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

ABSTRACT 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.

1 Follower
31 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "It is plausible to assume the presence of diff erent subsets of CSC with divergent mutations/genomic alterations within tumors, since heterogeneous tumors consist of unstable genomes. Upon chemo-or radiotherapy, the CSC clones with the advantageous genomic alterations to protect against therapy would be selected for and continue to sustain the tumor (Diehn et al. 2009a). Th us, radiation may selectively kill the relatively radiosensitive tumor cell populations leaving the therapy-resistant CSC alive, thus contributing to adaptive radio-resistance via the selective repopulation from the surviving CSC. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Radiation therapy has made significant contributions to cancer treatment. However, despite continuous improvements, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be attributable to the presence of cancer stem cells (CSC). The purpose of this review is to discuss CSC-specific mechanisms that confer radiation resistance. Conclusions: We focus our discussions on breast cancer and glioblastoma multiforme (GBM) and conclude that both CSC-intrinsic and CSC-extrinsic factors as well as adaptive responses in CSC caused by irradiation and microenvironmental changes all make contributions to CSC-mediated radioresistance. Our discussions emphasize CSC as novel therapeutic targets in order to potentiate radiotherapy efficacy.
    International Journal of Radiation Biology 02/2014; 90(8). DOI:10.3109/09553002.2014.892227 · 1.69 Impact Factor
Show more


31 Reads
Available from