Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia

Abstract

Ten antiangiogenic drugs targeting VEGF or its receptors are approved for cancer treatment. However, these agents, intended to block tumors' blood supply, may cause hypoxia, which may fuel tumor progression and treatment resistance. Emerging clinical data suggest that patients whose tumor perfusion or oxygenation increases in response to these agents may actually survive longer. Hence, strategies aimed at alleviating tumor hypoxia while improving perfusion may enhance the outcome of radiotherapy, chemotherapy, and immunotherapy. Here I summarize lessons learned from preclinical and clinical studies over the past decade and propose strategies for improving antiangiogenic therapy outcomes for malignant and nonmalignant diseases.

Figure 1. Hypoxia and acidosis resulting from impaired perfusion fuel tumor progression and treatment resistance

Adverse consequences of hypoxia and acidosis and some of the molecular players contributing to these: 1) Induction of cancer “stem cell” phenotype (e.g., Akt/β-catenin, OCT4) (Lee and Simon, 2012); 2) Resistance to radiotherapy, chemotherapy and immunotherapy (e.g., fewer oxygen radicals, cell cycle arrest) (Huang et al., 2013; Neri and Supuran, 2011; Wilson and Hay, 2011); 3) Tumor growth and genomic instability: Expression of growth factors (e.g., IGF1, TGF-α), oncogenes, tumor suppressor genes (Bindra et al., 2007; Bristow and Hill, 2008; Wilson and Hay, 2011); 4) Epithelial to mesenchymal transition (EMT), invasion and metastasis (e.g., CXCR4, Snail, Lox, cMET) (Finger and Giaccia, 2010; Semenza, 2014); 5) Inflammation, immunosuppression and fibrosis (e.g., IL-6, TGF-β, SDF1α, TAM polarization, Tregs, MDSCs) (Casazza et al., 2013; Chen et al., 2014; Colegio et al., 2014; Motz and Coukos, 2013; Palazón et al., 2012; Semenza, 2014); 6) Abnormal angiogenesis (e.g., HIFs/VEGF, Ang2) (Carmeliet and Jain, 2011); 7) Resistance to apoptosis/autophagy (e.g., BNIP3) (Semenza, 2014); and 8) Switch to anaerobic metabolism (e.g., Glut1, LDHA, PGK1) (Semenza, 2014; Vander Heiden et al., 2009). Many of these consequences are dependent on HIF1α while others are not. Therefore, improving tumor perfusion may alleviate these adverse consequences. Inset shows heterogeneous perfusion in a tumor leading to hypoxic and acidic regions. [Inset reproduced from (Vakoc et al., 2009)]. See also Movie S1.

Figure 2. Effect of vascular normalization on tumor perfusion/oxygenation

A, In a normal tissue, the blood vessels have normal structure and function due to balance of the signals downstream of the pro-angiogenic molecules (e.g., VEGF, Ang2) and antiangiogenic molecules (e.g., sVEGFR1, thrombospondins, semaphorins). In contrast, tumor vessels are structurally and functionally abnormal due to imbalance between pro- and antiangiogenic signals. This creates an abnormal microenvironment in tumors – characterized by hypoxia, acidosis and elevated fluid pressure – which fuels tumor progression and treatment resistance via multiple mechanisms shown in Figure 1. Inhibiting pro-angiogenic signaling or enhancing antiangiogenic signaling can prune some abnormal vessels and remodel the rest resulting in a “normalized vasculature”. Depending upon the extent of normalization versus pruning, tumor perfusion/oxygenation may increase, remain unchanged or decrease. Some tumors might be intrinsically resistant to a given AA agent and others may switch to non-sprouting mechanisms of vessels recruitment (e.g., vessel cooption) that are refractory to the given AA agent and continue to make abnormal vessels again. [Adapted and updated from Jain, 2001 and Sorensen et al, 2012]. See also Movie S2. B, The window of increased perfusion from vascular normalization depends on the dose and potency of antiangiogenic therapy. High doses may cause excessive pruning of tumor vessels resulting in a shorter window, and may starve a tumor of oxygen and other nutrients. High doses may also increase toxicity – including some fatal. [Adapted and updated from Jain, 2013].

Figure 3. Pathways that facilitate or hinder vascular normalization

Although most studies on vascular normalization have focused on VEGF, a number of molecular players can facilitate (green) or hinder normalization (red). Please note that the outcome may be dose and context-dependent. Table 2 provides further details about each of these molecular players. (Tumor cell is depicted near endothelial cells to save space.) [Adapted and updated from Goel et al, 2011].

Figure 4. Vascular normalization can reprogram the tumor microenvironment from immunosuppressive to immunosupportive

The abnormal tumor vasculature can impede T-effector cell infiltration into tumors, and create a hypoxic and acidic tumor microenvironment, which up-regulates PD-L1 on myeloid-derived suppressor cells (MDSCs), dendritic cells and cancer cells, impairs T-effector cell and polarizes tumor-associated macrophages (TAMs) to the immune inhibitory M2-like phenotype to suppress T-effector cell function. Hypoxia can also up-regulate multiple immune-suppressive growth factors and cytokines (e.g., VEGF, TGFβ). Vascular-normalization with appropriate dose and schedule of antiangiogenic treatment can normalize the tumor vasculature and generate a more homogeneous distribution of perfused tumor vessels, facilitating the infiltration of T-effector cells while reducing MDSC accumulation. In addition, alleviation of hypoxia and acidity by improved vascular perfusion polarizes TAMs to an immunostimulatory M1-like phenotype. [Adapted and updated from Huang et al, 2013].