The accelerated cell division of undifferentiated E/M cells might be supported by the high production of extracellular matrix proteins, observed in early passages (Figure 3C), whereas low cell densities of E/M-MP cells, or growth among more differentiated cells, enforces differentiation and the rapid loss of CD133 (Figures 7A,B).
To generate the various neural stem, progenitor and more differentiated glial species the following growth factor preparations were utilized: recombinant bFGF (Collaborative Biomedical Products), recombinant EGF, N-Shh and PDGF-AA (R&D Systems) and BMP2 (gift from Genetics Institute).
To generate the various neural stem, progenitor and more differentiated neuronal subtype species the following growth factor preparations were utilized: recombinant bFGF (Collaborative Biomedical Products), N-Shh and recombinant mouse β-NGF (R&D Systems), human BDNF (BioVision), BMP2 (gift from Genetics Institute) and LIF (Chemicon).
Furthermore, in xenograft experiments in mouse, VPA was shown to decrease tumour growth combined with a more differentiated phenotype of the NB cells (Cinatl et al, 1997, 2002).
We suggest that the findings reflect differing tumour growth rates, with those with the most rapid growth rate showing a less mature phenotype and reaching a size that is clinically detectable and leads to operation at an earlier age than tumours with a less rapid growth rate and a more differentiated phenotype.
However, in certain cases, differentiation-inducing agents can reactivate a tumour cell's differentiation programme and bypass this defective growth regulation, forcing cells into a more differentiated state that has a more favourable clinical prognosis.
Upon division, adult stem cells typically produce a transit-amplifying progenitor, a cell that acquires a more differentiated state, but exhibits a high capacity for growth.
Finally, epithelial-derived AREG, for example, may bind EGFR on more differentiated, neighboring stromal cells that induce other local growth factors, resulting in massive proliferation during ductal morphogenesis (see Figure 3 of [ 3]).
These results indicate that the restriction in L50 tumour growth may be largely explained by a more differentiated phenotype, and a reduced ability to undergo tumour neo-angiogenesis.
Clearly, IGF1, FGF2, and BMP2 trigger separate responses in the cells; IGF1 leads to increased expression of all genes analysed, however, the other two growth factors showed a much subtler and more differentiated response.
