Abstract
Anti-ANG2 and metronomic chemotherapy block metastasis in mouse models of postsurgical therapy.
Major finding: Anti-ANG2 and metronomic chemotherapy block metastasis in mouse models of postsurgical therapy.
Mechanism: ANG2 blockade inhibits macrophage recruitment via decreased expression of CCL2 and ICAM1.
Impact: ANG2 inhibition may serve as an effective adjuvant therapy to reduce metastatic recurrence.
Many cancer patients who undergo surgical intervention experience metastatic recurrence, underscoring the importance of developing mechanism-based postsurgical adjuvant therapies. Angiopoietin-2 (ANG2), which is commonly expressed by endothelial cells to prime the microenvironment for angiogenesis, has been proposed as a potential target of antiangiogenic drug development. Srivastava, Hu, and colleagues utilized two mouse models of spontaneous metastasis to assess the efficacy of targeting ANG2 in the postsurgical adjuvant setting to limit metastatic growth. In orthotopic breast cancer and anti-VEGF–refractory Lewis lung carcinoma tumor models, anti-ANG2 antibody treatment suppressed angiogenesis in metastatic nodules and reduced the incidence of bone and lung metastases. The combination of ANG2 inhibition with low-dose metronomic chemotherapy (LDMC) further reduced metastatic recurrence and increased overall survival in both models, and produced fewer adverse effects compared with maximum tolerated–dose chemotherapy. Mechanistically, stimulation of ANG2 in endothelial cells resulted in increased expression of chemokine (C-C motif) ligand 2 (CCL2) and intercellular adhesion molecule 1 (ICAM1) via synergistic activation of the NFκB and STAT3 signaling pathways. ANG2-mediated induction of CCL2 and ICAM1 were required for the recruitment of TIE2− metastasis-associated macrophages expressing the CCL2 receptor CCR2 and for adhesion of these macrophages to endothelial cells. In contrast, LDMC, but not anti-ANG2 therapy, diminished the mobilization of a subset of myeloid-derived cells that have been shown to confer resistance to anti-VEGF therapy. Importantly, in patients with breast cancer, expression of ANG2 correlated with expression of CCL2 and ICAM1 in high-grade, but not low-grade, samples, supporting the role of ANG2-driven chemokine and inflammatory signaling in promoting metastasis. Collectively, these data demonstrate the effectiveness of anti-ANG2 therapy in preventing metastatic growth and provide preclinical evidence for the application of anti-ANG2 in combination with LDMC in the postsurgical adjuvant setting.
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