ABSTRACT
Most human cancers are organized as a cellular hierarchy initiated and sustained by a self-renewing cell population of cancer stem cells that give rise to the full repertoire of cells composing the tumor and are responsible for their continuous growth and propagation (Reya et al. 2001, Pardal et al. 2003, Scadden 2004, Clarke and Fuller 2006, Polyak and Hahn 2006, Visvader 2011, Nguyen et al. 2012). Although the cancer stem cell (CSC) concept was postulated in early reports (Bruce and Van Der Gaag 1963, Park et al. 1971, Hamburger and Salmon 1977, Sabbath et al. 1985), defi nite proof of their existence was shown in leukemias, where cells with a CD34+CD38phenotype could initiate, regenerate and maintain the tumor entirely after transplantation into immunocompromised mice (Lapidot et al. 1994, Blair et al. 1997, Bonnet and Dick 1997). A number of phenotypically and functionally different CSCs have been subsequently identifi ed in epithelial cancers, including among others breast, head and neck, and prostate carcinomas, some of which can be detected by expressing the cell-surface glycoprotein CD44 (Al-Hajj et al. 2003, Al-Hajj and Clarke 2004, Collins et al. 2005, Li et al. 2007, Prince et al. 2007, Stingl and Caldas 2007, Hermann et
Division of Oncology, Center for Applied Medical Research, University of Navarra, Avda. Pio XII, 55, 31008 Pamplona, Spain. E-mail: jamcliment@unav.es
al. 2010). Notably, a CD44+ cell-specifi c gene expression signature containing a large number of stem-cell genes predicted the outcome of patients with breast cancer (Liu et al. 2007, Shipitsin et al. 2007). The CD133 glycoprotein is another cell surface marker expressed by neural and hematopoietic stem cells that defi nes the CSCs of brain, liver and colon carcinomas (Singh et al. 2004, Ma et al. 2007, O’Brien et al. 2007, Ricci-Vitiani et al. 2007, Hermann et al. 2010). Remarkably, glioblastoma CD133+ CSCs were more resistant to chemo and radiotherapy than the CD133 – cell population (Bao et al. 2006). Indeed, current therapies that successfully target the differentiated cancer cells may be ineffective against the CSCs, suggesting that novel drugs aiming to eliminate this cell population are required (Martinez-Climent et al. 2006, Zhang and Rosen 2006, Apperley 2007, Hermann et al. 2010, Visvader 2011, Nguyen et al. 2012). Thus, the CSC concept is not only changing our current understanding of cancer biology but is also having a hearing on cancer therapeutics.
