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Permanent link (DOI): https://doi.org/10.7939/R3MK65K27

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Targeting a Trigger: Platelet Derived Growth Factor Receptor Alpha in the Nodal Metastasis of Papillary Thyroid Cancer Open Access

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Other title
Subject/Keyword
Papillary thyroid cancer
Platelet derived growth factor alpha
PDGFRa
Epithelial Mesenchymal Transition
EMT
Invadopodia
Crenolanib
Snail
Slug
3D culture
Gelatinase assay
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Ekpe Adewuyi, Esther O
Supervisor and department
McMullen, Todd (Surgery)
Examining committee member and department
Raymond Lai (Laboratory Medicine and pathology)
David Williams (Surgery)
Robert Ingham (Medical Microbiology and Immunology)
Ing Swie Goping (Biochemistry)
Sam Wiseman (Surgery, University of British Columbia)
Department
Department of Surgery
Specialization
Experimental Surgery
Date accepted
2016-05-31T14:29:25Z
Graduation date
2016-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Recurrent, metastatic forms of papillary thyroid cancer (PTC) continue to challenge the status quo therapy regime which combines surgical resection with radioactive iodine ablation of remnant thyroid and metastatic deposits. Repetitive use of these methods following the initial failure to control the disease impacts negatively on the quality of life and survival. Investigational use of targeted therapies like tyrosine kinase inhibitors (TKIs) have become a major part of the quaternary care given to patients with the recurrent, metastatic disease. Unfortunately, the varied outcomes and adverse side effects which accompany their empirical use underscores the need for a much better understanding of the cellular processes driving metastatic disease in PTC. We previously identified platelet derived growth factor receptor alpha (PDGFRα) as an important biological marker for the metastatic spread of PTC. By extension, in the current work, the prognostic implication of activated PDGFRα in papillary thyroid tumor samples was evaluated. We hypothesized that PDGFRα induces aggressive phenotypes such as lymph node metastases, dedifferentiation and compromised iodide transporting abilities, in papillary thyroid tumors. The signaling consequences of PDGFRα, and the effects of its blockade by tyrosine kinase inhibitors were also investigated. We demonstrate that PDGFRα creates an invasive and migratory follicular cell phenotype lacking the ability to transport sodium iodide in vitro and in vivo. The invasive and migratory behaviour are consequences of cellular epithelial to mesenchymal transition, and the formation of ECM degrading invadopodial protrusions. The unique ability of PDGFRα to mediate thyroid follicular cell dedifferentiation, with the ensuing suppression of iodide uptake in PTC cells, results from the downregulation of TTF1 expression. In clinical samples, PDGFRα is predictive of nodal spread, radioactive iodine resistance, as well as disease recurrence. We also observed that the expression of PDGF-AA, a PDGFRα-specific ligand, is associated with the metastatic PTC disease. Interestingly, our findings challenge the current canonical description of PTC as a MAPK/ERK driven malignancy, and clearly demonstrate a vital role for the STAT3 and AKT pathways in driving this aggressive disease phenotype. PDGFRα represents the first opportunity for targeted therapy in thyroid cancer that directly influences tumor differentiation, migration and ECM degradation. We propose that blockade of PDGFRα may be a useful adjunct therapy given its ability to dramatically reduce the severity of the aggressive phenotypes, where previous attempts with drugs that disrupt other tyrosine kinases have failed.
Language
English
DOI
doi:10.7939/R3MK65K27
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
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