Biomedical Engineering Reference
In-Depth Information
During the next few decades cell surface markers for identifying stem cells
were discovered, and separation methods using flow cytometry enabled
collection of purified stem cells in quantities that could be studied. In 1994
Dick and his colleagues formally demonstrated that murine acute myeloid
leukemias contain a minority population of cells with stem cell markers and
properties, which can be propagated when transferred to other mice and can
generate a leukemic condition (Lapidot et al. 1994; Hope et al. 2004). This was
the first formal demonstration that the hierarchical organization of stem cells
and differentiated cells observed in the normal hematopoietic system also
characterizes the organization of cancer cells within a tumor.
This observation was followed nearly a decade later by Clarke's
demonstration of stem cells in a subpopulation isolated by flow cytometry
from human breast cancers (Al-Hajj et al. 2003). After this, a sequence of
studies rapidly demonstrated the presence of stem cells in a variety of human
cancers (Journal of Clinical Oncology, 2008). Many of these discoveries are
reported and elaborated upon in this volume.
Today, the evidence from many experts supports the concept that the
differentiated cells in normal tissues originate from stem cells, and the
concept that a malignant tumor originates from a cell with cancer stem cell
qualities. What remains to be understood is whether cancer stem cells are
derived from normal tissue stem cells, or whether mutations and altered gene
expression in more differentiated cells can result in generation of a cancer cell
with stem cell capabilities, or both.
The latter model entails the view that differentiated cells have plasticity
which enables them to assume stem cell characteristics if appropriate genes
are expressed. Two lines of recent research findings provide evidence that this
model of the genesis of cancer stem cells is worthy of serious consideration.
Recently several laboratories have demonstrated that introduction of just
four active genes into a mature differentiated cell can convert it into a cell with
embryonic stem cell characteristics (Takahashi and Yamanak 2006; Takahashi
et al. 2007; Yu et al. 2007).
Even more intriguing from the viewpoint of this volume are recent studies
exploring the transitions that occur in cancer cells which are undergoing the
process of invading and metastasizing from a primary site to a distant site in the
patient. In this case, cancer cells with some differentiated characteristics which
identify them as arising in a particular epithelial tissue (e.g., colon cancer)
undergo an epithelial-mesenchymal transition (EMT) which arms them with new
characteristics that include the capacity to invade other tissues and metastasize.
These cells, with acquired mesenchymal cell capabilities, have been shown to display
markers and characteristics of stem cells (e.g., CD44) and to lose markers and
characteristics of epithelial cells. Once they have reached a hospitable environment
which provides the necessary growth-promoting molecules and no longer produces
EMT-inducing signals, these malignant cells with stem cell characteristics undergo a
reverse mesenchymal-epithelial transition and form a new mass of cancer cells
which have the formerly displayed epithelial characteristics.
