Cellular abnormalities of blood vessels as targets in cancer

Bałuk, Peter; Hashizume, Hiroya; McDonald, Donald M.

doi:10.1016/j.gde.2004.12.005

Cited by 681 publications

(468 citation statements)

References 55 publications

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“…Angiogenesis, the process by which tumours develop a circulatory blood supply, results in the development of vascular networks that are both structurally and functionally abnormal. Compounds that disrupt new vessel formation (antiangiogenic) or destroy existing vessels (vascular disrupting) offer potential targets for novel anticancer therapy (Baluk et al, 2005). This strategy has been validated by recent studies of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab, which have shown improvement in clinical outcome in phase III randomised-controlled trials in colorectal (Hurwitz et al, 2004) and other common human cancers.…”

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confidence: 99%

DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents

et al. 2007

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Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is now frequently used in early clinical trial assessment of antiangiogenic and vascular disrupting compounds. Evidence of drug efficacy and dose-dependent response has been demonstrated with some angiogenesis inhibitors. This review highlights the critical issues that influence T 1 -weighted DCE-MRI data acquisition and analysis, identifies important areas for future development and reviews the clinical trial findings to date.

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confidence: 99%

DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents

et al. 2007

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“…However, unlike normal vasculature, tumor vessels are irregularly shaped and highly tortuous, and they lack uniform pericyte and basement membrane coverage (1,2). These structural changes contribute to vascular hyperpermeability, nonuniform blood flow and distribution, and high interstitial pressure, which together limit the effectiveness of anti-cancer chemotherapies and radiation therapies by impairing the delivery of drugs and oxygen to the tumor site (3).…”

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confidence: 99%

Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro

Ghosh

Thodeti

Dudley

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

179

183

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Tumor blood vessels exhibit abnormal structure and function that cause disturbed blood flow and high interstitial pressure, which impair delivery of anti-cancer agents. Past efforts to normalize the tumor vasculature have focused on inhibition of soluble angiogenic factors, such as VEGF; however, capillary endothelial (CE) cell growth and differentiation during angiogenesis are also influenced by mechanical forces conveyed by the extracellular matrix (ECM). Here, we explored the possibility that tumor CE cells form abnormal vessels because they lose their ability to sense and respond to these physical cues. These studies reveal that, in contrast to normal CE cells, tumor-derived CE cells fail to reorient their actin cytoskeleton when exposed to uniaxial cyclic strain, exhibit distinct shape sensitivity to variations in ECM elasticity, exert greater traction force, and display an enhanced ability to retract flexible ECM substrates and reorganize into tubular networks in vitro. These behaviors correlate with a constitutively high level of baseline activity of the small GTPase Rho and its downstream effector, Rho-associated kinase (ROCK). Moreover, decreasing Rho-mediated tension by using the ROCK inhibitor, Y27632, can reprogram the tumor CE cells so that they normalize their reorientation response to uniaxial cyclic strain and their ability to form tubular networks on ECM gels. Abnormal Rho-mediated sensing of mechanical cues in the tumor microenvironment may therefore contribute to the aberrant behaviors of tumor CE cells that result in the development of structural abnormalities in the cancer microvasculature.capillary ͉ contractility ͉ elasticity ͉ GTPase ͉ mechanotransduction

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“…In agreement with these data, we observed in vitro induction of apoptosis in HUVEC proliferating cells treated with 5 lM perifosine (data not shown), but no apoptosis was observed in perifosine-treated tumorderived 2H-11 endothelial cells. It is widely appreciated that tumor-associated endothelial cells have a unique activated phenotype and a different structure compared to those in normal quiescent tissues beacause of the exposure to a distinct set of stimuli in their local environment [56]. Furthermore, although tumor-associated angiogenesis has traditionally been defined as the sprouting of new vessels from preexisting vessels, it is becoming clear that the blood vessels that support tumor growth can also originate from cells recruited from the bone marrow or can even differentiate from tumor stem cells (vascular mimicry) [57,58].…”

Section: Discussionmentioning

confidence: 99%

Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34+ cells

et al. 2013

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The proapoptotic death receptor 5 (DR5) expressed by tumor associated endothelial cells (TECs) mediates vascular disrupting effects of human CD34 ? cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL 1 cells) in mice. Indeed, lack of DR5 on TECs causes resistance to CD34-TRAIL 1 cells. By xenografting in nonobese diabetic/severe combined immunodeficient mice the TRAIL-resistant lymphoma cell line SU-DHL-4V, which generates tumors lacking endothelial DR5 expression, here we demonstrate for the first time that the Akt inhibitor perifosine induces in vivo DR5 expression on TECs, thereby overcoming tumor resistance to the vascular disruption activity of CD34-TRAIL 1 cells. In fact, CD34-TRAIL 1 cells combined with perifosine, but not CD34-TRAIL 1 cells alone, exerted marked antivascular effects and caused a threefold increase of hemorrhagic necrosis in SU-DHL-4V tumors. Consistent with lack of DR5 expression, CD34-TRAIL 1 cells failed to affect the growth of SU-DHL-4V tumors, but CD34-TRAIL 1 cells plus perifosine reduced tumor volumes by 60 % compared with controls. In view of future clinical studies using membrane-bound TRAIL, our results highlight a strategy to rescue patients with primary or acquired resistance due to the lack of DR5 expression in tumor vasculature.

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Cellular abnormalities of blood vessels as targets in cancer

Cited by 681 publications

References 55 publications

DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents

DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents

Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro

Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34+ cells

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