Biomedical Engineering Reference
In-Depth Information
the CSCs that closely associate with the endothelial cells. In vivo, medulloblas-
toma cells transplanted with endothelial cells in immunocompromised mice
resulted in faster growing and larger tumors than in mice that were transplanted
with medulloblastoma cells without endothelial cells. Furthermore, they demon-
strated treatment of tumor-bearing mice with anti-VEGF, which abolishes angio-
genesis thereby reducing endothelial cells in vivo,decreased the number of CSCs
and the growth rate of the tumor. In the case of normal prostatic epithelial SCs, it
was shown that they reside proximal to the urethra at a band of smooth muscle
cells that secrete TGFb (Tsujimura et al. 2002). The secretion of TGFb in this
area may be important in maintaining the niche for prostatic CSCs, since this
factor is important in promoting quiescence of SCs (Salm et al. 2005). It would be
interesting to determine the effect of inhibitors of TGFb signaling on the forma-
tion of tumors in orthotopic tumor models. Therefore, as we gain a greater
understanding not only of the niche of prostate CSCs but also of the factors
and cells that contribute to maintaining this environment, further therapeutic
strategies can be devised.
5.5 Targeting Stem Cell Differentiation
Theoretically, the process of CSC differentiation is a process that, once understood in
more detail, could be targeted. If the prostatic CSCs could be pushed to differentiate
into less quiescent, AR-responsive cells then therapies that are efficacious for these
cells would be able to eradicate the entire tumor. If the balance of self-renewal and
differentiation were tipped entirely to differentiation then presumably the patient
could be cured and relapse prevented, due to the loss of all CSCs. This concept has
been pondered by several investigators (Lawson and Witte 2007; Mimeault et al.
2007b). Many questions still remain before any sort of therapy could be designed,
including (1) what is the definitive identification of the pathways required for self-
renewal? (2) can self-renewal pathways be turned off, or can differentiation pathways
be turned on sufficiently to drive all of the CSCs to differentiated progeny? (3) if you
eradicate one tumor do you still leave behind the propensity for another CSC to be
derived in a manner similar to the initial CSC? and, importantly, (4) what will be the
impact of derived therapies on normal stem cells?
6 Future Directions
The ability to study and understand the prostatic CSCs is hampered by several
factors, including (1) the scarcity of the cells (at most 1% of total cells), (2) a
relative lack in culturing techniques that maintain the SC state, (3) adequate
techniques that measure SC properties, such as self-renewal. These challenges are
currently being addressed and culture techniques have been developed allowing
the expansion of these cells, however, it is uncertain if these in vitro expanded cells
remain the same as in vivo cells. If the in vitro cultured CSCs do, in fact, retain all
