Chalmers Conferences, 9th European Conference on Mathematical and Theoretical Biology

Biphasic modulation of cancer stem cell driven solid tumor dynamics in response to reactivated replicative senescence
Heiko Enderling

Last modified: 2014-03-31


Cell senescence is a physiological program of irreversible growth arrest that is triggered after a variety of intracellular and extracellular events.  Its purpose is to protect tissue integrity by disabling mitosis in stressed or damaged cells.  The senescence program serves as a tumor suppressor, and cancer cells are believed to bypass senescence to advance to malignancy.  Recent studies have shown that senescence can be reactivated in cancer cells through a number of external perturbations, including oncogene activation, tumor suppressor gene withdrawal and irradiation.  We develop an agent-based model of solid tumor growth based on the cancer stem cell hypothesis, in which cancer stem cells drive tumor progression and non-stem cancer cells emerge to impede cancer stem cell dynamics. We show that intratumoral competition between the two cell types arises that modulates tumor progression and ultimately cancer presentation risk.  Model simulations reveal that reactivation of the replicative senescence program in non-stem cancer cells initially increases the total tumor burden as cell death is partially averted, but evolves to provide tumor control in the long term through increasing constraints on stem cell compartment kinetics.  Reactivation of replicative senescence prolongs non-stem cancer cell competition with cancer stem cells, thereby ultimately inhibiting malignant progression regardless of tumor size.


cancer; cancer stem cells; treatment