The role of Matrix Metalloproteinase-8 in anti-cancer immunity

Makin, Kate (2019) The role of Matrix Metalloproteinase-8 in anti-cancer immunity. Doctoral thesis, University of East Anglia.

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The existing literature suggests that MMP-8 is protective in the context of several cancers. In breast cancer (BC) patients, MMP-8 expression correlates with increased relapse free survival. In vivo,absence of Mmp8 increases tumour burden and lung metastasis in the MMTV-PyMT spontaneous mouse mammary cancer model. Data imply that the putative host-protective role of MMP-8 may be via its ability to orchestrate the immune system. Therefore, in vivo studies were required to establish the mechanistic link between MMP-8 and immunity. Using Mmp8 null mice orthotopically injected with MMTV-PyMT-derived mammary tumours, we have found conflicting data in this alternative model. There was no impact on tumour volume in the absence of Mmp8 and there were no consistent changes to intra-tumoural immune infiltrates by flow cytometry or cytokine gene expression in comparison to wild-type controls. As a caveat to these findings, upon sequencing of the Casp11 gene in Mmp8 nullmice, a 5 base-pair deletion was discovered, rendering caspase-11 non-functional. This finding prevented definitive conclusions to be made on the impact of MMP-8 in our existing mice, therefore investigations were carried out to ascertain whether the passenger mutation contributed to any results by using the Mmp8 KO mouse without the Casp11 mutation. However, using these animals there was still a lack of tumour or immune phenotype. This leads to two conclusions: firstly, our data suggests that the passenger mutation did not contribute to any phenotype or lack thereof. Moreover, MMP-8 did not suppress primary growth of orthotopically implanted BC tumours via co-ordination of the immune system. The discrepancy with previous findings advocates for further exploration of the differences between the spontaneous and orthotopic implant model in Mmp8 KO mice to pinpoint the role of MMP-8 in tumourigenesis.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Chris White
Date Deposited: 01 Jun 2020 09:13
Last Modified: 01 Jun 2020 09:13

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