ANGIOGENESIS AND HBP

"Glycosylation of angiogenic factors by the hexosamine biosynthetic pathway (HBP), a nutrient sensor with a novel metabolic-signaling role in angiogenesis?”"

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 Obiettivo del progetto (Objective)

'Angiogenesis, the growth of new blood vessels, is vital for tumour malignancy. Attempts to inhibit it by blocking VEGF has had limited success in the clinic with many patients innately resistant or acquiring resistance over time. Therefore, novel anti-angiogenic therapeutic strategies are required to improve overall efficacy and reduce resistance.

Novel work in the Carmeliet lab has highlighted the importance of the metabolic pathway in regulating the switch from a quiescent endothelial cell to a proliferative one. Little is known about how this angiogenic switch is regulated by metabolism and which metabolic pathways are even involved. One such pathway, the hexoasmine biosynthetic pathway (HBP) generates UDP-GlcNAc, necessary for post-translational modification of proteins via glycosylation. N-linked glycosylation can regulate growth factor receptor exposure on the surface and signaling, while O-linked glycosylation can rapidly alter the function and activity of nuclear and cytosolic proteins, alike phosphorylation.

Despite the important roles these modifications have, minimal research has been done into the role of glycosylation in angiogenesis. The proposal of this project is to investigate whether the HBP regulates angiogenesis via a specific “glycosylation switch”. In particular, using multi-disciplinary gene-discovery, pharmacological and genetic approaches in various animal models (zebrafish; mouse), I propose to investigate whether changes in nutrient supply regulate EC responses (quiescence versus proliferation) through selective HBP-mediated glycosylation of Flk1 or Notch and p53, and to explore the role and relevance of the HBP and key glycosylation pathways in EC quiescence / proliferation in vitro and (pathological) angiogenesis in vivo. The combination of genetic and translational studies might also open novel avenues to develop novel anti-angiogenic therapeutic strategies.'

Introduzione (Teaser)

Formation of new blood vessels called angiogenesis is vital for tumour malignancy. The hunt is on for new therapies to block angiogenesis, as current therapies are limited in their success.

Descrizione progetto (Article)

The current treatment for prevention of angiogenesis is the use of vascular endothelial growth factor (VEGF)-inhibitors. Unfortunately, most patients have innate resistance or acquire resistance over time to such inhibitors.

Prior research has highlighted the importance of the hexoasmine biosynthetic pathway (HBP) in transforming the quiescent endothelial cell (EC) into a proliferative state for angiogenesis. HBP is necessary for protein glycosylation. N- and O- types of glycosylation provide a short- and long-term regulatory link to nutrition.

Quiescent EC occurs in good nutritional circumstances. Ironically, shortage of oxygen (and energy) activates EC to revascularise damaged tissue but this process is also seen during neovascularisation of malignant cancers. The EU-funded ANGIOGENESIS AND HBP project looked at whether HBP co-regulates EC growth or quiescence by integrating nutrient availability with appropriate chemical signals.

Researchers investigated various elements of the HBP pathway. Expression of the UAP1 gene at the final step of HBP is the rate-limiting reaction. Inhibition of UAP1 expression resulted in massive decreases in EC sprouting. The researchers are developing knock-out mice to investigate this phenomenon further.

Work on O-glycosylation compared quiescent ECs with proliferative state. Results showed a marked decrease in O-linked N-acetylglucosamine modified proteins and O-GlcNAc transferase (OGT) in the angiogenic mode. Further work is needed to ascertain the roles of OGT in promoting autophagy when cell components are degraded during nutrient stress to provide energy. Autophagy is the process where dysfunctional or unnecessary cellular components are degraded by lysosomes.

A unique type of O-glycosylation is required during VEGF signalling for EC quiescence or proliferation. Mediated by three isoforms of fringe proteins, radical fringe is expressed far more in ECs than the other two.

It appears that tip cells (leading cells of vascular sprouts) in nutritionally poor environments experience decreased N-glycosylation that in turn stimulates autophagocytosis.

The ANGIOGENESIS AND HBP project has laid down a substantial knowledge platform on which to base further research on this critical stage of cancer malignancy. The precise molecular details of pathways involved can open up possibilities to develop new anti-angiogenic therapies.