Investigation of the MUC1-independent action of circulating galectins in metastasis promotion



Chen, Chen
(2014) Investigation of the MUC1-independent action of circulating galectins in metastasis promotion. Doctor of Philosophy thesis, University of Liverpool.

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Abstract

Galectins are galactoside-binding proteins that are expressed by various types of human cells. Recent studies have shown that the levels of circulating galectins are significantly higher in the bloodstream of cancer patients and promote cancer cell adhesion and aggregation by interaction with the cancer-associated mucin protein MUC1. However, previous studies have also shown that circulating galectins have MUC1-independent actions in metastasis promotion. This thesis further explores these MUC-1 independent actions. The studies reported here show that galectin-2, 3, -4 and -8, whose serum concentrations are all increased in cancer patients, induce secretion of various cytokines from endothelial cells in vitro and in vivo: (G-CSF, GM-CSF, IL-6 and sICAM-1 by galectin-3; G-CSF, IL-6 and GROα/CXCL1 by galectin-2; G-CSF, IL-6, GROα/CXCL1 and MCP-1/CCL2 by galectin-4 and -8). The secretion of these cytokines autocrinely/paracrinely enhances the endothelial expression of cell surface adhesion molecules, causing adhesion of cancer cells to the blood vascular endothelium. The galectin-induced secretion of cytokines is also shown to promote endothelial cell migration and tubule formation in angiogenesis. Intravenous introduction of a pathological galectin concentration into nude mice resulted in significant increase of circulating cytokine concentrations within 24 or 48 hours. Higher serum levels of these galectins correlated with higher serum levels of these cytokines in colon and breast cancer patients. Thus the increased circulation of galectins in the bloodstream of cancer patients promotes secretion from the blood vascular endothelium of metastasis-promoting cytokines that enhance circulating cancer cell adhesion and angiogenesis. These MUC1-independent actions of circulating galectins likely make an important contribution to the metastasis-promoting action of circulating galectins. Targeting the actions of circulating galectins in cancer patients therefore represents a promising therapeutic strategy to reduce metastasis and improve survival.

Item Type: Thesis (Doctor of Philosophy)
Additional Information: Date: 2013-09 (completed)
Subjects: ?? QP ??
Divisions: Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 07 Aug 2014 11:20
Last Modified: 25 Jan 2022 18:14
DOI: 10.17638/00018533
Supervisors:
URI: https://livrepository.liverpool.ac.uk/id/eprint/18533