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

Abstract

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 utilizing angiogenesis, some metastases may instead incorporate pre‐existing vessels from surrounding tissue (vessel co‐option). As 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 examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co‐option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co‐opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co‐opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co‐option occurred with high frequency, being present in >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. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature

“…Expanding on this, here we found that CD276 is expressed not only on angiogenic tumor vasculature but also on established vasculature that has been co-opted by the tumor. Because vessel co-option may contribute to resistance to current anti-angiogenic therapies (Bridgeman et al, 2016; Kuczynski et al, 2016), CD276 mAbs could aid in the effective targeting of both angiogenic and non-angiogenic tumor vasculature. In addition to tumor vessels, tumor cells also frequently overexpress CD276 (Brunner et al, 2012; Qin et al, 2013; Zang et al, 2010).…”

Limited Tumor Tissue Drug Penetration Contributes to Primary Resistance against Angiogenesis Inhibitors

“…Both from our group and from others there is a growing body of evidence that these non-sprouting vascularization mechanisms can interfere with the efficacy of the current antiangiogenic treatments 13, 60-63. Therefore, our current studies using subcutaneous models (where sprouting angiogenesis dominates) need to be extended into studies utilizing both orthotopic primary tumors of different origin and metastatic animal models in order to fully explore the potential of the platform presented in the current manuscript.…”

Consensus guidelines for the use and interpretation of angiogenesis assays

“…This clearly demonstrates that non-angiogenic tumor growth is not a rare phenotype. The same applies to primary lung carcinomas and lung metastases for which angiogenic and non-angiogenic HGPs have also been described [121, 122]. In the non-angiogenic, alveolar HGP, cancer cells fill the alveolar spaces and incorporate the capillary blood vessels of the alveolar walls.…”

“…In the non-angiogenic, alveolar HGP, cancer cells fill the alveolar spaces and incorporate the capillary blood vessels of the alveolar walls. Approximately, 40% of the lung metastases from clear cell renal cell carcinoma (ccRCC) present with a non-angiogenic HGP despite the fact that nearly all primary ccRCC relies on sprouting angiogenesis, driven by loss of VHL protein function [122]. …”