Date of Award

6-12-2014

Document Type

Thesis

Publisher

Santa Clara University

First Advisor

Prashanth Asuri

Abstract

Although metastasis is the primary cause of cancer deaths and results in 90% of all cancer fatalities currently, all attempts to discover anti-metastatic drugs have failed. Many of the traditional methods of studying cell migration, using two-dimensional (2D) platforms, only study two-dimensional migration, which is fundamentally different and more multifaceted than the three-dimensional migration that occurs in vivo. To more accurately capture this in vivo variation, we developed a two-and-a-half-dimensional (2.5D) cell culture platform to better study three-dimensional (3D) migration. This platform consists of a layer of alginate on top of a monolayer of cells grown on tissue culture polystyrene (TCPS). To test the parameters of the system, experimentation on Human Embryonic Kidney (HEK) 293T cell lines, and linked the 2.5D platform with attachment-independent amoeboid migration. U87 glioblastoma cell line proved to migrate using similar mechanisms, and was used to test anti-metastatic drug candidates. Axitinib, a current chemotherapy drug, blocked migration through pure alginate. Additionally, Cilengitide, a failed anti-metastatic drug candidate, was shown to increase migration in pure alginate. When attachment-mediated migration was induced, Cilengitide did not halt migration, but rather caused the cells to switch to an attachment-independent mechanisms, which corroborates with Phase II Food and Drug Administration (FDA) trials in which Cilengitide failed to stop metastasis. In the study of cancer metastasis, this platform can thus be used to not only to explain the failure of past clinical trials, but also to discover new anti-metastatic drug candidates.

Download

Share

COinS