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Title: Mechanogrowth factor (IGF-1Ec) and flourescent nanoparticles in colorectal cancer
Author: Alagaratnam, Swethan
ISNI:       0000 0004 9359 5049
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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The IGF-1 axis was an area of significant interest in cancer therapy following promising preclinical studies but led to disappointing clinical trials. Further scrutinization of this pathway is, therefore, warranted. The IGF-1 axis has been demonstrated to inhibit autophagy via the Akt/PI3K pathway and induce autophagy via the ERK pathway. Autophagy has been associated with chemotherapy resistance in tumour cells. My work in this thesis involved investigating the expression of an iso-form of IGF-1 referred to as IGF1-Ec or Mechanogrowth Factor (MGF) in colorectal cancer tissues and polyps with immunohistochemistry. Further work was done with fluorescent nanoparticles which have exciting potential to improve the diagnostic yield of investigations including colonosco-py, improve immunohistochemistry assessment of tissue biopsies and help in surgery with in-traoperative delineation of tumours. In addition, I investigated the relationship between autopha-gy and apoptosis with a view towards developing a model for further work in investigating the ef-fect of MGF in autophagy. Semi-quantitative immunohistochemistry for MGF on colonic tissues including normal, polyp and cancer tissues demonstrated a significantly higher expression of MGF in colonic polyps (with higher expression with worsening dysplasia, p=0.001) and cancer compared to normal colon tissues (p<0.001). Semiconductor CdTe quantum dots and gold nanoparticles were synthesised and conju-gated to the MGF peptide and antibody. Gold nanoparticles were successfully characterised with immunodots and applied to the HT29 and SW620 colorectal cancer cell lines and to tissues includ-ing normal, colon cancer and polyp tissues reflecting the results from conventional immunohisto-chemistry. Autophagy inducers were administered to the cell lines HT29 and SW620 and inhibited with the use of Bafilomycin and 3-MA. Immunohistochemistry for LC3B was used to confirm the induction of autophagy, and cell viability studies were used to demonstrate significantly increased cell viability with autophagy induction and significant reduction of cell viability with inhibition of autophagy (p<0.01 at 24 hours). This model can be subjected to the application of MGF and assess its effects on cell viability. MGF is overexpressed in colonic polyps and cancer with low levels of expression in normal colon tissues offering an opportunity for the use of fluorescent gold nanoparticles to augment polyp and cancer detection in colonoscopy and intraoperative tumour delineation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available