Abstract
Cancers are heterogeneous at the cellular level. Cancer stem cells/tumor initiating cells (CSC/TIC) both initiate tumorigenesis and are responsible for therapeutic resistance and disease relapse. Elimination of CSC/TIC should therefore be able to reverse therapy resistance. In principle, this could be accomplished by either targeting cancer stem cell surface markers or “stemness” pathways. Although the successful therapeutic elimination of “cancer stemness” is a critical goal, it is complex in that it should be achieved without depletion of or increases in somatic mutations in normal tissue stem cell populations. In this perspective, we will discuss the prospects for this goal via pharmacologically targeting differential Kat3 coactivator/Catenin usage, a fundamental transcriptional control mechanism in stem cell biology.
Highlights
Cancer is a major contributor to worldwide mortality[1]
We subsequently found that selectively blocking the CREB-binding protein (CBP)/catenin interaction with ICG001, with an increase in p300/catenin-mediated transcription leads to the initiation of differentiation in stem and progenitor cells including ES, iPS, spermatogonial stem cell (SSC) and CSC [Figure 3A][104,105,106,107,108]
The fundamental difference between SSC and CSC appears to be a preference for asymmetric over symmetric divisions respectively
Summary
Cancer is a major contributor to worldwide mortality[1]. There are minimally four broad resistance-inducing strategies that are employed by cancer cells including: (1) direct target reactivation; (2) activation of signals upstream or downstream of oncogenes; (3) engagement of parallel oncogenic pathways; and (4) adaptive survival mechanisms. A critical goal to change the course of cancer therapy is to develop strategies to safely eliminate CSC without deleterious effects to normal spermatogonial stem cell (SSC) populations. The question is: can we safely manipulate endogenous stem cell populations by taking advantage of their preferred modes of division to differentiate away the CSC population without eliminating normal SSCs?
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