ABSTRACT
Major advances in stem cell biology have revealed that the accumulation of genetic and/or epigenetic alterations in tissue-resident adult stem/ progenitor cells or their early progenies endowed with a high self-renewal capacity may result in their malignant transformation into cancer stem/ progenitor cells also designated as cancer-or tumor-initiating cells (Beachy et al. 2004, Liu et al. 2005, Kim et al. 2005, Rizo et al. 2006, Li and Neaves 2006, Vaish 2007, Nijhof et al. 2007, Shiras et al. 2007, Mimeault et al. 2007b, Gumucio et al. 2008, Mimeault and Batra 2010b, Sugiarto et al. 2011, Mimeault and Batra 2011b, Mimeault et al. 2012). Moreover, it has been shown that cancer progression is generally associated with the occurrence of distinct molecular events in cancer stem/progenitor cells and their progenies that may contribute to their acquisition of a more malignant
Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5870, USA. aE-mail: mmimeault@unmc.edu bE-mail: sbatra@unmc.edu *Corresponding authors
behavior. Typically, the inactivation of different tumor suppressor gene products combined with a stimulation of diverse oncogenic cascades initiated by different growth factors are involved in the progression of cancer to locally invasive and metastatic disease states (Beachy et al. 2004, Bell and Van Zant 2004, Larue and Bellacosa 2005, Li and Neaves 2006, Liu et al. 2006b, Nicolis 2007, Sengupta et al. 2007, Chen et al. 2007, Clement et al. 2007, Wang et al. 2007a, Marusyk and DeGregori 2008, Mimeault and Batra 2009, Mimeault and Batra 2010b, Motohara et al. 2011, Mimeault and Batra 2011b, Mimeault and Batra 2012). More specifi cally, the acquisition of a migratory phenotype by highly tumorigenic cancer stem/progenitor cells during epithelial-mesenchymal transition (EMT) process may lead to their invasion, dissemination and metastases at distant tissues or organs (Thiery 2002, Gotzmann et al. 2004, Derycke and Bracke 2004, Larue and Bellacosa 2005, Brabletz et al. 2005, Kuphal et al. 2005, Tso et al. 2006, Onoue et al. 2006, Mimeault and Batra 2007b, Mimeault et al. 2007b, Mani et al. 2008, Kabashima et al. 2009, Kurrey et al. 2009, Mimeault and Batra 2010b, Bao et al. 2011, Cao et al. 2011, Gulhati et al. 2011, Mimeault and Batra 2011b, Mimeault et al. 2012, Lamouille et al. 2012, Rhim et al. 2012, Zhang et al. 2012, Wang et al. 2012a). Additionally, the changes in the local microenvironment of cancer stem/progenitor cells, including in hypoxic zones and the release of soluble factors by host activated stromal cells at primary and secondary neoplasms, may also promote tumor growth (Lyden et al. 2001, Neiva et al. 2005, Li and Neaves 2006, Mimeault and Batra 2007b, Mimeault et al. 2007b, Olivotto and Dello 2008, Das et al. 2008, Gerlee and Anderson 2008, Mohyeldin et al. 2010, Box et al. 2010, Kuphal et al. 2010, Mimeault and Batra 2010b, Mathieu et al. 2011, Ma et al. 2011, Persano et al. 2011, Hashimoto et al. 2011, Shiozawa et al. 2011b, Mimeault and Batra 2011b, Mimeault et al. 2012).
