Normalization of the Vasculature for Treatment of Cancer and Other Diseases

Abstract

New vessel formation (angiogenesis) is an essential physiological process for embryologic development, normal growth, and tissue repair. Angiogenesis is tightly regulated at the molecular level. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks of cancer. The imbalance of pro- and anti-angiogenic signaling within tumors creates an abnormal vascular network that is characterized by dilated, tortuous, and hyperpermeable vessels. The physiological consequences of these vascular abnormalities include temporal and spatial heterogeneity in tumor blood flow and oxygenation and increased tumor interstitial fluid pressure. These abnormalities and the resultant microenvironment fuel tumor progression, and also lead to a reduction in the efficacy of chemotherapy, radiotherapy, and immunotherapy. With the discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis, efforts have focused on novel therapeutics aimed at inhibiting VEGF activity, with the goal of regressing tumors by starvation. Unfortunately, clinical trials of anti-VEGF monotherapy in patients with solid tumors have been largely negative. Intriguingly, the combination of anti-VEGF therapy with conventional chemotherapy has improved survival in cancer patients compared with chemotherapy alone. These seemingly paradoxical results could be explained by a “normalization” of the tumor vasculature by anti-VEGF therapy. Preclinical studies have shown that anti-VEGF therapy changes tumor vasculature towards a more “mature” or “normal” phenotype. This “vascular normalization” is characterized by attenuation of hyperpermeability, increased vascular pericyte coverage, a more normal basement membrane, and a resultant reduction in tumor hypoxia and interstitial fluid pressure. These in turn can lead to an improvement in the metabolic profile of the tumor microenvironment, the delivery and efficacy of exogenously administered therapeutics, the efficacy of radiotherapy and of effector immune cells, and a reduction in number of metastatic cells shed by tumors into circulation in mice. These findings are consistent with data from clinical trials of anti-VEGF agents in patients with various solid tumors. More recently, genetic and pharmacological approaches have begun to unravel some other key regulators of vascular normalization such as proteins that regulate tissue oxygen sensing (PHD2) and vessel maturation (PDGFRβ, RGS5, Ang1/2, TGF-β). Here, we review the pathophysiology of tumor angiogenesis, the molecular underpinnings and functional consequences of vascular normalization, and the implications for treatment of cancer and nonmalignant diseases.

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…Different human cancers are variably sensitive to antiangiogenic drugs (e.g., inhibitors of endothelial TK receptors or antibodies that block vascular growth factors); furthermore, tumors of a generally refractory type may sporadically show dramatic responses to antiangiogenic drugs (Carmeliet and Jain, 2011b; Chung et al., 2010; Goel et al., 2011; Leite de Oliveira et al., 2011). It can be argued that tumor type or subtype‐specific aspects of the biology of associated endothelial cells (e.g., gene expression programs) may have a role in determining such different responses.…”

Targeting Inflammation to Improve Tumor Drug Delivery

“…Thus, vascular normalization restores tumor perfusion by fortifying the vessel wall and the vascular network structure, which also decreases interstitial fluid pressure due to the reduced amount of fluid leaking from the vessels. Anti-angiogenic treatments worked well in preclinical models but failed in clinical trials [24], and combinatorial approaches have been employed extensively both in preclinical and clinical studies with varying degrees of success [9,25] whereby the anti-angiogenic drug aims to normalize and not destroy the vessels and it is combined with chemotherapy to eradicate the tumor.…”

“…Thus, vascular normalization restores tumor perfusion by fortifying the vessel wall and the vascular network structure, which also decreases interstitial fluid pressure due to the reduced amount of fluid leaking from the vessels. Anti-angiogenic treatments worked well in preclinical models but failed in clinical trials [24], and combinatorial approaches have been employed extensively both in preclinical and clinical studies with varying degrees of success [9,25] whereby the anti-angiogenic drug aims to normalize and not destroy the vessels and it is combined with chemotherapy to eradicate the tumor.Apart from anti-angiogenic treatment, tumor perfusion and tumor vessel function can be significantly improved using metronomic chemotherapy [26], in which lower doses of the chemotherapeutic agent are administered more frequently. In fact, metronomic administration is currently being tested in clinical trials, as it was shown to be more efficacious than maximum tolerated dose treatment in preclinical studies [27].…”

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

“…It is suggested that even though the leaky and irregular tumor vasculatures seems to provide larger gap to allow the nanoparticles traversing through the tumor interstitial and, eventually, nearby the tumor cells, it also reduces the amount of blood flow resulting in flow stasis and causing high IFP. [154] It is known that most of the tumors have high IFP resulting from irregular vasculatures, which can be a barrier for effective nanoparticle delivery in the tumors. [37] On contrary, to enhance the vascular permeability, vascular normalization strategies aim to transforming the aberrant tumor vasculatures into closely resembling normal vasculatures in order to enhance the structural and functional integrity of the vasculature networks by increasing the pericytes coverage, reducing the IFP and leakiness of the vessels (Figure 5A).…”