The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of inducing angiogenesis, some cancers vascularize by the non-angiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option prevails in human breast cancer liver metastases, a setting where results with anti-angiogenic therapy have been disappointing. In our preclinical mechanistic studies, we show that cancer cell motility mediated by the Arp2/3 complex is required for vessel co-option in liver metastases in vivo and that combined inhibition of angiogenesis and vessel co-option is more effective than inhibiting angiogenesis alone in this setting. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option may be a warranted therapeutic strategy.

Purpose To evaluate the feasibility of using 3D Magnetic Resonance Elastography (MRE) to determine the stiffness of the pancreas in healthy volunteers. Materials and Methods Twenty healthy volunteers underwent 1.5-T MRE exams using an accelerated echo planar imaging (EPI) pulse sequence with low-frequency vibrations (40 and 60 Hz). Stiffness was calculated with a 3D direct inversion algorithm. The mean shear stiffness in five pancreatic subregions (uncinate, head, neck, body and tail) and the corresponding liver stiffness were calculated. The intrasubject coefficient of variation (CV) was calculated as a measure of the reproducibility for each volunteer. Results The mean shear stiffness (average of values obtained in different pancreatic subregions) was (1.15±0.17) kPa at 40 Hz, and (2.09±0.33) kPa at 60 Hz. The corresponding liver stiffness was higher than the pancreas stiffness at 40 Hz [(1.60±0.21) kPa, mean pancreas-to-liver stiffness ratio: 0.72], but similar at 60Hz [(2.12±0.23) kPa, mean ratio: 0.95]. The mean intrasubject CV for each pancreatic subregion was lower at 40 Hz than 60 Hz (P<0.05 for all subregions, range: 11.9–15.7% at 40 Hz and 16.5–19.6% at 60 Hz). Conclusion 3D pancreatic MRE can provide promising and reproducible stiffness measurements throughout the pancreas, with more consistent data acquired at 40 Hz.