The aim of this review is to summarize current knowledge on nestin expression in human tumors and corresponding tumor cell lines. Nestin belongs to class VI of the intermediate filaments and it is expressed primarily in mammalian nervous tissue during embryonic development. In adults, nestin occurs only in a small subset of cells and tissues. This protein has been observed in the subventricular zone of the adult mammalian brain, where neurogenesis is localized. Nestin expression has also been detected in various types of human solid tumors, as well as in the corresponding established cell lines. This article provides an up-to-date overview of tumors in which nestin has been found. Another aim of this review is to summarize recent findings on the intracellular localization of nestin in human tumor cells, especially with regard to the possible correlation between nestin expression and the malignant phenotype of transformed cells. Nestin expression in vascular endothelial cells during angiogenesis is also reviewed. Special attention is paid to the detection of nestin in cancer stem cells because this protein, together with the CD133 surface molecule, is considered to be a possible marker of cancer stem cells, especially in tumors of neuroectodermal origin.

Background: Nestin was originally identified as a class VI intermediate filament protein that is expressed in stem cells and progenitor cells in the mammalian CNS during development. This protein is replaced in the adult organism by other intermediate filament proteins; however, nestin may be re-expressed under certain pathological conditions such as ischemia, inflammation, brain injury, and neoplastic transformation. Nestin has been detected in many kinds of tumors, especially in tumors derived from the CNS. Co-expression of nestin and the CD133 surface molecule is considered to be a marker for cancer stem cells in neurogenic tumors. Our work was aimed at a detailed study of nestin expression in osteosarcomas and osteosarcoma-derived cell lines.

The three most frequent pediatric sarcomas, i.e., Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma, were examined in this study: three cell lines derived from three primary tumor samples were analyzed from each of these tumor types. Detailed comparative analysis of the expression of three putative cancer stem cell markers related to sarcomas-ABCG2, CD133, and nestin-was performed on both primary tumor tissues and corresponding cell lines. The obtained results showed that the frequency of ABCG2-positive and CD133-positive cells was predominantly increased in the respective cell lines but that the high levels of nestin expression were reduced in both osteosarcomas and rhabdomyosarcomas under in vitro conditions. These findings suggest the selection advantage of cells expressing ABCG2 or CD133, but the functional tests in NOD/SCID gamma mice did not confirm the tumorigenic potential of cells harboring this phenotype. Subsequent analysis of the expression of common stem cell markers revealed an evident relationship between the expression of the transcription factor Sox2 and the tumorigenicity of the cell lines in immunodeficient mice: the Sox2 levels were highest in the two cell lines that were demonstrated as tumorigenic. Furthermore, Sox2-positive cells were found in the respective primary tumors and all xenograft tumors showed apparent accumulation of these cells. All of these findings support our conclusion that regardless of the expression of ABCG2, CD133 and nestin, only cells displaying increased Sox2 expression are directly involved in tumor initiation and growth; therefore, these cells fit the definition of the cancer stem cell phenotype.