Antiangiogenic Therapies Targeting the Vascular Endothelia Growth Factor Signaling System

Royal Melbourne Hospital, Western Hospital, and Ludwig Institute for Cancer Research, Parkville, Victoria, Australia.
Critical reviews in oncogenesis 01/2012; 17(1):51-67. DOI: 10.1615/CritRevOncog.v17.i1.50
Source: PubMed


Angiogenesis is critical to the growth of human tumors and the development of metastasis. Amongst the many proangiogenic mechanisms identified, the vascular endothelial growth factor (VEGF) signaling pathway has been implicated as the key regulator of tumor neovascularisation. Various therapeutic agents targeting the VEGF pathway have been successfully developed, with many now approved and in routine clinical use. In general, VEGF-mediated angiogenesis can be inhibited by 2 approaches: antibodies directed against VEGF ligands or VEGF receptors (VEGFRs) and tyrosine kinase inhibitors targeting the VEGFRs. Thus far, clinical benefits achieved with VEGF-targeted agents are limited by their modest efficacy and the development of resistance. With no shortage of drugs in development, the lack of well-validated biomarkers to predict for response or resistance to VEGF-directed therapies is now becoming a key factor limiting the further rational development of this class of anticancer agent. This review discusses the biology of VEGF signaling, the clinical efficacy of VEGF-targeting therapies, potential mechanisms of resistance, and emerging predictive biomarkers.

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    • "When VEGF is overexpressed, it contributes to disease. Cancers that express VEGF are able to grow and metastasize (19). After mice were treated with Ad-hLF, we detected VEGF expression in tumor tissues using immunohistochemistry. Brown nuclei indicated VEGF-positive cells and blue nuclei indicated VEGF-negative cells. "
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    ABSTRACT: Human lactoferrin (hLF) is a multifunctional glycoprotein that inhibits cancer growth. However, the inhibitory effect of this glycoprotein in cervical cancer remains inconclusive. This study investigated the efficacy of hLF on the inhibition of U14 cervical cancer in vivo. Recombinant adenovirus carrying hLF (Ad-hLF) were constructed. Mice inoculated with U14 cells were randomly allocated to four treatments: i) Phosphate-buffered saline (negative control), ii) Ad-green fluorescent protein (negative control), iii) Ad-hLF (studied) or iv) cyclophosphamide (CTX; positive control). Tumor growth, as well as levels of natural killer (NK) cells, CD4(+) and CD8(+) peripheral blood T lymphocyte subpopulations, serum cytokines and vascular endothelial growth factor (VEGF) in tumor tissues were detected. Compared with the negative controls, tumor growth was inhibited by hLF and mice lifespans in the Ad-hLF-treated group were prolonged to reach the levels of the CTX-treated group. The activity of tumor-killing NK cells was upregulated by hLF. Moreover, the number of CD4(+) and CD8(+) peripheral blood T lymphocyte subpopulations increased following treatment with Ad-hLF. Treatment with Ad-hLF increased the levels of serum interferon-γ, serum interleukin-2 (IL-2) and tumor necrosis factor-α, and decreased the levels of serum IL-4 in tumor-bearing mice. The expression of VEGF in tumor tissues was downregulated by hLF. In conclusion, hLF inhibits the growth of U14 solid tumors by modulating the immune response of tumor-bearing mice.
    Oncology letters 03/2014; 7(3):820-826. DOI:10.3892/ol.2013.1776 · 1.55 Impact Factor
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    • "Based on this knowledge, an extensive number of molecular targets have been proposed for which new (inhibitory) drugs have been designed. These drugs range from antibodies that neutralize growth factors and/or receptors (Brown et al. 2010; Ellis and Reardon 2009) to small molecular entities that inhibit the various signaling pathways (Fig. 2) (Keri et al. 2006; Tie and Desai 2012). For angiogenesis inhibition, VEGFtargeted therapies have been studied most extensively. "
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    ABSTRACT: Many studies on the molecular control underlying normal cell behavior and cellular responses to disease stimuli and pharmacological intervention are conducted in single-cell culture systems, while the read-out of cellular engagement in disease and responsiveness to drugs in vivo is often based on overall tissue responses. As the majority of drugs under development aim to specifically interact with molecular targets in subsets of cells in complex tissues, this approach poses a major experimental discrepancy that prevents successful development of new therapeutics. In this review, we address the shortcomings of the use of artificial (single) cell systems and of whole tissue analyses in creating a better understanding of cell engagement in disease and of the true effects of drugs. We focus on microvascular endothelial cells that actively engage in a wide range of physiological and pathological processes. We propose a new strategy in which in vivo molecular control of cells is studied directly in the diseased endothelium instead of at a (far) distance from the site where drugs have to act, thereby accounting for tissue-controlled cell responses. The strategy uses laser microdissection-based enrichment of microvascular endothelium which, when combined with transcriptome and (phospho)proteome analyses, provides a factual view on their status in their complex microenvironment. Combining this with miniaturized sample handling using microfluidic devices enables handling the minute sample input that results from this strategy. The multidisciplinary approach proposed will enable compartmentalized analysis of cell behavior and drug effects in complex tissue to become widely implemented in daily biomedical research and drug development practice.
    Cell and Tissue Research 09/2013; 354(3). DOI:10.1007/s00441-013-1714-7 · 3.57 Impact Factor
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    • "Of the VEGF splice variants, VEGF 165 is best characterized and is primarily found in many different cells and tissues that express the VEGF gene. Generally , VEGF family members have functions, such as, endothelial cell growth, angiogenesis, and vasculogenesis [10] [11] [12]. These functions are mainly mediated via the binding and activating of VEGF receptor (VEGFR) [13]. "
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    ABSTRACT: Vascular endothelial growth factors (165) (VEGF(165)) is the most potent and widely used pro-angiogenic factor. Here we determined optimal culture condition of recombinant human VEGF(165) (rhVEGF(165)) in Escherichia coli (E. coli). rhVEGF(165) expression was the highest in 0.25% of L-arabinose induction concentration, at 20 °C induction temperature, and for 5 h induction time under the control of araBAD promoter using pBADHisA vector. In biological activity test, rhVEGF(165) significantly increased the proliferative activity of CPAE cells (p < 0.001) and upregulated the expressions of endothelial cell growth-related genes, such as platelet endothelial cell adhesion molecule (PECAM-1), endothelial-specific receptor tyrosine kinase (TEK), kinase insert domain protein receptor (KDR), and tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1) in calf pulmonary artery endothelial (CPAE) cells.
    Protein Expression and Purification 10/2012; 87(2). DOI:10.1016/j.pep.2012.10.004 · 1.70 Impact Factor
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