CD133: to be or not to be, is this the real question?

Abstract

CD133 (promini-1) is a member of the transmembrane glycoprotein family, was initially described as a specific marker to select human hematopoietic progenitor cells. Then, it was recognised as important marker to identify and isolate the specific cell subpopulation termed "cancer stem cells". Many studies showed that CD133(+) cells have stemness properties such as self-renewal, differentiation ability, high proliferation and they are able also to form tumours in xenografts. Moreover it has been demonstrated that CD133(+) cells more resistant to radiation and standard chemotherapy than CD133(-) cells. Although this, others investigations demonstrated that also CD133(-) cells can show the same characteristics of those positive for CD133(+). Hence, some inconsistencies among published data on CD133 function can be ascribed to different causes questioning the main role as specific marker of cancer stem cells. In fact, many authors indicate that CD133 is expressed both in differentiated and undifferentiated cells, and CD133(-) cancer cells can also initiate tumours. Indeed, it is still a matter of debate whether CD133(+) cells truly represent the ultimate tumourigenic population. However, the belief that CD133 may act as a universal marker of CSCs has been met with a high degree of controversy in the research community. In this review there is an attempt to highlight: i) the role and function of CD133, with an overview on the current stage of knowledge about this molecule, ii) the difficulty often encountered in its identification iii) the utility of CD133 expression as a prognostic marker.

Keywords: Prominin-1 (CD133); cancer stem cells; circulating tumor cells; epigenetic regulation; epithelial-mesenchymal transition; glycosylation.

Figure 1

Schematic representation of transmembrane glycoprotein, CD133. A structure model of CD133 proposed by Miraglia et al. This protein has an extracellular N-terminus, a cytoplasmic C-terminus, 2 small cysteine rich cytoplasmic loops and 2 very large extracellular loops each containing 4 potential sites for N-linked glycosylation.

Figure 2

A model of the origin of the cancer stem cells. Mutations in stem cells, progenitors cells or differentiated cells might give rise to cancer stem cells. The resultant cancer stem cell has lost the ability to regulate its own cell division. These cells represent a rare population responsible for tumor initiation, invasive growth and possibly dissemination in distant organs.

Figure 3

Epithelial cell plasticity. In response to extracellular signals, epithelial cells undergo epithelial-mesenchymal transition (EMT) are characterized by loss of epithelial marker and acquisition of fibroblast-like phenotype. EMT has been closely associated with the acquisition of aggressive traits by carcinoma cells; infect epithelial cells loose their polarity and cell-cell adhesion and gain migratory and invasive properties to become mesenchymal cells.

Figure 4

Cytometric analyses for CD133. Expression level of CD133 was about 4%. The enrichment of CD133⁺ cells was obtained after cell sorting with an increase from 4% to 40%.

Figure 5

Schematic representation of the hypoxia inducible factor pathway. In normoxia HIFα subunit is hydroxylated by proline hydroxylase (PHD). The hydroxylated (OH) HIFα is recognised by a product of the von Hippel-Lindau tumour suppressor gene (VHL) which tags the HIFα-OH with polyubiquitin for subsequent degradation by the ubiquitin-proteosome pathway. In hypoxia HIFα and HIFβ subunits dimerize, then translocate in the nucleus where subunits interact with hypoxia regulatory elements (HREs), recruiting the transcriptional co-activator p300, activating the full transcription of downstream genes which regulate cell survival, motility, metabolism and angiogenesis.