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.
    Full-text · Article · Aug 2015 · Neoplasia (New York, N.Y.)
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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.
    Full-text · Article · Jul 2015 · Neuron
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    • "Binding of normal ligands to tumor cell receptors (VEGFR, PDGFR, EFGR), to tumor blood vessel endothelial cell receptors (VEGFR) and to pericyte cell receptors (PDGFR) leads to activation of numerous signaling cascades [80]. To be more specific,(i) prostaglandin-induced vascular cell permeability after activation of IP3 signalling; (ii) actin cytoskeletal rearrangement induced by caveolin, E-cadherin, Muc-1 proteins, and Rho and MKK signalling pathways [81]; (iii) nitric oxide production via PLC and PI3K cascade [82]; (iv) cell proliferation via Ras signalling; and finally (v) cell migration through FAK1 pathway [83], define the core cellular processes that result in angiogenesis. "
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    ABSTRACT: The introduction of therapies that inhibit tumor angiogenesis and particularly target to vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) (VEGF inhibitors/VEGFi) have revolutionized the treatment of various cancer types. Although their clinical benefit can be optimal for cancer-affected patients, the safety of these targeted agents is of special concern especially for longer-term adjuvant or maintenance treatment. Importantly, VEGFi therapy has been significantly associated with hypertension (HTN) as an adverse effect and therefore the control of blood pressure (BP) after the administration of these drugs remains a challenging matter to be faced. The aim of this review is to summarize studies which investigate the association of VEGFi agents with HTN manifestation and the possible risks associated with this complication. Additionally, given that the optimal management of HTN caused by VEGFi remains obscure, this review will focus on prevention strategies including BP monitoring plans and propose potential therapeutic approaches.
    Full-text · Article · Jun 2015
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