Elimination of both cancer stem cells and progenitor cells as essential for tumor eradication.

Abstract

e22179 Background: Cancer stem cells (CSC) have been identified in several malignancies. Elimination of CSCs requires precise identification of markers and development of mechanisms to target them specifically. It is possible that in spite of elimination of CSCs, the tumor may recur. Dedifferentiation of progenitor cells may help replenish cancer stem cells. Methods: A mathematical model of a cancer stem cell system with four layers has been constructed to reflect the hierarchy of cancer stem cells, progenitor cells and, transit-amplifying cells and pre-differentiated cells. This model is constructed in the lines of the phase space model described by Kirkland. Dedifferentiation parameters were introduced to allow for dedifferentiation when the stem cell pool receded below 40% of its normal size. The effects of stem cell antagonists (SCA) and differentiating agents (DA) were simulated to study the perturbations caused by them on the growth of the tumor. Results: SCAs when used alone result in the establishment of a new equilibrium across different layers within the tumor by de-differentiation. DAs which act only on progenitor cells cause an increase in the number of cells in the subsequent layers and contribute to an increase in the size of the tumor. DAs which act only on the pre-differentiated layer of cells move cells from this layer into a terminally differentiated layer of cells which results in a new but lower equilibrium. DAs which act on the progenitor, transit amplifying and pre-differentiated cells cause the establishment of a new equilibrium which is lower than that of all agents which act on individual layers of cells. A combination of an SCA and a DA which acts on multiple layers eliminates the re-establishment of a new equilibrium and leads to decline in cell populations in all the layers, thus reducing the possibility of recurrence. Conclusions: SCAs when used individually are not effective in eliminating the tumor. DAs which act only on progenitor cells can fuel tumor growth but DAs which act on multiple layers have a profound effect in slowing the growth of the tumor but do not eliminate the tumor. This model implies that a combination of an SCA and a DA which acts on multiple layers may have a better chance at eliminating the tumor.