Safely targeting cancer stem cells via selective catenin coactivator antagonism - PubMed (original) (raw)

Review

. 2014 Sep;105(9):1087-92.

doi: 10.1111/cas.12471. Epub 2014 Sep 6.

Affiliations

Review

Safely targeting cancer stem cells via selective catenin coactivator antagonism

Heinz-Josef Lenz et al. Cancer Sci. 2014 Sep.

Abstract

Throughout our life, long-lived somatic stem cells (SSC) regenerate adult tissues both during homeostatic processes and repair after injury. The role of aberrant regulation of SSC has also recently gained prominence in the field of cancer research. Following malignant transformation, so termed cancer stem cells (CSC), endowed with the same properties as SSC (i.e. the ability to both self-renew and generate differentiated progenitors), play a major part in tumor initiation, therapy resistance and ultimately relapse. The same signaling pathways involved in regulating SSC maintenance are involved in the regulation of CSC. CSC exist in a wide array of tumor types, including leukemias, and brain, breast, prostate and colon tumors. Consequently, one of the key goals in cancer research over the past decade has been to develop therapeutic strategies to safely eliminate the CSC population without damaging the endogenous SSC population. A major hurdle to this goal lies in the identification of the key mechanisms that distinguish CSC from the normal endogenous tissue stem cells. This review will discuss the discovery of the specific CBP/catenin antagonist ICG-001 and the ongoing clinical development of the second generation CBP/catenin antagonist PRI-724. Importantly, specific CBP/catenin antagonists appear to have the ability to safely eliminate CSC by taking advantage of an intrinsic differential preference in the way SSC and CSC divide.

Keywords: Asymmetric; CREB-binding protein; Wnt/catenin; p300; symmetric.

© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

PubMed Disclaimer

Figures

Fig 1

Fig 1

Cancer stem cells both self-renew and undergo differentiative divisions to maintain or expand the cancer stem cell population or generate transient amplifying cells that go on to rapidly divide to form the bulk of the tumor.

Fig 2

Fig 2

The ultimate decision for a cell to retain potency or initiate differentiation is dependent upon numerous inputs from various signaling pathways (e.g. JAK/STAT, Wnt, Growth Factors, Hippo, Notch and Hedgehog) that also play critical roles during development. In the end, those multiple pathways must be integrated and funneled down into a simple decision point. β-catenin plays a central role in integrating these signals.

Fig 3

Fig 3

Chemical structure of the CBP/catenin antagonist ICG-001.

Fig 4

Fig 4

Wnt signaling is a complex pathway, believed to be involved in the regulation of divergent processes, including the maintenance of pluripotency and commitment to differentiation. We developed a model in which β-catenin/CBP-mediated transcription is critical for the maintenance of potency, whereas β-catenin/p300-mediated transcription is the first critical step to initiate differentiation. Hence, the balance between CBP and p300-mediated β-catenin transcription regulates the balance between maintenance of potency, and the initiation of commitment to differentiate in stem and progenitor cells.

Fig 5

Fig 5

Model depicting symmetric and asymmetric modes of division. The intrinsic difference between normal somatic stem cells (SSC) and cancer stem cells (CSC) is that normal SSC favor asymmetric division whereas CSC favor symmetric divisions. Treatment of CSC with CBP/catenin antagonists causes CSC to undergo symmetric differentiative divisions, thereby eventually clearing CSC from the niche. In sharp contrast, SSC undergo asymmetric divisions when treated with CBP/catenin antagonists.

Similar articles

Cited by

References

    1. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11. - PubMed
    1. Singh SR. Stem cell niche in tissue homeostasis, aging and cancer. Curr Med Chem. 2012;19:5965–74. - PubMed
    1. Miki T, Yasuda SY, Kahn M. “Wnt/Β-catenin signaling in embryonic stem cell self-renewal and somatic cell reprogramming. Stem Cell Rev. 2011;7:836–46. - PubMed
    1. Takahashi-Yanaga F, Kahn M. Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res. 2010;16:3153–62. - PubMed
    1. Merchant AA, Matsui W. Targeting hedgehog – a cancer stem cell pathway. Clin Cancer Res. 2010;16:3130–40. - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources