Contrast enhanced MRI and intravital fluorescence microscopy indicate improved tumor microcirculation in highly vascularized melanomas upon short-term anti-VEGFR treatment

Abstract

Anti-angiogenic therapy by blocking VEGF signalling combined with standard chemotherapy is a novel strategy for clinical cancer treatment. The mechanisms for enhanced antitumoral effects are still a matter of controversial debate. Tumor vessel "normalization" upon anti-angiogenic therapy leading to improved drug delivery has been proposed as possible mechanism. Therefore, aim of the study was to investigate tumor microvascular function upon anti-VEGFR treatment in highly vascularized melanomas. A detailed intravital-microscopic analysis of tumor microcirculation including the distribution pattern of vessel diameters and blood flow velocities was performed in melanomas grown in dorsal skinfold chambers of hamsters. Animals with highly vascularized established tumors were treated by a VEGFR tyrosin kinase inhibitor (SU5416) on 3 repetitive days. Tumor tissue oxygenation was measured by phosphorescence quenching technique. Overall tumor microcirculation of subcutaneous tumors was investigated by contrast enhanced MRI (CE-MRI). Vessel density was significantly decreased in treated animals. A significant shift in the distribution patterns towards increased vessel diameters and faster red blood cell velocities in remaining tumor vessels was observed upon anti-VEGF treatment, compensating reduced vascular density. Moreover, a trend towards elevated pO(2) levels in treated tumors was observed. Compared to controls, inflow kinetics of tumors quantified by CE-MRI as well as overall uptake of contrast agent in tumor tissue were significantly increased following short-term SU5416 treatment. In conclusion the results confirm temporarily improved tumor microvascular function in highly vascularized melanomas upon short term anti-VEGFR treatment leading to enhanced tumor blood supply and oxygenation potentially improving the efficacy of simultaneous chemo- or radiotherapy.

Targeting oncogenic serine/threonine-protein kinase BRAF in cancer cells inhibits angiogenesis and abrogates hypoxia

“…Finally, the effect of PLX4720 on SK-MEL-28 tumor vasculature is in line with the phenotype observed by treating melanoma tumors with VEGFreceptor inhibitor. As a matter of fact, in the SK-MEL-3 melanoma model, treatment with sunitinib caused a significantly decrease in vessel density, but the pressure of oxygen and uptake of contrast agent used in resonance imaging were increased (50).…”

The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities

“…Across several different human tumor cell lines, including gliomas, mammary ovary, and melanoma carcinomas, VEGF-targeting therapies, including antibodies (e.g., DC-101, bevacizumab) and kinase inhibitors (e.g., sunitinib and semaxanib), create a transient vessel normalization window, leading to improvements in vessel function and a concomitant decrease in hypoxia as assessed by PIMO, PET imaging, or pO 2 electrode measurements (69,78,271,290). In addition, supplemental radiation therapy administered during this normalization window decreases in tumor growth compared with radiation administered outside the normalization window ( P < 0.05), ascribable to a transient decrease of hypoxia.…”

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

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