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ABSTRACT: Preclinical and clinical evidence shows that antiangiogenic agents can decrease tumor vessel permeability and interstitial fluid pressure (IFP) in a process of vessel "normalization." The resulting normalized vasculature has more efficient perfusion, but little is known about how tumor IFP and interstitial fluid velocity (IFV) are affected by changes in transport properties of the vessels and interstitium that are associated with antiangiogenic therapy. By using a mathematical model to simulate IFP and IFV profiles in tumors, we show here that antiangiogenic therapy can decrease IFP by decreasing the tumor size, vascular hydraulic permeability, and/or the surface area per unit tissue volume of tumor vessels. Within a certain window of antiangiogenic effects, interstitial convection within the tumor can increase dramatically, whereas fluid convection out of the tumor margin decreases. This would result in increased drug convection within the tumor and decreased convection of drugs, growth factors, or metastatic cancer cells from the tumor margin into the peritumor fluid or tissue. Decreased convection of growth factors, such as vascular endothelial growth factor-C (VEGF-C), would limit peritumor hyperplasia, and decreased VEGF-A would limit angiogenesis in sentinel lymph nodes. Both of these effects would reduce the probability of lymphatic metastasis. Finally, decreased fluid convection into the peritumor tissue would decrease peritumor edema associated with brain tumors and ascites accumulation in the peritoneal or pleural cavity, a major complication with a number of malignancies.
Cancer Research 04/2007; 67(6):2729-35. · 7.86 Impact Factor
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ABSTRACT: The role of placenta growth factor (PlGF) in pathologic angiogenesis is controversial. The effects of PlGF on growth, angiogenesis, and metastasis from orthotopic tumors are not known. To this end, we stably transfected three human cancer cell lines (A549 lung, HCT116 colon, and U87-MG glioblastoma) with human plgf-2 full-length cDNA. Overexpression of PlGF did not affect tumor cell proliferation or migration in vitro. The growth of PlGF-overexpressing tumors grown orthotopically or ectopically was impaired in all three tumor models. This decrease in tumor growth correlated with a decrease in tumor angiogenesis. The PlGF-overexpressing tumors had decreased vessel density and increased vessel diameter, but vessel permeability was not different from the parental tumors. Tumors overexpressing PlGF exhibited higher levels of PlGF homodimers and PlGF/vascular endothelial growth factor (VEGF) heterodimers but decreased levels of VEGF homodimers. Our study shows that PlGF overexpression decreases VEGF homodimer formation and inhibits tumor progression.
Cancer Research 05/2006; 66(8):3971-7. · 7.86 Impact Factor
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ABSTRACT: This paper presents model-based information-theoretic methods to quantify the complexity of tumor microvasculature, taking into account shape, textural, and structural irregularities. The proposed techniques are completely automated, and are applicable to optical slices (3-D) or projection images (2-D). Improvements upon the prior literature include: (i) measuring local (vessel segment) as well as global (entire image) vascular complexity without requiring explicit segmentation or tracing; (ii) focusing on the vessel boundaries in the complexity estimate; and (iii) added robustness to image artifacts common to tumor microvasculature images. Vessels are modeled using a family of super-Gaussian functions that are based on the superquadric modeling primitive common in computer vision. The superquadric generalizes a simple ellipsoid by including shape parameters that allow it to approximate a cylinder with elliptical cross-sections (generalized cylinder). The super-Gaussian is obtained by composing a superquadric with an exponential function giving a form that is similar to a standard Gaussian function but with the ability to produce level sets that approximate generalized cylinders. Importantly, the super-Gaussian is continuous and differentiable so it can be fit to image data using robust non-linear regression. This fitting enables quantification of the intrinsic complexity of vessel data vis-a-vis the super-Gaussian model within a minimum message length (MML) framework. The resulting measures are expressed in units of information (bits). Synthetic and real-data examples are provided to illustrate the proposed measures.
Microvascular Research 12/2005; 70(3):165-78. · 2.83 Impact Factor
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Christopher G Willett,
Yves Boucher,
Dan G Duda,
Emmanuelle di Tomaso,
Lance L Munn, Ricky T Tong,
Sergey V Kozin,
Lucine Petit,
Rakesh K Jain,
Daniel C Chung, [......],
Kenneth S Cohen,
David T Scadden,
Alan J Fischman,
Jeffrey W Clark,
David P Ryan,
Andrew X Zhu,
Lawrence S Blaszkowsky,
Paul C Shellito,
Mari Mino-Kenudson,
Gregory Y Lauwers
Journal of Clinical Oncology 12/2005; 23(31):8136-9. · 18.37 Impact Factor
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Annelii Ny,
Marta Koch,
Martin Schneider,
Elke Neven, Ricky T Tong,
Sunit Maity,
Christian Fischer,
Stephane Plaisance,
Diether Lambrechts,
Christophe Héligon, [......],
Sabine Wyns,
Florea Lupu,
André Brändli,
Kris Vleminckx,
Désiré Collen,
Mieke Dewerchin,
Edward M Conway,
Lieve Moons,
Rakesh K Jain,
Peter Carmeliet
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ABSTRACT: Lymph vessels control fluid homeostasis, immunity and metastasis. Unraveling the molecular basis of lymphangiogenesis has been hampered by the lack of a small animal model that can be genetically manipulated. Here, we show that Xenopus tadpoles develop lymph vessels from lymphangioblasts or, through transdifferentiation, from venous endothelial cells. Lymphangiography showed that these lymph vessels drain lymph, through the lymph heart, to the venous circulation. Morpholino-mediated knockdown of the lymphangiogenic factor Prox1 caused lymph vessel defects and lymphedema by impairing lymphatic commitment. Knockdown of vascular endothelial growth factor C (VEGF-C) also induced lymph vessel defects and lymphedema, but primarily by affecting migration of lymphatic endothelial cells. Knockdown of VEGF-C also resulted in aberrant blood vessel formation in tadpoles. This tadpole model offers opportunities for the discovery of new regulators of lymphangiogenesis.
Nature Medicine 10/2005; 11(9):998-1004. · 22.46 Impact Factor
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Frank Winkler,
Sergey V Kozin, Ricky T Tong,
Sung-Suk Chae,
Michael F Booth,
Igor Garkavtsev,
Lei Xu,
Daniel J Hicklin,
Dai Fukumura,
Emmanuelle di Tomaso,
Lance L Munn,
Rakesh K Jain
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ABSTRACT: The recent landmark Phase III clinical trial with a VEGF-specific antibody suggests that antiangiogenic therapy must be combined with cytotoxic therapy for the treatment of solid tumors. However, there are no guidelines for optimal scheduling of these therapies. Here we show that VEGFR2 blockade creates a "normalization window"--a period during which combined radiation therapy gives the best outcome. This window is characterized by an increase in tumor oxygenation, which is known to enhance radiation response. During the normalization window, but not before or after it, VEGFR2 blockade increases pericyte coverage of brain tumor vessels via upregulation of Ang1 and degrades their pathologically thick basement membrane via MMP activation.
Cancer Cell 01/2005; 6(6):553-63. · 26.57 Impact Factor
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ABSTRACT: Elevated interstitial fluid pressure, a hallmark of solid tumors, can compromise the delivery of therapeutics to tumors. Here we show that blocking vascular endothelial growth factor (VEGF) signaling by DC101 (a VEGF-receptor-2 antibody) decreases interstitial fluid pressure, not by restoring lymphatic function, but by producing a morphologically and functionally "normalized" vascular network. We demonstrate that the normalization process prunes immature vessels and improves the integrity and function of the remaining vasculature by enhancing the perivascular cell and basement membrane coverage. We also show that DC101 induces a hydrostatic pressure gradient across the vascular wall, which leads to a deeper penetration of molecules into tumors. Thus, vascular normalization may contribute to the improved survival rates in tumor-bearing animals and in colorectal carcinoma patients treated with an anti-VEGF antibody in combination with cytotoxic therapies.
Cancer Research 07/2004; 64(11):3731-6. · 7.86 Impact Factor
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ABSTRACT: Transport parameters determine the access of drugs to tumors. However, technical difficulties preclude the measurement of these parameters deep inside living tissues. To this end, we adapted and further optimized two-photon fluorescence correlation microscopy (TPFCM) for in vivo measurement of transport parameters in tumors. TPFCM extends the detectable range of diffusion coefficients in tumors by one order of magnitude, and reveals both a fast and a slow component of diffusion. The ratio of these two components depends on molecular size and can be altered in vivo with hyaluronidase and collagenase. These studies indicate that TPFCM is a promising tool to dissect the barriers to drug delivery in tumors.
Nature Medicine 03/2004; 10(2):203-7. · 22.46 Impact Factor
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Christopher G Willett,
Yves Boucher,
Emmanuelle di Tomaso,
Dan G Duda,
Lance L Munn, Ricky T Tong,
Daniel C Chung,
Dushyant V Sahani,
Sanjeeva P Kalva,
Sergey V Kozin, [......],
Alan C Hartford,
Alan J Fischman,
Jeffrey W Clark,
David P Ryan,
Andrew X Zhu,
Lawrence S Blaszkowsky,
Helen X Chen,
Paul C Shellito,
Gregory Y Lauwers,
Rakesh K Jain
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ABSTRACT: The effects of vascular endothelial growth factor (VEGF) blockade on the vascular biology of human tumors are not known. Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure and the number of viable, circulating endothelial and progenitor cells, and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients. These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors.
Nature Medicine 03/2004; 10(2):145-7. · 22.46 Impact Factor
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Frank Winkler,
Sergey V Kozin, Ricky T Tong,
Sung-Suk Chae,
Michael F Booth,
Igor Garkavtsev,
Lei Xu,
Daniel J Hicklin,
Dai Fukumura,
Emmanuelle Di Tomaso,
Lance L Munn,
Rakesh K Jain,
E L Steele
