ABSTRACT
The Cancer Stem Cell (CSC) hypothesis, which postulates that cancer is hierarchically organized like normal tissues, namely comprising of a small number of (cancer) stem cells and bulk of tumor/differentiated cells, threw new light on the subject: which cancer cells will be the initiators or be the cause of tumor recurrences (Clarke et al. 2006, Clarke and Fuller 2006, Dittmar et al. 2009, Li et al. 2007, Nagler et al. 2011b, Wicha et al. 2006). CSCs have been referred to as cancer cells exhibiting stem cell properties, such as the capability to self-renew and to differentiate into a diversity of various cell types, thereby maintaining (and even restoring) organ tissue homeostasis (Clarke et al. 2006, Clarke and Fuller 2006, Dittmar et al. 2009, Li et al. 2007, Nagler et al. 2011b, Wicha et al. 2006). Due to their ability to initiate tumor growth it is now commonly believed that tumors arise from a single CSC or a CSC pool (Clarke et al. 2006, Clarke and Fuller 2006, Dittmar et al. 2009, Li et al. 2007, Nagler et al. 2011b, Wicha et al. 2006). Moreover,
Center for Biomedical Education and Research, Institute of Immunology, Witten/Herdecke University, Stockumer Str. 10. aE-mail: thomas.dittmar@uni-wh.de bE-mail: bernd.niggemann@uni-wh.de cE-mail: kurt.zänker@uni-wh.de dE-mail: thomas.dittmar@uni-wh.de *Corresponding author
since as per defi nition only this particular cell type/population exhibits tumor-initiation capacity, CSCs have also been suggested to be the seeds of metastases (Charafe-Jauffret et al. 2009, Croker et al. 2008, Hermann et al. 2007, Kucia et al. 2005, Li et al. 2007). In fact, specifi c metastatic CSCs (mCSCs (Li et al. 2007)) have already been identifi ed in pancreatic cancer (Hermann et al. 2007) and breast cancer (Charafe-Jauffret et al. 2009). Thereby, the traffi cking of normal stem cells and metastasis of CSCs most likely involve similar mechanisms, including the pivotal SDF-1α/CXCR4 axis (Kucia et al. 2005), which act as a navigation system for circulating tumor (stem) cells in order to metastasize in organ-specifi c manner (Dittmar et al. 2008). In fact, pancreatic mCSCs have been demonstrated to be CXCR4 positive, whereas primary tumor pancreatic CSC lack the expression of the SDF-1α receptor concomitant with the absence of metastatic spreading capacity (Hermann et al. 2007). An analysis of 33 breast cancer cell lines showed that nearly two-third of them contained an ALDEFLOUR positive population that displayed stem cell characteristics in vitro and in NOD/SCID xenografts (Charafe-Jauffret et al. 2009). Moreover, animal studies provided evidence that only the ALDEFLOUR positive cells were responsible for mediating metastasis (Charafe-Jauffret et al. 2009) indicating the crucial role of CSCs in inducing secondary tumors. However, the authors did not investigate whether metastasizing ALDEFLOUR positive cells were CXCR4 positive.
