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A possible IDO1- TSP1 role in breast cancer dormancy

Lopes Bastos, Bruno 2017. A possible IDO1- TSP1 role in breast cancer dormancy. PhD Thesis, Cardiff University.
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Disseminated breast cancer cells have been found in the perivascular niche of lung, brain and bone marrow. Research has suggested that thrombospondin 1 (TSP1), an antiangiogenic protein secreted by endothelial cells, is involved in cancer dormancy. My research aims to clarify the role of TSP1 in cancer dormancy. On the other hand, breast tumours overexpress indoleamine 2,3-dioxygenase (IDO1) which degrades intracellular tryptophan, a key amino acid of TSP1. I aim to investigate whether cancer cells induce endothelial IDO1 expression and therefore limit TSP1 synthesis. I hypothesize that the decrease of TSP1 might enable cancer cell proliferation and angiogenesis. To evaluate whether endothelial cells can induce cancer dormancy, MDA-MB-231 cells were cultured on the top of an endothelial monolayer or treated with endothelial conditioned medium. Ki67, p21 and cell cycle analysis showed that endothelial cells induce cell cycle arrest in MDA-MB-231 cells but not senescence. ki67 was also decreased when MDA-MB-231 cells were cultured with TSP1. MDA-MB-231 revealed to be more resistant to docetaxel, a breast cancer drug, when pre-cultured with TSP1. Conditioned medium experiments showed that MDA-MB-231 cells are capable of inducing endothelial IDO1 expression and it also increased tryptophan degradation, which was prevented by siRNA IDO1 knockdown. Interestingly, endothelial TSP1 secretion was revealed to be decreased under low tryptophan concentration. Immunohistochemistry of breast cancer tissue showed that there was a negative correlation between vascular IDO1 and stromal TSP1. IFNγ, a potent inducer of IDO1, showed to be able to induce endothelial IDO1 and a decrease in endothelial TSP1. Taken together, the data presented here suggests that endothelial cells induce breast cancer dormancy and drug resistance via TSP1. My research also suggests that an IFNγ/IDO1 pathway might decrease TSP1 synthesis leading to cancer cell proliferation and angiogenesis.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 2 October 2017
Last Modified: 05 Nov 2019 03:25

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