Normalization of the Vasculature for Treatment of Cancer and Other Diseases
Tóm tắt
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.
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Tài liệu tham khảo
Baish JW, 2000, Cancer Res, 60, 3683
Baum O, 2010, Microcirculation, 17, 447
Boucher Y, 1990, Cancer Res, 50, 4478
Boucher Y, 1991, Cancer Res, 51, 6691
Browder T, 2000, Cancer Res, 60, 1878
Cohen-Jonathan E, 2001, Cancer Res, 61, 2289
Delmas C, 2003, Clin Cancer Res, 9, 6062
Ehrmann RL, 1968, J Natl Cancer Inst, 41, 1329
Emblem KE, 2011, Proceedings of the 2011 Meeting of the International Soceity for Magnetic Resonance in Medicine
Folkman MJ, 1962, Surg Forum, 13, 81
Gorski DH, 1999, Cancer Res, 59, 3374
Greenblatt M, 1968, J Natl Cancer Inst, 41, 111
Gullino PM, 1982, Biomedical Thermology
Gullino PM, 1978, J Natl Cancer Inst, 61, 639
Hansen-Algenstaedt N, 2000, Cancer Res, 60, 4556
Hockel M, 1999, Cancer Res, 59, 4525
Huang X, 2002, Cancer Res, 62, 5727
Ide AG, 1939, Am J Radiol, 42, 891
Jain RK, 1988, Cancer Res, 48, 2641
Jain RK, 1988, Cancer Res, 48, 7022
Kozin SV, 2001, Cancer Res, 61, 39
Lee CG, 2000, Cancer Res, 60, 5565
Less JR, 1992, Cancer Res, 52, 6371
Less JR, 1991, Cancer Res, 51, 265
Leunig M, 1992, Cancer Res, 52, 6553
Lu-Emerson C, 2009, Rev Neurol Dis, 6, E81
Ma J, 2001, Cancer Res, 61, 5491
Maione F, 2009, J Clin Invest, 119, 3356
Quaegebeur A, 2010, Curr Top Microbiol Immunol, 810, 71
Relf M, 1997, Cancer Res, 57, 963
Roh HD, 1991, Cancer Res, 51, 6695
Schlingemann RO, 1991, Am J Pathol, 138, 1335
Stohrer M, 2000, Cancer Res, 60, 4251
Teicher BA, 1995, Oncol Res, 7, 237
Tsukada K, 2009, 100th Annual Meeting of AACR
Winkler F, 2004, Cancer Cell, 6, 553
Yoshiji H, 1997, Cancer Res, 57, 3924