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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    • "Nevertheless, our findings do not differentiate the function of FZD7 on tumor initiation from its function on cell proliferation in the bulk of metastases during metastatic growth. This is distinct from conventional view on cancer stem cells, in which tumor initiation is a separate entity from cell proliferation in the bulk of tumor[45]. It is possible that the tumor initiation of melanoma stem cells and the proliferation potential in the bulk of melanomas are regulated by shared mechanisms, which might explain the prevalence of stem cells observed in melanoma[8]. "
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    ABSTRACT: Metastases are thought to arise from cancer stem cells and their tumor initiating abilities are required for the establishment of metastases. Nevertheless, in metastatic melanoma, the nature of cancer stem cells is under debate and their contribution to metastasis formation remains unknown. Using an experimental metastasis model, we discovered that high levels of the WNT receptor, FZD7, correlated with enhanced metastatic potentials of melanoma cell lines. Knocking down of FZD7 in a panel of four melanoma cell lines led to a significant reduction in lung metastases in animal models, arguing that FZD7 plays a causal role during metastasis formation. Notably, limiting dilution analyses revealed that FZD7 is essential for the tumor initiation of melanoma cells and FZD7 knockdown impeded the early expansion of metastatic melanoma cells shortly after seeding, in accordance with the view that tumor initiating ability of cancer cells is required for metastasis formation. FZD7 activated JNK in melanoma cell lines in vitro and the expression of a dominant negative JNK suppressed metastasis formation in vivo, suggesting that FZD7 may promote metastatic growth of melanoma cells via activation of JNK. Taken together, our findings uncovered a signaling pathway that regulates the tumor initiation of melanoma cells and contributes to metastasis formation in melanoma.
    Full-text · Article · Jan 2016 · PLoS ONE
    • "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.
    No preview · Article · Mar 2015 · Life sciences
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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.
    Full-text · Article · Feb 2014 · EMBO Molecular Medicine
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