Targeting Cancer Stem Cells
From Takahashi and Yamanaka, Cell
2006, Here, we demonstrate induction of
pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing
four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions.
Unexpectedly, Nanog was dispensable. These cells, which we designated iPS
(induced pluripotent stem) cells, exhibit the morphology and growth properties
of ES cells and express ES cell marker genes. Subcutaneous transplantation of
iPS cells into nude mice resulted in tumors containing a variety of tissues
from all three germ layers”.”
Nude mice are deficient in the
the immune system, so they allowed tumor formation by iPS cells and did not
attack them. This observation indicated that when mature differentiated cells
like fibroblasts which have specific functions, de-differentiate to immature
pluripotent stem cells, they magnify the property of self-renewal and skew
towards uncontrolled self-proliferation as opposed to differentiation. This
indicates that tumor formation could be initiated by de-differentiated cells,
where signaling pathway activity regulating self-renewal is amplified. Such
cells called cancer stem cells could be exploited as targets for cancer
therapy, as these signnaling pathways have basal activity in normal stem cells
and are amplified in cancer stem cells. One such signaling pathway is the
Wnt-beta catenin signaling pathway which promotes cancer stemness. For example Beta-catenin
inhibitors are experimental cancer treatments currently being evaluated in
early-phase clinical trials, focusing primarily on agents like tegavivint and
FOG-001. There are currently no FDA-approved drugs that directly target the
Wnt/β-catenin pathway due to challenges with toxicity and the complexity of
cellular adhesion.atenin inhibitors are being tested in clinical trials. So
alternate molecules in the cancer stem cell signaling pathways need to be
validated as targets for cancer stem cell therapy.
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