Ovarian Cancer: Novel Mechanism Regulating Angiogenesis

MedicalResearch.com:
Egle Avizienyte, PhD
Senior Research Fellow, Institute of Cancer Sciences
Faculty of Medical and Human Sciences
The University of Manchester, Manchester M20 4BX

MedicalResearch.com: What are the main findings of the study?

Dr. Avizienyte: Angiogenesis, the formation of new blood vessels, has been validated as a target in ovarian cancer. However, the benefit from anti-angiogenic therapies, e.g. Vascular Endothelial Growth Factor (VEGF) pathway inhibitors that are currently used in the clinic for the treatment of ovarian cancer has been modest, largely because of redundancy in angiogenic cytokines that regulate tumour angiogenesis.

In this study we validated heparan sulphate 6-O-sulfotranferases 1 and 2 (HS6ST-1 and -2) as targets for developing new therapeutic anti-angiogenic agents for the treatment of ovarian cancer. The data generated in our laboratory show that HS6STs induce the angiogenic programme in ovarian cancer cells and has a major effect on tumour angiogenesis.

Heparan sulphate (HS) is a linear polysaccharide composed of repeating disaccharides that consist of N-substituted glucosamine and a hexuronic acid. The chains of HS are linked to core proteins at cell surface or extracellular matrix and serve as co-receptors for many cell surface signalling molecules. The residue in HS that is prominently involved in the regulation of a number of cellular signalling pathways is a sulphate at 6-O position in glucosamine (6S).6S levels in HS chain are regulated by HS 6-O-sulfotransferases (HS6STs) and extracellular 6-O-endosulfatases (Sulfs) which desulfate 6S.

In this study we demonstrate the critical functional significance of 6-O-sulphation in regulating tumour angiogenesis through paracrine and autocrine regulatory mechanisms that involve HB-EGF signalling in ovarian carcinoma cells. Autocrine HB-EGF/EGFR signalling leads to the activation of angiogenic programme in ovarian cancer cells that involves expression of FGF2, IL-6 and IL-8 in cancer cells which induce angiogenic phenotypes in endothelial cells. Down-regulation of HS6STs and HS 6S levels in ovarian cancer cells impairs establishment of xenograft tumours and their growth in animals through defects in tumour angiogenesis. We also show elevated expression of HS6ST-1 in the majority of ovarian carcinomas when compared to the normal ovarian tissue suggesting the relevance of this isoform in ovarian tumorigenesis.
MedicalResearch.com: Were any of the findings unexpected?
Dr. Avizienyte: We identified a novel mechanism that regulates ovarian cancer angiogenesis by HS 6-O-sulfation-dependent HB-EGF-induced signalling, which impacts the expression of angiogenic cytokines FGF2, IL-6 and IL-8 that play a major role in ovarian tumour angiogenesis. Unexpectedly, our findings revealed novel autocrine and paracrine mechanisms for tumour cell HS-dependent regulation of angiogenesis.

MedicalResearch.com: What should clinicians and patients take away from your report?

Dr. Avizienyte: To date six randomised clinical trials have showed the improvement in progression-free and overall survival when VEGF inhibitors have been added to conventional cytotoxic chemotherapy. Thus VEGF and angiogenesis have been validated as targets for the treatment of ovarian cancer. Despite these achievements the effects of VEGF inhibitor therapy are still modest and new therapeutic agents targeting angiogenic programmes in cancer cells are urgently needed.

Our work strongly suggests that targeting HS6STs may be beneficial in reducing ovarian tumour growth through inhibition of angiogenic programme involving HB-EGF, FGF2, IL-6 and IL-8 in ovarian cancer cells and angiogenic signalling in endothelial cells.

In numerous previous studies we reported the synthesis of site specifically sulphated HS oligosaccharides lacking 6S which acted as competitive inhibitors of endogenous HS. These oligosaccharides inhibited signalling in tumours and cytokine-induced infiltration of blood vessels to subcutaneous sponges in animals.

The studies performed in our laboratory support two concepts:

1) molecules targeting HS6STs or competing with HS 6S sulphation may have a potential as novel anti-angiogenic agents for the treatment of ovarian cancer where they may inhibit a broad spectrum of angiogenic cytokines;

2) HB-EGF, FGF2, IL-6 and IL-8 signature presents a potential biomarker for selecting patients that may benefit from therapies targeting HS 6-O-sulphation.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. Avizienyte: The future research will focus on completing HS6ST target validation studies. Despite our data showing the significance of 6-O-sulphation through HS6STs, validation of the HS6STs as targets in appropriate experimental models using clinical ovarian cancer tissue, e.g. ovarian tumours and ovarian cancer patients’ ascites-derived ovarian cancer cells, is missing. Another question that is necessary to address is how HS6STs impact the response to cytotoxic and anti-angiogenic therapies that are currently used in the clinic for the treatment of ovarian cancer. It is very likely that combinations of cytotoxic agents with HS6ST inhibitors will have enhanced anti-angiogenic and anti-tumour activity.

The future research will provide the experimental data that will justify the development of small molecule inhibitors of HS6STs.

Citation:

Ovarian Cancer Cell Heparan Sulfate 6-O-Sulfotransferases Regulate an Angiogenic Program Induced by HB-EGF/EGF Receptor Signaling

Cole CL1, Rushton G, Jayson GC, Avizienyte E.

J Biol Chem. 2014 Apr 11;289(15):10488-501. doi: 10.1074/jbc.M113.534263. Epub 2014 Feb 22.