Antiangiogenic Therapy of Cerebral Melanoma Metastases Results in Sustained Tumor Progression via Vessel Co-Option

Abstract

Purpose: In the brain, tumors may grow without inducing angiogenesis, via co-option of the dense pre-existent capillary bed. The purpose of this study was to investigate how this phenomenon influences the outcome of antiangiogenic therapy.Experimental Design: Mice carrying brain metastases of the human, highly angiogenic melanoma cell line Mel57-VEGF-A were either or not treated with different dosages of ZD6474, a vascular endothelial growth factor (VEGF) receptor 2 tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor. Effect of treatment was evaluated using contrast-enhanced magnetic resonance imaging (CE-MRI) and (immuno)morphologic analysis.Results: Placebo-treated Mel57-VEGF-A brain metastases evoked an angiogenic response and were highlighted in CE-MRI. After treatment with ZD6474 (100 mg/kg), CE-MRI failed to detect tumors in either prevention or therapeutic treatment regimens. However, (immuno)histologic analysis revealed the presence of numerous, small, nonangiogenic lesions. Treatment with 25 mg/kg ZD6474 also resulted in efficient blockade of vessel formation, but it did not fully inhibit vascular leakage, thereby still allowing visualization in CE-MRI scans.Conclusions: Our data show that, although angiogenesis can be effectively blocked by ZD6474, in vessel-dense organs this may result in sustained tumor progression via co-option, rather than in tumor dormancy. Importantly, blocking VEGF-A may result in undetectability of tumors in CE-MRI scans, leading to erroneous conclusions about therapeutic efficacy during magnetic resonance imaging followup. The maintenance of VEGF-A-induced vessel leakage in the absence of neovascularization at lower ZD6474 doses may be exploited to improve delivery of chemotherapeutic agents in combined treatment regimens of antiangiogenic and chemotherapeutic compounds.

Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis

“…By inhibiting angiogenesis, minute metastatic deposits should remain dormant, turning cancer into a chronic disease. However, the angiogenesis dependency of tumors in vessel-dense organs may be not strict because tumors may incorporate pre-existent vasculature (Leenders et al, , 2004. Our results point to a possible novel role for antiangiogenic therapy: anti-VEGF therapy in patients with primary cancers might decrease the chance of metastatic spread, not simply by decreasing vascular density, but rather by preventing the formation of metastatic tissue.…”

“…Interestingly, treated tumors still presented with a nodular phenotype, but the nodules lacked These results suggest that metastatic emboli escape the tumor during early stages of tumor growth. Furthermore, they show that ZD6474 treatment does not inhibit metastatic outgrowth in lungs, possibly reflecting the potential to grow by cooption in highly vascularized tissues (Passalidou et al, 2002;Leenders et al, 2004). Furthermore, the intravascular localization of these metastases, very near to air-filled alveoli, may enable tumor growth without additional angiogenesis.…”

Angiogenesis and lymphangiogenesis are downregulated in primary breast cancer

“…Once the tumour has established, tumour cells can grow into solid neoplasms by exploiting the host's preexisting vessels, without the need for new blood vessel formation, especially in vessel-dense organs. This 'co-opting' of vessels could lead to tumour progression even in the absence of neoangiogenesis (Leenders et al, 2004).…”

Microvascular endothelial cell heterogeneity: general concepts and pharmacological consequences for anti-angiogenic therapy of cancer

“…Under the influence of the VEGFR2 inhibitor ZD6474, tumor angiogenesis in the brain was blocked with a concomitant decrease in vessel density, but tumor growth was not inhibited. Instead, tumor progression sustained via cooption of pre-existing vessels (Leenders et al 2004). Interestingly, VEGFR2 was also present on the tumor cells (personal communication, Dr. W.P.J.…”