Biomedical Engineering Reference
In-Depth Information
protein with 12 membrane spanning segments and is the receptor for the
Hedgehog (HH) family of signaling molecules. PTCH and the HHs play a
central role in the cell fate and patterning of early embryonic cells. Alteration
in the growth regulation of stem cells was invoked to explain the role of the
PTCH gene in causing basal cell carcinomas in patients with nevoid basal cell
carcinoma syndrome (Dean, 1997).
11 Stem Cell Activation and Specific Cancers
While a model of a small population of self-renewing cells as the key to all
cancers is an attractive idea, can the model be extended to the wide variety of
tumor types and specific agents implicated in causing these tumors? Three
distinct types of cancers have been described—embryonic, conditional growth,
and renewal (Knudson, 1993). Embryonic cancers derive from rapidly dividing
embryonic tissue and therefore contain a population of actively dividing stem
cells. The prototype embryonic cancer is retinoblastoma (Knudson, 1971), but
Wilm's tumor, Ewing's sarcoma, childhood bone and brain cancers each fall
under this rubric. Retinoblastoma arises in embryonic cells in the developing
eye, known as retinoblasts. These cells are highly proliferative and are naturally
activated stem cells. The mutation or loss of the RB1 gene transforms these
embryonic stem cells into cancer stem cells. These cells would be expected to
have lost the response to growth regulatory signals shutting down the stem cell,
once the development of the eye was complete. Other childhood cancers could
involve multipotent stem cells in other tissues suffering genetic damage during
development. These cancers require the fewest number of genetic events,
because the target cell is a fully activated stem cell.
Stem cells can also be activated during the normal process of expansion of
certain tissues due to the action of hormones, particularly during puberty
(conditional growth tissues) (Knudson, 1993). Examples would be the breast
and prostate, which undergo dramatic expansion and growth during puberty
under the control of estrogen, testosterone, and other hormones (Trichopoulos
et al., 2005). Activated stem cells in the breast would be the target cell for breast
cancer. Inactivation of specific tumor suppressor genes, like TP53, would
transform the breast tissue stem cells into unregulated cells, initially resulting
in pre-malignant lesions. There is good evidence that p53 haploinsufficiency
accelerates cancer onset, perhaps by diminishing DNA repair, thereby facilitat-
ing mutation of activated stem cells. These uncontrolled stem cells would be the
target for additional events leading to the progression of the pre-malignant
lesion into a fully malignant tumor.
Consistent with this model, the major risk factors for breast cancer involve
hormonal and reproductive variables (Gail et al., 1989). Women with an early
onset of puberty have a higher rate of breast and ovarian cancers than those
with later menarche. Pregnancies, especially those starting at a relatively
