Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Collaborative Specialization

Molecular Imaging

Supervisor

Thiessen, Jonathan D.

2nd Supervisor

Lee, Ting-Yim

Co-Supervisor

Abstract

Background: Cancer cells have a complex microenvironment that helps create optimal conditions for cancer proliferation. Nutrients such as glucose will pass through a tortuous and leaky vascular structure developed by cancer cells, and are subsequently distributed and transported inside the cancer cells to meet their metabolic demands. This leaky and poorly organized vasculature leads to a buildup in the interstitial fluid pressure surrounding the tumor, subsequently resulting in tumor hypoxia. Due to an overreliance on glycolysis, more acid and protons are produced by cancer cells, leading to a more acidic environment which, in combination with tumor hypoxia, often leads to a poor patient outcome. This thesis aims to explore the intrinsic relationship between tumor perfusion, glycolysis and its pH environment using a C6 rat model of glioma.

Methods: All subjects were implanted with 1 million C6 glioma cells using stereotactic surgery. The growth of tumor cells was monitored either with computed tomography perfusion (CTP) or magnetic resonance imaging (MRI). Once tumors had reached the optimal size, tumor perfusion was measured using CTP. Tumor glycolytic metabolism was measured using positron emission tomography (PET) with 18F-flurodeoxyglucose (FDG) and MR spectroscopy imaging (MRSI) using hyperpolarized [1-13C]pyruvate. Chemical exchange saturation (CEST) MRI was also used to investigate tumor glucose distribution (glucose contrast enhancement, or ∆CEST) and pH environments (intra-/extracellular pH, pHi and pHe respectively and simultaneously) during/after a glucose infusion/injection. All experimental procedures were completed within 24 hours. Measurements of tumor perfusion, glycolysis, ∆CEST and pH environments were correlated using Pearson’s correlation.

Results: Tumor perfusion measurement of permeability surface-area product (PS) was significantly correlated with tumor glycolysis measurement of Lac:Pyr from hyperpolarized MRSI as well as ∆CEST. Tumor Lac:Pry was also significantly correlated with tumor pHi. Tumor metabolic rate of glucose derived from dynamic PET was significantly correlated with tumor pHi and pHe.

Conclusion: This research showed the possibility of measuring the intracellular and extracellular pH environment simultaneously. Multimodal imaging approaches provided a more complete picture of the tumor microenvironment and helped elucidate the intrinsic relationship between tumor perfusion, glycolysis and the pH environment.

Summary for Lay Audience

Cancer cells have a complex microenvironment that helps create optimal conditions for them to survive and grow. Nutrients that are essential for cancer growth such as glucose will be delivered to the cancer cells using a poorly developed vessel system that is also developed by cancer cells. The amount of nutrients delivered is based on the energy needs of cancer cells. These delivered nutrients will then be used for energy production to support the cancer cells’ survival. Glycolysis is an energy production method that is mainly used by cancer cells. During glycolysis, glucose acts as a fuel, and helps to produce enough energy to meet the energy demands of cancer cells. However, this energy production process is very inefficient, leading to the production of acids as a side product. As a result, this makes the environment where cancer cells reside very acidic. This acidic environment will further help cancer cells to avoid detection by the host’s immune system, killing off the healthy cells around the tumor, and help cancer cells to spread into the surrounding areas. Moreover, the acidic cancer environment will lead to the formation of more vessels and further help the delivery of nutrients to cancer cells. This completes the vicious cycle between the delivery of cancer nutrients, the energy needs of cancer cells, and the acidic environment around cancer cells.

It is important to explore the relationships between the delivery process of nutrients to cancer cells to meet their metabolic demand, cancer cells’ energy production and the production of acid due to the inefficient energy production commonly found in cancer. Measuring these changes with non-invasive imaging methods, we will get more insight into cancer cell growth and spreading. Ultimately, we can use this information to achieve a better treatment outcome by stopping this vicious loop.

This thesis aims to explore these intrinsic relationships among cancer nutrients delivery, energy need and the acidic environment; and better understanding the environment that the cancer cells reside using a number of complementary medical imaging methods in a clinically translatable animal cancer model.

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