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Title: Discovery of molecular signatures underlying angiogenic versus non angiogenic tumours
Author: Komsany, Alia
ISNI:       0000 0004 7966 2356
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Angiogenesis has long been considered an essential prerequisite for tumour growth and progression. However, this understanding is being overturned by studies showing that many human tumours can metastasise without angiogenesis, suggesting that their microcirculation may be provided by non - sprouting vessels. Vessel co-option, a mechanism whereby tumour cells may incorporate and or migrate along pre-existing vessels presents an alternative mode of tumour blood supply. Vessel co-option has been found to manifest in many malignancies, occurring with increased frequency in highly vascularised tissues, such as the brain, lung and liver. 10-30% of primary and metastatic lung cancer, in addition to liver metastasis originating from different primary sources, have been found to utilise this alternative mode of blood supply. Furthermore, owing to the fact anti angiogenic drugs were designed to target new blood vessel growth, co-option as a result has also been proposed as a mechanism that could drive drug resistance to anti - angiogenic therapy. However, vessel co-option in the context of lung metastases has not been investigated extensively and likewise it's potential to induce drug resistance in lung metastases is not well established. The aim of the work described in this thesis was therefore to investigate and further understand the molecular underpinnings that determine whether a tumour will exhibit a co-optive phenotype or an angiogenic phenotype and thus shed light on co-optive drug resistance molecular mechanisms in the context of lung metastases. Using a lung metastasis mouse model of co-option established originally by Andy Reynolds at the ICR in London, a multi omics approach was utilised to profile the "in vitro" and in "vivo" settings and identify potential molecular candidates that discriminate between angiogenesis and vessel co - option. These studies revealed the potential role the cellular microenvironment plays in dictating metastatic potential in addition to metabolic cellular profiles, ultimately driving the decision to co - opt existing vessels or promote angiogenesis. Moreover, preliminary proteomic and metabolomic data points towards potential differential regulation of metabolic pathways, cell signalling pathways and proteins involved in adhesion that show distinct profiles within tumour cells with different metastatic potential and tissues from co - opting versus angiogenic models. Of particular interest is the possible role of Carbonic anhydrase 2, the Na+/H+ exchanger protein family and pH regulation in general towards controlling the cellular tumorigenic potential and possibly the fate of angiogenic versus co optive tumours. To further drill down on this, subsequent proteomic analysis carried out on laser capture micro dissected tumours and vessels have further confirmed the role of metabolism, with proteins involved in lipid metabolism and reactive oxidative species metabolism being found to be upregulated in co optive vessels when compared to their angiogenic counterparts. In addition to this, the differential abundance of Carbonic anhydrase 2 was similarly confirmed, as well as proteins implicated in both adhesion and migration processes. In summary, these studies have contributed to paving the necessary groundwork in relation to understanding co-option in a pre-clinical model of lung metastases. They have not only confirmed what has been already noted in the literature but have also highlighted potential new molecular targets and pathways, worthy of further study and investigation.
Supervisor: Kessler, Benedikt M. ; Pezzella, Francesco Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available