The hunt for elusive cancer stem cells

The efficacy of cancer therapeutics remains limited because tumors comprise heterogeneous cell populations, with distinct phenotypic and functional properties. Among those, cancer stem cells (CSCs) represent a small cell subpopulation with self-renewal, differentiation and tumor initiation capacity and have been linked to treatment failure. Unlike differentiated cells, CSCs evade the cytotoxic effects of chemotherapy and radiation contributing to the development of recurrent tumors, which are more aggressive and unresponsive to treatment. The underlying biochemical events that allow this cell population to persist are not fully understood. In this manuscript, Sullivan et al. describe the functions of tissue transglutaminase (TG2) as a survival factor and potential target in mesenchymal glioma stem cells [1]. TG2 belongs to a family of structurally and functionally related proteins that catalyze calciumdependent transamidation between glutamine residues of a donor protein and primary amino groups of another acceptor protein or polyamine. In addition to catalyzing epsilon-(gamma-glutamyl)lysine isopeptide bonds, TG2 also binds and hydrolyzes guanosine 5’-triphosphate (GTP), acting as GTP-ase linking cell surface receptors to intracellular effectors. Ca2+ and GTP levels finely regulate the two functions of the protein; the crosslinking activity being allosterically activated by high Ca2+ concentrations, and inhibited by high intra-cellular GTP levels [2]. Aberrant TG2 expression was correlated with several pathological conditions, including cancer, and new evidence links TG2 to the CSC phenotype. Cao et al. demonstrated that the transforming growth factor (TGF)-β, a cytokine abundantly secreted in the ovarian cancer microenvironment, activates NF-κB, upregulating TG2 and promoting the formation of cancer cell spheroids [3]. TG2 expression was increased in ovarian CSCs derived from human tumors and defined by co-expression of CD44+ and CD117+ [3]. TG2 upregulation was also recorded in the highly tumorigenic subpopulation of CD44+/CD24breast CSCs [4], contributing to selfrenewal, chemo-resistance and mammosphere-forming capacity and in epidermal CSCs (ECSC) where it promoted sphere formation and tumorigenicity [5]. Here, Sullivan and colleagues describe a new connection between the CSC-marker ALDH and TG2 expression in glioma stem cells (GSCs) [1]. TG2 was found to be robustly expressed in mesenchymal compared to proneural GSCs. Two potent TG2 inhibitors monodansylcadaverine (MDC), a TG2 substrate and News