The actual function of CD133 is just emerging, and until recently, an implication in the determination of haematopoietic stem cells (HSCs) and neuroepithelial progenitors was the only known role [
17]. Most recent publications reported on the association of CD133 with Src kinase [
18], which is instrumental in tumour initiation and during transition from an epithelial to a mesenchymal phenotype (EMT) [
11]. In the present study, we demonstrate a potential for CD133 to induce a tumour-initiating phenotype in cells endowed with very low tumourigenicity. Tumour seeding frequency in CD133
high HEK293 cells was leastwise 1,000-fold higher than in CD133
low counterparts, although the cellular and morphologic features of these cells were indistinguishable in vitro. Especially, no traits of EMT were observed in these cells, including unchanged expression levels of typical EMT markers such as vimentin, N-cadherin, or smooth muscle actin (data not shown). This lack of difference between CD133
high and CD133
low cells in vitro is perfectly in accordance with previous reports on the knock-down of CD133 in colon carcinoma CaCo-2 cells, which was likewise without any measurable outcome in vitro [
19,
20]. From their results, Horst et al. [
19,
20] deduced a lack of function for CD133 in the regulation or induction of a TIC phenotype in vitro. The impact of CD133 on the tumour seeding capacity however suggests that it is important for the survival and/or regulation of tumour-seeding cells in the in vivo context. For example, anchorage-independent growth and/or communication with the microenvironment could account for differences between results from in vitro and in vivo studies. An involvement of CD133 in the cell-to-cell communication of HSCs and mesenchymal stem cells (MSCs) has been reported [
21]. Migratory HSCs display a polarised localisation of CD133 at a rear part of the cell, a structure termed uropod, which is uplifted and does not contact the layer of MSCs beneath. Upon contact of the uropod with MSCs, HSCs become more sessile and cease migration [
21]. Potential ligands of CD133 on MSCs or other cell types of the microenvironment have as yet not been explored, although they appear of great interest for the understanding of CD133's role in the communication of stem cells with their niche. Similar to HSCs, CD133 might serve tumourigenic cells as a means of contact and communication with the microenvironment in vivo, thus providing them with the capacity to interact and engraft. Accordingly, CD133
+/CD24
+ marked clonogenic TICs derived from single colon carcinoma cells in spheroid cultures or limiting dilutions [
22]. CD133
+/CD24
+ cells possessed a multilineage differentiation potential, both in vitro and in vivo, while CD133
− cells did not. Interestingly, stromal cells in tumours generated upon xenotransplantation of CD133
+/CD24
+ cells were derived from the host and did not originate from CD133
+/CD24
+ tumour cells, hence indicating that CD133 might also be required for the proper communication of tumour cells and cells of the host's microenvironment [
22].
In summary, CD133 has the potential to induce a tumour-initiating phenotype in low tumourigenic HEK293 cells in vivo. Since these results are descriptive only, future research will aim at the elucidation of molecular mechanisms of CD133-induced tumourigenicity, its putative role in the formation of metastases, which could be linked to interactions with Src kinase, and potentially pinpoint novel therapeutic intervention options.