Biomedical Engineering Reference
In-Depth Information
glioblastoma cell lines (Hirschmann-Jax et al., 2004). Furthermore, analysis of
several cell lines that had been maintained in culture for long periods of time
demonstrated a small population of SP cells. In the rat glioma C6 cell line, a
population of cells containing SP characteristics was isolated from a non-SP
population. Through the use of growth factors these investigators could main-
tain these cells in culture, and show that only the SP cells gave rise to both
populations, and produced cells with both neuronal and glial markers that were
tumorigenic in mice (Kondo et al., 2004). This latter study provided strong
evidence that in this cell line, the SP population reflected a population with a
capacity for self-renewal and limited maturation. However, this isolation
approach is imperfect as the SP compartment is composed of stem and non-
stem cells, and some stem cells are not in the SP fraction (Zhou et al., 2002). For
example, non-stem cell tumor cells often express ABCG2 and ABCB1. These
genes are highly expressed in drug-resistant cells, and histopathologic studies
have reported increased expression of the ABCB1 transporter in more differ-
entiated tumors (Mizoguchi et al., 1990; Nishiyama et al., 1993). In addition, in
a variety of cell lines, differentiating agents induce expression of ABCB1, inhibit
cell growth, and increase the expression of markers of maturation (Bates et al.,
1989; Mickley et al., 1989).
Additional limitations exist in using cancer cell lines cultured in vitro to
study stem cell biology and drug resistance. Although SP cells and cells with
stem cell properties have been reported in cultured cell lines, it is difficult to
reconcile the hypothesis that only a small fraction of cells in culture possess the
ability to proliferate and self-renew with the rapid doubling time of cells in
culture. Current paradigms envision a small stem cell compartment possessing
cells with the capacity for perpetual self-renewal existing alongside a much
larger proliferative compartment whose cells have a finite ability to proliferate
before presumably arresting and/or undergoing apoptosis. These paradigms
can explain the low cloning efficiency of most cell lines, their inefficiency at
colony formation in soft agar, and their limited tumorigenicity. But none can
explain how the stem cells remain a constant fraction of the total population, if
indeed they do. Any proposal will require stem cells to divide slowly, and must
recognize that in a cell line derived from a solid tumor the number of cells
undergoing apoptosis is relatively small. One possibility is that there is an
interchange of cells between a proliferative compartment and the stem cell
pool. That such an interchange might occur is not improbable since the cell
line almost certainly originated from a stem cell with a proliferative advantage.
13 Major Cancers and Risk Factors
Environmental risk factors have been identified for most of the most common
cancers. These risk factors can be classified by their potential role in either
activating stem cells or mutating target genes.
