An assessment of breast cancer cell invasion into the bone marrow

Laverty, Thomas (2023) An assessment of breast cancer cell invasion into the bone marrow. PhD thesis, University of Glasgow.

Abstract

Breast cancer is the most commonly diagnosed cancer in women. With the largest clinical problem coming in the form of metastasis. Breast cancer is known to metastasise to secondary tumour sites within the body, namely the liver, brain, lungs and bone marrow. Upon colonisation of the bone marrow, disseminated breast cancer cells (DBCC) interact with resident bone marrow niche cells such as mesenchymal stem cells (MSCs). These interactions are partly responsible for the phenomenon of dormancy observed in DBCCs. In time DBCCs can reawaken, resulting in recurrence and aggressive secondary metastasis, with a very poor clinical outcome for patients. In order for further investigation into this phenomenon, an in vitro dormant breast cancer cell model was developed using the breast cancer cell line MCF7. This model was then used to investigate the triggers of dormant breast cancer cell reawakening.

A hallmark of cancer is an altered metabolic profile, as such the model described above was utilised in order to investigate the influence of secreted factors likely present within the bone marrow niche, on the behaviour of dormant breast cancer cells. Conditioned media from both adipogenic and osteogenic lineage MSCs was shown to be capable of triggering proliferation in the dormant breast cancer cell model. Investigation into the contents of the secretome revealed several pathways shown to be upregulated. These pathways may have an effect on the reawakening of the dormant breast cancer cells. The most interesting pathways revealed by this analysis were the arginine and proline metabolism pathway along with citrulline metabolism, with both providing interesting avenues of exploration.

In this thesis a dormant breast cancer cell model is described and utilised in order to investigate potential triggers of reactivation. Using this model to screen various potential activators of the dormant cancer, the secretome of both adipogenic and osteogenic lineage MSCs was shown to cause an upregulation in the proliferation of dormant MCF7 cells. Specific metabolites of interest were identified such as ornithine, an intermediary molecule in the urea cycle, capable of generating arginine necessary for cellular proliferation. This model thus, can be used for future experiments in order to further investigate the causes behind breast cancer cell dormancy and reawakening.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Dalby, Professor Matthew
• Date of Award: 2023
• Depositing User: Theses Team
• Unique ID: glathesis:2023-83699
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 03 Jul 2023 13:25
• Last Modified: 04 Jul 2023 07:46
• Thesis DOI: 10.5525/gla.thesis.83699
• URI: https://theses.gla.ac.uk/id/eprint/83699