Studies of tumor heterogeneity, tumor microenvironment, and radiotherapy: A mathematical and computational approach
MetadataShow full item record
Radiotherapy uses high doses of energy to eradicate cancer cells and thus destroy the bulk of tumors. Radiobiologists try to precisely deliver radiation to a targeted area in order to maximize the cancer cell kill rate while trying to minimize damage to normal cells. To achieve this goal, various treatment schedules have been developed, but there still remain significant obstacles to improving the effectiveness of these schedules. It has been observed that various factors play important roles in the effectiveness of treatment. One important factor is tumor heterogeneity, that is, the genetic and epigenetic variations in tumors. This cellular diversity can influence the efficacy of radiotherapy due to the different radiosensitivities among cancer cells. In addition, the interplay between this heterogeneous cellular population and the tumor microenvironment can negatively affect the treatment process. In this thesis, deterministic and stochastic mathematical models are developed to explore the role of heterogeneity and the impact of cellular repair on radiotherapy outcomes. The results suggest that shrinking a tumor is not sufficient to control the disease; the fraction of cells resistant to treatment must also be reduced. In addition, supposedly optimal treatment schedules can lead to markedly different results even in patients with the same type of cancer, due to cellular and microenvironmental differences among tumors. Therefore, based on these variations, it is important to design new therapeutic approaches for each cancer type and even each patient. The modified Gillespie algorithm for discontinuous time changing rates is applied to explore the impact of plasticity, as well as random demographic factors on the tumor control probability. The random modification of tumor microenvironment is shown to influence the efficiency of radiotherapy. Increasing the standard deviation leads to an initial rise in the tumor control probability, which thereafter drops over time if a tumor is not eradicated entirely. The results also confirm that plasticity in a tumor reduces the tumor control probability, especially in highly resistant tumors. In addition, in the presence of plasticity, combining radiotherapy with a targeted therapy increasing the differentiation of CSCs does not increase the probability of CSC and tumor removal greatly. Finally, the impact of regulatory negative feedback on the sphere formation potential of a single CSC is explored. The sphere formation efficiency and average sphere size are shown to escalate when CSC division and dedifferentiation are subject to negative regulatory feedback.
Cite this version of the work
Farinaz Forouzannia (2019). Studies of tumor heterogeneity, tumor microenvironment, and radiotherapy: A mathematical and computational approach. UWSpace. http://hdl.handle.net/10012/14306
Showing items related by title, author, creator and subject.
Burazin, Andrijana (University of Waterloo, 2014-01-15)In this thesis, the theory of poroelasticity, namely the Mixture Theory version -- a homogenized, macroscopic scale approach used to describe fluid flow through a porous medium -- is employed in three separate cases ...
Mostofinejad, Amirmahdi (University of Waterloo, 2019-05-21)Tumour-induced angiogenesis is affected by an interplay between different cell types, the mechanical stresses in the extracellular matrix (ECM), and the cell signalling networks. The morphology of the newly-created cells ...
Image-based spatio-temporal model of drug delivery in a heterogeneous vasculature of a solid tumor — Computational approach Kashkooli, Farshad M.; Soltani, Madjid; Rezaeian, Mohsen; Taatizadeh, Erfan; Hamedi, Mohammad-Hossein (Elsevier, 2019-05)The solute transport distribution in a tumor is an important criterion in the evaluation of the cancer treatment efficacy. The fraction of killed cells after each treatment can quantify the therapeutic effect and plays as ...