Investigating the actin cytoskeleton in cancer

Brown, Jennifer (2016) Investigating the actin cytoskeleton in cancer. PhD thesis, University of Glasgow.

Abstract

Dynamic alterations in the actin cytoskeleton, under the regulation of the Rho/ROCK pathway, permit cell motility, cell-to-cell and cell-to-matrix adhesion, and have also been shown to participate in apoptosis and cell proliferation. These facets of cellular behaviour all have the capacity to become dysregulated in cancer; components of the Rho/ROCK pathway are known to play varying roles in these processes, both within primary tumours and within the tumour microenvironment.
The LIM kinases are phosphorylated and activated by ROCK, leading to inactivation of cofilin and subsequent stabilisation of actin filaments. In addition, LIM kinase 2 serves as a p53 target and is upregulated in response to DNA damage. In some solid tumours (e.g. breast and prostate), LIM kinase levels are elevated. However, we found that LIM kinase 2 expression is downregulated in colon cancer, with a progressive reduction noted with advancing tumour stage. I found that LIMK2 expression in colon cancer is under epigenetic regulation, with hypermethylation of the promoters leading to transcriptional silencing; this implicates LIMK2 as a tumour suppressor gene in this context. This has potential translational implications as loss of LIMK2 could be utilised as a biomarker to stratify patients in the future.
Elevated mechanical tension within the tumour microenvironment is known to be an adverse prognostic indicator due to its association with desmoplasia. ROCK activation has previously been shown to increase epidermal tissue stiffness and thickness, but little was known about the mechanisms by which this occurs. I found that ROCK activation leads to the deposition of extracellular matrix components, with a presumed consequent further increase in stromal stiffness. This indicates that a positive feedback cycle is established in the tumour microenvironment, maintaining a fibrotic stromal reaction that permits tumour progression.
These results highlight the disparate roles that the actin cytoskeleton and constituents of the Rho/ROCK pathway play in tumour initiation and propagation, indicating the need for further research.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Cancer, actin cytoskeleton, Rho kinase, fibrosis, colorectal cancer.
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: Olson, Professor Michael F.
• Date of Award: 2016
• Depositing User: Dr Jennifer Brown
• Unique ID: glathesis:2016-7266
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 12 May 2016 08:12
• Last Modified: 20 May 2016 16:07
• URI: https://theses.gla.ac.uk/id/eprint/7266