Therapeutic Implications of the Cancer Stem Cell Hypothesis

Department of Radiation Oncology, Stanford University, School of Medicine, Stanford, CA, USA.
Seminars in radiation oncology (Impact Factor: 4.03). 05/2009; 19(2):78-86. DOI: 10.1016/j.semradonc.2008.11.002
Source: PubMed


A growing body of evidence indicates that subpopulations of cancer stem cells (CSCs) drive and maintain many types of human malignancies. These findings have important implications for the development and evaluation of oncologic therapies and present opportunities for potential gains in patient outcome. The existence of CSCs mandates careful analysis and comparison of normal tissue stem cells and CSCs to identify differences between the two cell types. The development of CSC-targeted treatments will face a number of potential hurdles, including normal stem cell toxicity and the acquisition of treatment resistance, which must be considered in order to maximize the chance that such therapies will be successful.

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    • "This scenario remained unchanged over the last decades, underlying the need for novel therapeutic strategies. The hypothesis that tumors are sustained by cells with stem-like properties, so-called cancer stem cells (CSCs) is changing the paradigm in cancer treatment, since they represent a minority of cells with distinct properties from those constituting the bulk of the tumor and are associated with metastasis, radio/chemo-resistance and poor clinical outcome [5] [6]. "
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    ABSTRACT: Aims: Osteosarcoma is the most common pediatric bone malignancy with high propensity to metastasize and relapse. Emerging evidence suggest that osteosarcoma is sustained by a subset of self-renewing cancer stem like cells (CSCs) relying on mechanisms to evade apoptosis and survive in response to drugs-induced DNA damage. We proposed to decipher the mechanisms underlying the resistance of CSCs to doxorubicin-induced apoptosis. Main methods: CSCs were isolated using a sphere-forming assay and tested for sensitivity to doxorubicin-induced apoptosis, using MTT cell viability and BrdU proliferation assays, TUNEL staining and caspases 3/7 activity. Bcl-2 family proteins were analyzed by Western blot. Doxorubicin uptake was determined by confocal microscopy and bioluminescence imaging. Key findings: We showed that osteosarcoma sphere stem-like cells expressed the multidrug-related efflux transporters P-glycoprotein and BCRP and are highly resistant to doxorubicin-induced apoptosis. Conversely after exposure to doxorubicin, these cells displayed an up-regulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL with concomitant down-regulation of Bak and decreased caspase 3/7 activity. Inhibition of drug efflux transporters enhanced the cellular uptake of doxorubicin, being encompassed by an up-regulation the pro-apoptotic protein Bak and suppression of Bcl-2, favoring the commitment of CSCs towards apoptosis. Significance: These results seemingly suggest that the high apoptotic threshold of CSCs to doxorubicin-induced cell dead stimuli is mainly dependent on the drug concentration reaching tumor cells that are governed by efflux transporter activity. Therefore, modulation of these transporters may be effective in potentiating the proapoptotic effects of doxorubicin, and emerges as an attractive strategy to sensitize osteosarcoma CSCs to chemotherapy.
    Life sciences 03/2015; 130. DOI:10.1016/j.lfs.2015.03.009 · 2.70 Impact Factor
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    • "The potential mechanisms underlying this resistance to endocrine therapy involve ER‐coregulatory proteins and cross‐ talk between the ER pathway and other growth‐factor signalling networks (Osborne et al, 2005). A growing body of evidence is accumulating supporting the hypothesis that cancer stem cells, or tumour‐initiating cells, drive and maintain many types of human malignancies (Diehn et al, 2009). The cancer stem cell hypothesis has shed new light on the development of resistance to therapy, proposing that there exists a pool of malignant cells with stem/progenitor cell properties and increased capacity to resist common chemotherapeutic treatments , compared to their more differentiated non‐tumourigenic counterparts, and therefore responsible for tumour recurrence after treatment (Reya et al, 2001). "
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    ABSTRACT: Development of resistance to therapy continues to be a serious clinical problem in breast cancer management. Cancer stem/progenitor cells have been shown to play roles in resistance to chemo- and radiotherapy. Here, we examined their role in the development of resistance to the oestrogen receptor antagonist tamoxifen. Tamoxifen-resistant cells were enriched for stem/progenitors and expressed high levels of the stem cell marker Sox2. Silencing of the SOX2 gene reduced the size of the stem/progenitor cell population and restored sensitivity to tamoxifen. Conversely, ectopic expression of Sox2 reduced tamoxifen sensitivity in vitro and in vivo. Gene expression profiling revealed activation of the Wnt signalling pathway in Sox2-expressing cells, and inhibition of Wnt signalling sensitized resistant cells to tamoxifen. Examination of patient tumours indicated that Sox2 levels are higher in patients after endocrine therapy failure, and also in the primary tumours of these patients, compared to those of responders. Together, these results suggest that development of tamoxifen resistance is driven by Sox2-dependent activation of Wnt signalling in cancer stem/progenitor cells.
    EMBO Molecular Medicine 02/2014; 6(1). DOI:10.1002/emmm.201303411 · 8.67 Impact Factor
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    • "These naïve side populations are capable of differentiating into a variety of cancer cell phenotypes and recapitulating the tumor heterogeneity in animal models (19–21). In general, naïve cancer cells are marked with stem cell markers such as CD133 and are more resistant to radiation and chemotherapy than other cancer cell populations (22,23). "
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    ABSTRACT: Id1 and NF-κB are highly expressed in oral squamous cell carcinoma (OSCC). Whether they have a synergistic role in the carcinogenesis of OSCC is unclear. The current study was designed to demonstrate the synergy of both Id1 and NF-κB in the underlying disease mechanisms of OSCC using in vitro and in vivo animal models. Id1 and NF-κB strengthened the expression of both CD133 and BMI-1 in OSCC cell cultures. CD133+ and BMI-1+ keratinocytes from OSCC tissues and cell cultures initiated the growth of xenograft tumors in SCID/Beige mice. Id1 and NF-κB regulate the expression of CD133 and BMI-1 in an additive or synergistic manner in OSCC, which is associated with the generation of naïve and self-renewable keratinocytes and initiate the growth of xenograft tumors in vivo.
    International Journal of Oncology 02/2014; 44(5). DOI:10.3892/ijo.2014.2309 · 3.03 Impact Factor
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