NORMALIZATION OF THE VASCULATURE FOR TREATMENT OF CANCER AND OTHER DISEASES

By S. Goel, D. Duda, Lei Xu, Lance L. Munn, Y. Boucher, Dai Fukumura, Rakesh K. Jain. Physiological Reviews, 2011

1,574 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/80c0c1d4024aed2cccf352242d2649d670cc1e22

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Citations in the corpus

Tumor angiogenesis and vascular normalization: alternative therapeutic targets (2017, background): “Moreover, loss of perivascular coverage induced increased vessel immaturity and enhanced metastases [6, 150].”
Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors (2012, background): “Finally, hypoxia lowers the efficacy of radiation, chemotherapy, and immunotherapy (22, 55).”
The role of mechanical forces in tumor growth and therapy (2014, neutral): “Furthermore, a hypoxic microenvironment can select for cells that can survive in a harsh microenvironment, which enhances the invasive and metastatic potential of cancer cells and lowers the efficacy of radiation and immunotherapy (1, 43-45).”
Accessories to the crime: functions of cells recruited to the tumor microenvironment. (2012, neutral): “…angiogenic regulatory factors in their TME, or to pharmacological suppression of VEGF—evidence so-called ''vascular normalization ,'' in which vessels are less torturous, with better pericyte coverage, and improved and less erratic blood flow (De Bock et al., 2011; Goel et al., 2011; Jain, 2005).”
Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. (2013, background): “These effects can be reversed by agents that selectively target the VEGF-VEGFR signaling axis, such as VEGFblocking antibodies (e.g., bevacizumab), or inhibitors of VEGFR tyrosine kinase activity (e.g., lenvatinib) (Goel et al., 2011).”
Vascularization and Angiogenesis in Tissue Engineering: Beyond Creating Static Networks. (2016, background): “Apart from that, mural cells play a role in the regulation of vascular permeability, which means that stabilized vessels will leak less fluid into the tissue, resulting in lower interstitial fluid pressure [23].”
Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B-cells (2012, neutral): “Solid tumors are often poorly vascularized, leading to regions of hypoxia and glucose deficiency (Goel et al., 2011; Schroeder et al., 2005), which must be overcome for cancer cells to continue proliferation and survive.”
Vascular normalization as an emerging strategy to enhance cancer immunotherapy (2013, neutral): “sion, hypoxia, acidity, and a high interstitial fluid pressure (5, 6, 9).”
ANTIANGIOGENESIS STRATEGIES REVISITED: FROM STARVING TUMORS TO ALLEVIATING HYPOXIA (2014, neutral): “Adapted and updated from Goel et al. (2011).”
Angiogenic signaling pathways and anti-angiogenic therapy for cancer (2023, background): “According to clinical and preclinical research, the effects of vascular normalization are closely related to the “time window”.(50) It indicates the period during which the blood vessels exhibit a normal phenotype after proper drug administration.”
Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. (2013, background): “of tumors using both direct and indirect antiangiogenesis agents, including metronomic chemotherapy.(5,102,103) Several new insights”