse mammosphere-and tumorsphereforming cells co-fractionate with mammary epithelial stem cells (Liao et al, 2007;Cicalese et al, 2009) and mammary TIC (Liu et al, 2007), respectively. Moreover, agents that affect the frequency of sphere-forming cells correspondingly alter the frequency of mammary epithelial stem cells and TIC suggesting that these cells initiate sphere-formation (Dontu et al, 2003(Dontu et al, , 2004Liao et al, 2007;Mani et al, 2008;Cicalese et al, 2009).…”

Section: Differential Expression Of Notch Pathway-related Genesmentioning

confidence: 99%

Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer

et al. 2011

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“…The formation of mammospheres, threedimensional clusters of cells which can self-renew and grow in an anchorage-independent manner, is thought to represent another hallmark of TICs. Studies by Dontu et al [10][11][12] showed that normal mammary stem cells undergo primarily asymmetric self-renewal to form mammospheres, whereas the differentiated cells undergo apoptosis. Malignant TICs behave similarly, though with an even higher propensity for symmetric self-renewal.…”

Section: The Tumor-initiating Cell (Tic) Hypothesismentioning

confidence: 99%

Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

Creighton

Chang‐Claude

Rosen

2010

J Mammary Gland Biol Neoplasia

232

192

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There is increasing support for the hypothesis that most tumors contain a subpopulation of cells, referred to here as tumor initiating cells (TICs), with the ability to self-renew and to regenerate all the cell types within the tumor. TICs are enriched in breast cancer patients after common treatments, indicating their intrinsic therapeutic resistance. Two independently-derived gene transcription "signatures" of TICs from different studies indicate enrichment of TICs within the recently-identified "claudin-low" intrinsic molecular subtype of breast cancer. These are characterized by high expression of markers associated with epithelial-mesenchymal transition (EMT), suggesting that claudin-low cells may arise from more immature stem or progenitor cells than other breast cancers. EMT is a process by which cells acquire molecular alterations that facilitate dysfunctional cell-cell adhesive interactions and junctions, as well as a more spindle-shaped morphology. These processes may promote cancer cell progression and invasion into the surrounding microenvironment. Induction of EMT in immortalized human mammary epithelial cells results in an increased ability to form mammospheres, and in the expression of stem cell and TIC markers, suggesting that there may be a direct link between the EMT and the gain of TIC properties. Targeting specific molecular pathways-such as Notch, Wnt, and TGFß-associated with development and EMT in the TIC subpopulation, in addition to conventional chemo-and radiation therapies that target the bulk tumor, may ultimately provide a more effective strategy in treating breast cancer. Here, we review recent evidence of the involvement of EMT in breast cancer TICs, focusing on clinical studies.

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Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells

Cited by 699 publications

References 40 publications

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer

Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

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