CD44+CD24− prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis

Hurt, Elaine M.; Kawasaki, Brian T.; Klarmann, George J.; Thomas, Sabu; Farrar, William L.

doi:10.1038/sj.bjc.6604242

Cited by 383 publications

(375 citation statements)

References 25 publications

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“…These cancer-initiating cells have also been identified in the established androgen-dependent cell line LNCaP 43 and in androgen- independent prostate cancer cell lines DU145 43,44 and PC-3. 25,45 In this study, we showed that, in PC-3 cells, expression of CSC markers CD44 and CD133 was downregulated by c-T3 treatment (Fig.…”

Section: Discussionmentioning

confidence: 92%

Gamma‐tocotrienol as an effective agent in targeting prostate cancer stem cell‐like population

Luk

Yap²,

Chiu

et al. 2011

Intl Journal of Cancer

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Emerging evidence supports that prostate cancer originates from a rare subpopulation of cells, namely prostate cancer stem cells (CSCs). Conventional therapies for prostate cancer are believed to mainly target the majority of differentiated tumor cells but spare CSCs, which may account for the subsequent disease relapse after treatment. Therefore, successful elimination of CSCs may be an effective strategy to achieve complete remission from this disease. Gamma‐tocotrienols (γ‐T3) is one of the vitamin‐E constituents, which have been shown to have anticancer effects against a wide range of human cancers. Recently, we have reported that γ‐T3 treatment not only inhibits prostate cancer cell invasion but also sensitizes the cells to docetaxel‐induced apoptosis, suggesting that γ‐T3 may be an effective therapeutic agent against advanced stage prostate cancer. Here, we demonstrate for the first time that γ‐T3 can downregulate the expression of prostate CSC markers (CD133/CD44) in androgen‐independent prostate cancer cell lines (PC‐3 and DU145), as evident from Western blotting analysis. Meanwhile, the spheroid formation ability of the prostate cancer cells was significantly hampered by γ‐T3 treatment. In addition, pretreatment of PC‐3 cells with γ‐T3 was found to suppress tumor initiation ability of the cells. More importantly, although CD133‐enriched PC‐3 cells were highly resistant to docetaxel treatment, these cells were as sensitive to γ‐T3 treatment as the CD133‐depleted population. Our data suggest that γ‐T3 may be an effective agent in targeting prostate CSCs, which may account for its anticancer and chemosensitizing effects reported in previous studies.

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Section: Discussionmentioning

confidence: 92%

Gamma‐tocotrienol as an effective agent in targeting prostate cancer stem cell‐like population

Luk

Yap²,

Chiu

et al. 2011

Intl Journal of Cancer

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show abstract

“…Indeed, such CD44 þ CD24 À cells from prostate and breast cancer cells exhibited increased tumor-initiating capacity compared with their PC in severe combined immunodeficiency mice. [29][30][31][32][33] The sorted CD44 þ CD24 À cells are hereafter referred to as CSCs. Collectively, our data suggest that both CSCs and spheres exhibited diverse stem cell-associated characteristics, consistent with previous reports.…”

Section: Resultsmentioning

confidence: 99%

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Sastry

Al-Muftah

et al. 2014

Cell Death Differ

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Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies is one of the major limiting factors of cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated cancer cells and CSC. Here we demonstrated the potential role of proapoptotic protein BAD in the biology of CSC in melanoma, prostate and breast cancers. We enriched CD44 þ /CD24 À cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic, ABT-737. Both pharmacological agents that inhibit survival kinases and growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44 þ CSC of 83% breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in prostate cancer, suggesting a role of BAD in tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for cancer therapy but also as a marker of tumor progression.

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“…Indeed, previous evidence from our laboratory showed that EphA2 drives melanoma cells toward a conversion of their mesenchymal style to an amoeboid-like behavior, finally leading to a successful lung and lymph node peritoneal metastasis (16). Several reports have acknowledged the CD44 high /CD24 low ratio as a reliable indicator of stemness in prostate and breast carcinoma cells (32,33). In this light, we analyzed the expression of these two markers in EphA2-silenced PC3 cells.…”

Section: Epha2-silenced Prostate Cancer Cells Lose Their Ability To Imentioning

confidence: 95%

EphA2 Induces Metastatic Growth Regulating Amoeboid Motility and Clonogenic Potential in Prostate Carcinoma Cells

Taddei

Parri

Angelucci

et al. 2011

Molecular Cancer Research

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EphA2 kinase regulates cell shape, adhesion, and motility and is frequently overexpressed in several cancers, including melanoma, prostate, breast, and colon cancers and lung carcinoma. Although a function in both tumor onset and metastasis has been proposed, the role played by EphA2 in tumor progression is still debated. In melanoma, EphA2 has been reported to affect cell migration and invasiveness allowing cells to move by a proteolysis-independent strategy, commonly referred as amoeboid motility. With the aim to understand the role of EphA2 in prostate cancer metastatic spreading, we stably silenced EphA2 expression in a model of aggressive metastatic prostate carcinoma. Our results show that EphA2 drives the metastatic program of prostate carcinoma, although its involvement greatly differs among metastatic steps. Indeed, EphA2 expression (i) greatly affects prostate carcinoma cell motility style, guiding an amoeboid movement based on Rho-mediated cell rounding and independent from metalloprotases, (ii) is ineffective on transendothelial migration, adhesion onto extracellular matrix proteins, and on resistance to anoikis, (iii) regulates clonogenic potential of prostate carcinoma, thereby increasing anchorage-independent growth and self-renewal, prostasphere formation, tumor onset, dissemination to bone, and growth of metastatic colonies. Our finding indicate that EphA2-overexpressing prostate carcinoma cells gain an invasive benefit from their amoeboid motility style to escape from primary tumors and then, enhancing their clonogenic potential successfully target bone and grow metastases, thereby acknowledging EphA2 as a target for antimetastatic therapy of aggressive prostate cancers. Mol Cancer Res; 9(2); 149-60. Ó2011 AACR.

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CD44+CD24− prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis

Cited by 383 publications

References 25 publications

Gamma‐tocotrienol as an effective agent in targeting prostate cancer stem cell‐like population

Gamma‐tocotrienol as an effective agent in targeting prostate cancer stem cell‐like population

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

EphA2 Induces Metastatic Growth Regulating Amoeboid Motility and Clonogenic Potential in Prostate Carcinoma Cells

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