Interstitial fluid pressure as an alternate regulator of angiogenesis independent of hypoxia driven HIF-1α in solid tumors

2012 ◽  
Vol 30 (12) ◽  
pp. 2038-2045 ◽  
Author(s):  
Khin Zarchi Aung ◽  
Barry P. Pereira ◽  
Pamela H.S. Tan ◽  
Hwan-Chour Han ◽  
Saminathan S. Nathan
Keyword(s):  
Solid Tumors ◽  
Interstitial Fluid ◽  
Fluid Pressure ◽  
Interstitial Fluid Pressure

scholarly journals Normalization of the Vasculature for Treatment of Cancer and Other Diseases

2011 ◽  
Vol 91 (3) ◽  
pp. 1071-1121 ◽  
Author(s):  
Shom Goel ◽  
Dan G. Duda ◽  
Lei Xu ◽  
Lance L. Munn ◽  
Yves Boucher ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Solid Tumors ◽  
Tumor Angiogenesis ◽  
Interstitial Fluid ◽  
Tumor Hypoxia ◽  
Fluid Pressure ◽  
Tumor Vasculature ◽  
Interstitial Fluid Pressure ◽  
Vascular Normalization ◽  
Anti Vegf

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.

scholarly journals Mathematical Model of the Effect of Interstitial Fluid Pressure on Angiogenic Behavior in Solid Tumors

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Colin Phipps ◽  
Mohammad Kohandel
Keyword(s):  
Mathematical Model ◽  
Growth Factors ◽  
Solid Tumors ◽  
Tumor Angiogenesis ◽  
Interstitial Fluid ◽  
Fluid Pressure ◽  
Interstitial Fluid Pressure ◽  
Angiogenic Growth Factors ◽  
Antiangiogenic Therapies ◽  
Mode Of Transport

We present a mathematical model for the concentrations of proangiogenic and antiangiogenic growth factors, and their resulting balance/imbalance, in host and tumor tissue. In addition to production, diffusion, and degradation of these angiogenic growth factors (AGFs), we include interstitial convection to study the locally destabilizing effects of interstitial fluid pressure (IFP) on the activity of these factors. The molecular sizes of representative AGFs and the outward flow of interstitial fluid in tumors suggest that convection is a significant mode of transport for these molecules. The results of our modeling approach suggest that changes in the physiological parameters that determine interstitial fluid pressure have as profound an impact on tumor angiogenesis as those parameters controlling production, diffusion, and degradation of AGFs. This model has predictive potential for determining the angiogenic behavior of solid tumors and the effects of cytotoxic and antiangiogenic therapies on tumor angiogenesis.

scholarly journals Spatial Measurements of Perfusion, Interstitial Fluid Pressure and Liposomes Accumulation in Solid Tumors

10.3791/54226 ◽  
2016 ◽  
Author(s):  
Shawn Stapleton ◽  
Daniel Mirmilshteyn ◽  
Jinzi Zheng ◽  
Christine Allen ◽  
David A. Jaffray
Keyword(s):  
Solid Tumors ◽  
Interstitial Fluid ◽  
Fluid Pressure ◽  
Interstitial Fluid Pressure
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