Weis SM, Cheresh DATumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17: 1359-1370

Department of Pathology and Moores University of California-San Diego Cancer Center, University of California-San Diego, La Jolla, California, USA.
Nature medicine (Impact Factor: 27.36). 11/2011; 17(11):1359-70. DOI: 10.1038/nm.2537
Source: PubMed


As angiogenesis is essential for tumor growth and metastasis, controlling tumor-associated angiogenesis is a promising tactic in limiting cancer progression. The tumor microenvironment comprises numerous signaling molecules and pathways that influence the angiogenic response. Understanding how these components functionally interact as angiogenic stimuli or as repressors and how mechanisms of resistance arise is required for the identification of new therapeutic strategies. Achieving a durable and efficient antiangiogenic response will require approaches to simultaneously or sequentially target multiple aspects of the tumor microenvironment.

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    • "Therefore, the success of any anti-EGFR therapy might be limited to the early stages of cancer progression when EGFR inhibitors would effectively target the young, developing intratumoral vasculature, which provides the conduits for early-on primary tumor cell dissemination. In contrast, more mature vessels could be stabilized with protective pericytes that would protect the underlying endothelium from either too high or too low concentrations of VEGF [67] [68]. These considerations can provide additional reasons for the modest success of anti-EGFR inhibitors used in clinic for late-stage cancer patients, whose primary tumors might have larger proportion of co-opted blood vessels that are less sensitive to diminishment of VEGF caused by EGFR therapeutics. "
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    ABSTRACT: Many malignant characteristics of cancer cells are regulated through pathways induced by the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Herein, we show that besides directly affecting the biology of cancer cells per se, EGFR also regulates the primary tumor microenvironment. Specifically, our findings demonstrate that both the expression and signaling activity of EGFR are required for the induction of a distinct intratumoral vasculature capable of sustaining tumor cell intravasation, a critical rate-limiting step in the metastatic cascade. An intravasation-sustaining mode of intratumoral angiogenic vessels depends on high levels of tumor cell EGFR and the interplay between EGFR-regulated production of interleukin 8 by tumor cells, interleukin-8–induced influx of tumor-infiltrating neutrophils delivering their unique matrix metalloproteinase-9, and neutrophil matrix metalloproteinase-9–dependent release of the vascular permeability and endothelial growth factor, VEGF. Our data indicate that through VEGF-mediated disruption of endothelial layer integrity and increase of intratumoral vasculature permeability, EGFR activity significantly facilitates active intravasation of cancer cells. Therefore, this study unraveled an important but overlooked function of EGFR in cancer, namely, its ability to create an intravasation-sustaining microenvironment within the developing primary tumor by orchestrating several interrelated processes required for the initial steps of cancer metastasis through vascular routes. Our findings also suggest that EGFR-targeted therapies might be more effective when implemented in cancer patients with early-staged primary tumors containing a VEGF-dependent angiogenic vasculature. Accordingly, early EGFR inhibition combined with various anti-VEGF approaches could synergistically suppress tumor cell intravasation through inhibiting the highly permeable angiogenic vasculature induced by EGFR-overexpressing aggressive cancer cells.
    Neoplasia (New York, N.Y.) 08/2015; 17(8):634-649. DOI:10.1016/j.neo.2015.08.002 · 4.25 Impact Factor
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    • "During development, growing tissues and organs require adequate vascularization and this can occur via different mechanisms of blood vessel formation, namely vasculogenesis, sprouting angiogenesis, and intussusception (Carmeliet and Jain, 2011; Herbert and Stainier, 2011; Potente et al., 2011; Quaegebeur et al., 2011; Weis and Cheresh, 2011). The process of sprouting angiogenesis is an important mechanism of new vessel formation in most organs, during development , but also in different pathological settings (Carmeliet and Jain, 2011; Jain and Carmeliet, 2012; Potente et al., 2011). "
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    ABSTRACT: The vascular and the nervous system are responsible for oxygen, nutrient, and information transfer and thereby constitute highly important communication systems in higher organisms. These functional similarities are reflected at the anatomical, cellular, and molecular levels, where common developmental principles and mutual crosstalks have evolved to coordinate their action. This resemblance of the two systems at different levels of complexity has been termed the "neurovascular link." Most of the evidence demonstrating neurovascular interactions derives from studies outside the CNS and from the CNS tissue of the retina. However, little is known about the specific properties of the neurovascular link in the brain. Here, we focus on regulatory effects of molecules involved in the neurovascular link on angiogenesis in the periphery and in the brain and distinguish between general and CNS-specific cues for angiogenesis. Moreover, we discuss the emerging molecular interactions of these angiogenic cues with the VEGF-VEGFR-Delta-like ligand 4 (Dll4)-Jagged-Notch pathway. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 07/2015; 87(2):271-296. DOI:10.1016/j.neuron.2015.06.038 · 15.05 Impact Factor
    • "Therefore, the angiogenesis has become an attractive target in therapeutic approaches due to its key role in tumor growth, invasion and metastasis [2] [3] [6] [7] [8]. "
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    ABSTRACT: The strategy of antiangiogenic drugs is based on inhibiting formation of new blood vessels as alternative to limit cancer progression. In this work, we investigated the antitumor and antiangiogenic potential ofeight thalidomide derivatives. Most of the molecules was not cytotoxic but 2a, 2d and 3d revealed weak antiproliferative activity on HL-60, Sarcoma 180 (S180) and normal peripheral blood mononuclear cells. Thalidomide, 2a and 2b were able to inhibit tumor growth (53.5%, 67.9% and 67.4%, respectively) in S180-bearing mice and presented moderate and reversible toxicity on liver, kidneys and spleens. Both analogues (2a and 2b) inhibited cell migration of endothelial (HUVEC) and melanoma cells (MDA/MB-435) at 50 μg/mL. Immunohistochemistry labeling assays with CD-31 (PECAM-1) antibody showed microvascular density (MVD) was significantly reduced in thalidomide, 2a and 2b groups (30 ± 4.9, 64.6 ± 1.8 and 46.5 ± 19.5%, respectively) (p < 0.05). Neovascularization evaluated by Chorioallantoic Membrane Assay (CAM) with compounds 2a and 2b showed reduction of vessels' number (12. 9 ± 2.3 and 14.8 ± 3.3%), neovascularization area (13.1 ± 1.7 and 14.3 ± 1.7%) and total length of vessels (9.2 ± 1.5 and 9.9 ± 1.9%). On the other hand, thalidomide did not alter vascularization parameters. Consequently, addition of thiosemicarbazone pharmacophore group into the phthalimidic ring improved the in vivo antitumor and antiangiogenic potential of the analogues 2a and 2b. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Chemico-biological interactions 06/2015; 239:174-183. DOI:10.1016/j.cbi.2015.06.037 · 2.58 Impact Factor
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