Tumor vessel stabilization and remodeling by anti-angiogenic therapy with bevacizumab.

Bevacizumab-resistant tumor vessels were characterized by an increased vessel diameter and normalization of vascular structures by the recruitment of mature pericytes and smooth muscle cells. Here, we analyzed human liver metastases which were taken at clinical relapse in patients with colorectal adenocarcinoma treated with anti-angiogenic therapy using the humanized monoclonal anti-VEGF bevacizumab. Tumor vessels which are resistant to anti-VEGF therapy are increased in size and characterized by a normalization of the vascular bed. These results were confirmed using NOD SCID mice as animal model and xenograft transplantation of human PC-3 prostate carcinoma cells in combination with bevacizumab treatment. Our results confirmed that anti-angiogenic therapy results in enhanced vascular remodeling by vascular stabilization. This process is apparently accompanied by enhanced necrosis of tumor tissue. These processes interfere with the efficacy of anti-angiogenic therapy because of reduced susceptibility of stabilized vessels by this therapy. These results demonstrate the importance for the development of second generation anti-angiogenic combination therapy concepts to rule out the balance between vascular stabilization followed by a possible de-stabilization making the remained vessels susceptible to a second wave of anti-angiogenic therapy.