Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies

Abstract

Angiogenesis has long been considered an important target for cancer therapy. Initial efforts have primarily focused on targeting of endothelial and tumor-derived vascular endothelial growth factor signaling. As evidence emerges that angiogenesis has significant mechanistic complexity, therapeutic resistance and escape have become practical limitations to drug development. Here, we review the mechanisms by which dynamic changes occur in the tumor microenvironment in response to antiangiogenic therapy, leading to drug resistance. These mechanisms include direct selection of clonal cell populations with the capacity to rapidly upregulate alternative proangiogenic pathways, increased invasive capacity, and intrinsic resistance to hypoxia. The implications of normalization of vasculature with subsequently improved vascular function as a result of antiangiogenic therapy are explored, as are the implications of the ability to incorporate and co-opt otherwise normal vasculature. Finally, we consider the extent to which a better understanding of the biology of hypoxia and reoxygenation, as well as the depth and breadth of systems invested in angiogenesis, may offer putative biomarkers and novel therapeutic targets. Insights gained through this work may offer solutions for personalizing antiangiogenesis approaches and improving the outcome of patients with cancer.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Resistance and escape from antiangiogenesis therapy is multifactorial; it is driven by the intrinsic properties of cancer cell subpopulations and members of the tumor microenvironment, resulting in the evolution of an advantaged tumor ecosystem in response to the stimulus of antiangiogenic therapy. AldoA, Aldolase-A; APO, apolipoprotein; DLL, delta-like ligand; ENA, epithelial neutrophil-activating peptide; FGF, fibroblast growth factor; GCSF, granulocyte colony-stimulating factor; Glut-1, glucose transporter 1; GRO, growth-regulated oncogene; HGF, hepatocyte growth factor; HIF1-α, hypoxia-inducible factor-1 alpha; HRG, histidine-rich glycoprotein; IGF, insulin-like growth factor; IGFBP, IGF binding protein; IL, interleukin; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; PAI, plasminogen activator inhibitor; PDGF, platelet-derived growth factor; PI3K, phosphoinositide 3–kinase; PlGF, placental growth factor; RANTES, regulated and normal T cell expressed and secreted; SDF, stromal cell–derived factor; U-PA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor.