Vessel co‐option is common in human lung metastases and mediates resistance to anti‐angiogenic therapy in preclinical lung metastasis models

Victoria L Bridgeman, Peter B Vermeulen, Shane Foo, Agnes Bilecz, Frances Daley, Eleftherios Kostaras, Mark R Nathan, Elaine Wan, Sophia Frentzas, Thomas Schweiger, Balazs Hegedus, Konrad Hoetzenecker, Ferenc Renyi‐Vamos, Elizabeth A Kuczynski, Naveen S Vasudev, James Larkin, Martin Gore, Harold F Dvorak, Sandor Paku, Robert S Kerbel, Balazs Dome, Andrew R Reynolds

Anti-angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti-angiogenic therapies are poorly understood. Importantly, rather than utilising angiogenesis, some metastases may instead incorporate pre-existing vessels from surrounding tissue (vessel co-option). Since anti-angiogenic therapies were designed to target only new blood vessel growth, vessel co-option has been proposed as a mechanism that could drive resistance to anti-angiogenic therapy. However, vessel co-option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti-angiogenic therapy in lung metastases is not established. Here we examine the mechanism of tumour vascularisation in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identify four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing and pushing) that each vascularise via a different mechanism. In the alveolar HGP, cancer cells invade the alveolar air spaces, which facilitates the co-option of alveolar capillaries. In the interstitial HGP, cancer cells invade into the alveolar walls to co-opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grow by co-opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularise by angiogenesis. Importantly, vessel co-option occurred with high frequency, being present in over 80% of the cases examined. Moreover, we provide evidence that vessel co-option mediates resistance to the anti-angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co-option in lung metastases occurs through at least three distinct mechanisms, that vessel co-option occurs frequently in lung metastases and that vessel co-option could mediate resistance to anti-angiogenic therapy in lung metastases. Novel therapies designed to target both angiogenesis and vessel co-option are therefore warranted.