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Title: The role of WAVE (WASP-family-verprolin homologousproteins) 1, 2 and 3 on cellular migration and invasion of colorectal cancer
Author: Toms, Anne-Marie
ISNI:       0000 0004 6057 9384
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2016
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Colorectal carcinoma (CRC) is the second most common cause of cancer deaths in the UK. More than half of patients are diagnosed at a late stage with around a quarter of patients having metastases at diagnosis (stage IV). Approximately 50% of diagnosed patients will progress to metastatic disease. The metastatic spread of malignant cells to distant sites in the body accounts for the majority of cancer-related death and significantly decreases patient survival. Whilst cell migration is a physiologically important process, when uncontrolled, it can be a contributing factor to the metastatic phenotype. Actin polymerisation enables the dynamic restructuring of the cytoskeleton which is fundamental to cell migration and is stimulated by the Arp (actin-related protein) 2/3 protein complex which in turn is activated by members of the WAVE (WASP Verprolin homologous protein) family. Clinico-pathological data was updated for a cohort of patients that had been involved in a previous colorectal tissue/carcinoma sampling study. The stored frozen tissue samples were analysed using histological and molecular biology techniques including conventional polymerase chain reaction, quantitative polymerase chain reaction, immunohistochemistry and in vitro gene knockdown studies. WAVE 1 and 3 expression was targeted separately in the RKO and CaCo2 cell lines utilising ribozyme transgene transfection to assess the effect knockdown on cell functions. A high WAVE 2 expression level is associated with more aggressive and higher stage primary tumours and also a shorter overall survival time and disease free survival time. WAVE 3 expression is higher in colorectal tissues compared to normal tissues but otherwise showed no significant difference. WAVE 1 did not show an increase in expression levels compared to normal colorectal tissues. The In vitro functional assays revealed a significant reduction in cell invasion and motility following WAVE 3 knockdown in CaCo2 cells. Knockdown of WAVE 1 in RKO cells resulted in a significant reduction in invasion and a moderate reduction in motility that was not significant. These results suggest WAVE1 and 3 proteins are involved in several metastatic traits and that WAVE 2 has significant correlation with higher stage disease. The data outlined here provides justification to further explore WAVE1, 2 and 3 as potential contributors of colorectal cancer progression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: R Medicine (General)