Targeting cell adhesion as a method of sensitising metastatic tumour cells to TRAIL-induced apoptosis
<p>Due to its selectivity in killing cancer cells, Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has provided a potential new agent for cancer treatment. However, despite promising pre-clinical results, it appears that TRAIL therapies will be most effective when used in comb...
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| Format: | Thesis |
| Language: | English |
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2011
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| _version_ | 1826285477386256384 |
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| author | Phipps, L |
| author2 | Muschel, R |
| author_facet | Muschel, R Phipps, L |
| author_sort | Phipps, L |
| collection | OXFORD |
| description | <p>Due to its selectivity in killing cancer cells, Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has provided a potential new agent for cancer treatment. However, despite promising pre-clinical results, it appears that TRAIL therapies will be most effective when used in combination with a sensitizing agent. In light of previous evidence suggesting that cell adhesion could influence sensitivity to Tumour necrosis factor family ligands, this thesis presents a study of the effects of disrupting matrix adhesion on the sensitivity of human MDA-MB-231 breast and 1205Lu melanoma cell lines to TRAIL-induced apoptosis.</p><p>This was investigated using a number of models including i) culturing cells on normal and low attachment plates; ii) disrupting the transcription of genes involved in cell attachment and spreading in MDA-MB-231 cells using shRNA to Myocardin-related transcription factors-A and B (MRTF-A/B); iii) disrupting the integrin signalling pathway using inhibitors or siRNA to β integrin subunits, talin, integrin-linked kinase (ILK), focal adhesion kinase (FAK) and SRC. With the exception of ILK depletion, disruption of cell adhesion and spreading in all models resulted in sensitisation to TRAIL-induced apoptosis. Cells under these conditions also showed alterations in death receptor signalling and amplification of intrinsic apoptosis pathway signalling through caspase-9. Both MRTF-A/B depleted cells and those treated with the SRC family kinase inhibitor PP2 showed alterations in signalling through ERK1/2. When investigated in an experimental model of metastasis in mice, FAK and SRC inhibitors increased the clearance of MDA-MB-231 cells from the mouse lung when used in combination with recombinant human TRAIL therapy.</p><p>By utilizing these models, the work in this thesis has shown that disrupting cell adhesion could provide a new combination strategy to sensitise tumour cells to TRAIL therapy.</p> |
| first_indexed | 2024-03-07T01:29:25Z |
| format | Thesis |
| id | oxford-uuid:93198943-a7fa-4b30-aaed-c92d7e0a4ba6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:29:25Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:93198943-a7fa-4b30-aaed-c92d7e0a4ba62022-03-26T23:29:59ZTargeting cell adhesion as a method of sensitising metastatic tumour cells to TRAIL-induced apoptosisThesishttp://purl.org/coar/resource_type/c_db06uuid:93198943-a7fa-4b30-aaed-c92d7e0a4ba6Biology (medical sciences)OncologyCell Biology (see also Plant sciences)TumoursMedical SciencesEnglishOxford University Research Archive - Valet2011Phipps, LMuschel, R<p>Due to its selectivity in killing cancer cells, Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has provided a potential new agent for cancer treatment. However, despite promising pre-clinical results, it appears that TRAIL therapies will be most effective when used in combination with a sensitizing agent. In light of previous evidence suggesting that cell adhesion could influence sensitivity to Tumour necrosis factor family ligands, this thesis presents a study of the effects of disrupting matrix adhesion on the sensitivity of human MDA-MB-231 breast and 1205Lu melanoma cell lines to TRAIL-induced apoptosis.</p><p>This was investigated using a number of models including i) culturing cells on normal and low attachment plates; ii) disrupting the transcription of genes involved in cell attachment and spreading in MDA-MB-231 cells using shRNA to Myocardin-related transcription factors-A and B (MRTF-A/B); iii) disrupting the integrin signalling pathway using inhibitors or siRNA to β integrin subunits, talin, integrin-linked kinase (ILK), focal adhesion kinase (FAK) and SRC. With the exception of ILK depletion, disruption of cell adhesion and spreading in all models resulted in sensitisation to TRAIL-induced apoptosis. Cells under these conditions also showed alterations in death receptor signalling and amplification of intrinsic apoptosis pathway signalling through caspase-9. Both MRTF-A/B depleted cells and those treated with the SRC family kinase inhibitor PP2 showed alterations in signalling through ERK1/2. When investigated in an experimental model of metastasis in mice, FAK and SRC inhibitors increased the clearance of MDA-MB-231 cells from the mouse lung when used in combination with recombinant human TRAIL therapy.</p><p>By utilizing these models, the work in this thesis has shown that disrupting cell adhesion could provide a new combination strategy to sensitise tumour cells to TRAIL therapy.</p> |
| spellingShingle | Biology (medical sciences) Oncology Cell Biology (see also Plant sciences) Tumours Medical Sciences Phipps, L Targeting cell adhesion as a method of sensitising metastatic tumour cells to TRAIL-induced apoptosis |
| title | Targeting cell adhesion as a method of sensitising metastatic tumour cells to TRAIL-induced apoptosis |
| title_full | Targeting cell adhesion as a method of sensitising metastatic tumour cells to TRAIL-induced apoptosis |
| title_fullStr | Targeting cell adhesion as a method of sensitising metastatic tumour cells to TRAIL-induced apoptosis |
| title_full_unstemmed | Targeting cell adhesion as a method of sensitising metastatic tumour cells to TRAIL-induced apoptosis |
| title_short | Targeting cell adhesion as a method of sensitising metastatic tumour cells to TRAIL-induced apoptosis |
| title_sort | targeting cell adhesion as a method of sensitising metastatic tumour cells to trail induced apoptosis |
| topic | Biology (medical sciences) Oncology Cell Biology (see also Plant sciences) Tumours Medical Sciences |
| work_keys_str_mv | AT phippsl targetingcelladhesionasamethodofsensitisingmetastatictumourcellstotrailinducedapoptosis |