The vascular-endothelial protein tyrosine phosphatase: a novel therapeutic target in the tumour vasculature

摘要

Background: The microvasculature of solid tumours is characterized by profound structural and functional abnormality, which mediates several deleterious aspects of tumour behavior. As such, the development of therapeutic strategies to mitigate vascular dysfunction within tumours is an important goal. The Vascular Endothelial Protein Tyrosine Phosphatase (VE-PTP) attenuates the activity of the endothelial cell (EC) Tie-2 receptor tyrosine kinase, a key mediator of vessel maturation. In this study, I aimed to determine the effects of pharmacological VE-PTP inhibition on EC Tie-2 receptor activation and the resultant impact on breast cancer angiogenesis, progression, metastasis and treatment. udMethods: AKB-9778 is a first-in-class VE-PTP inhibitor. I examined its effects on ECs in vitro and on embryonic angiogenesis in vivo using zebrafish assays. The impact of AKB-9778 therapy on the solid tumour vasculature was studied using orthotopic models of primary murine mammary carcinoma as well as both spontaneous and experimental models of metastasis. Finally, I used endothelial nitric oxide synthase (eNOS) deficient mice to establish the causal role of eNOS in mediating the effects of VE-PTP inhibition. udResults: AKB-9778 induced ligand-independent Tie-2 activation in ECs and impaired embryonic zebrafish angiogenesis. In mouse models of breast cancer, AKB-9778 (i) delayed the early phase of tumour growth by enforcing vascular maturity; (ii) slowed progression of micrometastases by preventing extravasation of tumour cells into distant organs (prolonging survival); and (iii) stabilized established primary tumour vessels, enhancing tumour blood perfusion and radiation response. The effects of AKB-9778 on tumour vessels were mediated in part by eNOS activation. udConclusions: The results demonstrate that pharmacological VE-PTP inhibition can normalize the structure and function of tumour vessels through Tie-2 activation. This vascular normalization delays tumour growth and metastasis, and enhances response to concomitant cytotoxic treatments.