Date of Award

5-31-2016

Document Type

Open Access Thesis

Degree Name

Master of Science (MS)

Department

Physics, Applied

First Advisor

Jonathan Celli

Second Advisor

Chandra Yelleswarapu

Third Advisor

Stephen Arnason

Abstract

Past studies have shown that tumor growth generally follows an exponential growth function or, with a limiting growth constraint, the sigmoid Gompertzian function, where a terminal tumor size is reached at late times. The classical Gompertzian description of tumor growth applies in the case of two-dimensional (2D) in vitro cell studies due to the effect of physical limitations on possible growth area. This project asked whether Gompertzian form applies to the in vitro growth of multifocal 3D tumor nodules, whose size is determined by aggregation events as well as cell proliferation. Previous reports have indicated that these three-dimensional (3D) spheroids appear to reach a terminal size, even though the full available 3D volume is not occupied. In this scenario it is not immediately obvious if individual nodules are growth-constrained by nutrient or oxygen diffusion, or rather if the ensemble of all nodules exhibits Gompertzian form. 3D in vitro ovarian cancer cells were chosen as the population to be studied. The ovarian cancer cells were grown in overlay on a laminin-rich extracellular matrix (ECM). This model system is a common and widely used cell culture platform in cancer cell research. Using this system, division of the ovarian cancer cells into heterogeneous clusters that aggregate into larger clusters, and then reach a steady bimodal distribution of small and large aggregates, was observed. The average volume as well as the total volume of these two cell aggregate groups were measured over time to determine the nodules’ growth behavior would plateau without a growth area limitation. Biological processes may limit the size and behavior of cells within sphere-like multicellular nodules differently than a simple layer of cells on a petri dish. The standard deviation of the rapidly growing nodule volume population within a 3D in vitro ovarian cancer sample was shown to grow according to a quadratic function, while the population of small nodules stays constant over time. The overall growth behavior of the total volume of the rapidly growing nodules was Gompertzian. The spread between the increasing average size of the large and growing nodule population and the constant average size of the population of small nodules increased exponentially. A particle velocity tracking program was used to search for a relationship between the lateral velocity of the nodules within the field of view and the average size of the rapidly growing nodules. The average lateral velocity of all nodules was shown to weakly decrease over time. This indicates that the behavior of 3D grown ovarian cancer cells follow a dissemination pattern in which small cells or nodules of ovarian cancer cells demonstrate higher dissemination than large nodules. The motion of smaller cell nodules or single cells may be advantageous in the in vivo, as well as the in vitro settings. This advantage may produce the bimodal distribution of mobile small aggregates and large slow-moving and growing aggregates, and in turn, this behavior may demonstrate that dissemination of small aggregates of ovarian cancer cells occurs in a 3D environment.

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