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The role of heparan sulphate proteoglycans in extracellular vesicle-mediated growth factor delivery

Veiga, Sara Isabel Ferreira 2021. The role of heparan sulphate proteoglycans in extracellular vesicle-mediated growth factor delivery. PhD Thesis, Cardiff University.
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The crosstalk between cells in the tumour microenvironment is important for disease progression. Prostate cancer cells secrete extracellular vesicles (EVs), which play a key role in regulating the phenotype of local fibroblasts. Heparan sulphate (HS) glycosaminoglycan (GAG) chains, associated with heparan sulphate proteoglycans (HSPGs), have previously been implicated in EV-mediated communication; in delivery of transforming growth factor beta-1 (TGF-β1) to fibroblasts and in triggering a distinctive myofibroblast differentiation. HSPGs, however, are known to bind a variety of other growth factors and cytokines, and we hypothesise that vesicular-associated HS plays an important role in the simultaneous delivery of complex factors to recipient cells. We anticipated that removal of EV-associated HS would result in attenuated delivery of factors and altered biology. Removal of HS-GAG chains by heparinase III digestion, or selective attenuation of single-HSPG core proteins by genetic manipulation, did not grossly impact biophysical measurements of vesicles. Nonetheless, differences in protein expression between control vs. HS and HSPG-modified EVs were certainly apparent. Removal of HS resulted in loss of several factors from the EV surface. Manipulating core proteins, however, produced complex data with examples of both loss and gain of factors, likely due to the roles of HSPGs in cargo loading during biogenesis. Functional enrichment analysis of these factors suggests roles in cancer-relevant processes such as angiogenesis, tumour invasion and immune function. Loss of EV-associated HS was functionally impactful, with a demonstrable attenuation of fibroblast to myofibroblast differentiation, and attenuated several EV-mediated signalling pathways. EV-activated fibroblasts were further shown to secrete different pro- and anti-inflammatory cytokines following HS modulation of EVs. To explore the immune effects and inflammatory characteristics promoted by EVs, THP1 cells were used as a model for myeloid polarisation. Preliminary data points to a fibroblast secretome capable of inducing an anti-inflammatory THP-1 phenotype. This study provides insight into the complex modalities by which HSPGs control the phenotype of EVs and emphasises the importance of this mechanism of growth factor delivery in processes such as stromal modulation in cancer.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 10 December 2021
Last Modified: 10 Dec 2021 09:33

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