DOCSLIB.ORG

Administration of VEGF Receptor Tyrosine Kinase Inhibitor Increases VEGF Production Causing Angiogenesis in Human Small-Cell Lung Cancer Xenografts

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Administration of VEGF Receptor Tyrosine Kinase Inhibitor Increases VEGF Production Causing Angiogenesis in Human Small-Cell Lung Cancer Xenografts 525-532 1/8/08 14:28 Page 525 INTERNATIONAL JOURNAL OF ONCOLOGY 33: 525-532, 2008 525 Administration of VEGF receptor tyrosine kinase inhibitor increases VEGF production causing angiogenesis in human small-cell lung cancer xenografts TAKAAKI SASAKI, SACHIE TANNO, KIYOKO SHIBUKAWA, SHINOBU OSANAI, JUNICHI KAWABE and YOSHINOBU OHSAKI Respiratory Medicine, Asahikawa Medical College, Asahikawa, Hokkaido, Japan Received February 27, 2008; Accepted May 13, 2008 DOI: 10.3892/ijo_00000036 Abstract. Angiogenesis is mediated mainly by vascular endo- Introduction thelial growth factor (VEGF), and VEGF causes rapid growth in cancers, including human small-cell lung cancer (SCLC). Cancer therapy with high specificity and few adverse effects The anti-angiogenic strategy of treating cancer using VEGF has been pursued since anti-cancer agents were introduced. receptor (VEGFR) inhibition is currently of great interest. We Increasing our knowledge of cancer cell biology will help tested the effects of the VEGFR2 tyrosine kinase inhibitor develop better cancer therapies. Low molecular weight (TKI) vandetanib on the proliferation of two kinds of SCLC compounds that inhibit specific functions of the malignant cell lines: SBC-1 cells, with detectable VEGFR2 expression cells have been introduced to anti-cancer therapy. Some and MS-1-L cells, without detectable VEGFR2 expression. of these compounds were designed to block growth factor To evaluate the anti-tumor and anti-angiogenic effects of receptor signaling in human cancer by interacting with a vandetanib in vivo, we grafted SBC-1 and MS-1-L cells into specific portion of the growth factor receptors. Such mice. After a 3-week treatment, we measured the tumor size compounds include small molecules that inhibit ligand- and histologically evaluated necrosis and apoptosis using induced activation of the growth factor receptor tyrosine H&E and TUNEL staining, respectively. The microvessels in kinase, small molecule tyrosine kinase inhibitors (TKI) (1). the xenografts were also quantified by immunostaining of These agents have the potential to develop into therapies CD31. Vandetanib did not affect the proliferation of SBC-1 with high specificity and low toxicity (2). cells, but stimulated the growth of MS-1-L cells. In the Several small molecule TKIs with anti-angiogenic SCLC xenograft model, vandetanib inhibited growth and properties are currently under preclinical as well as early tumor angiogenesis in a dose-dependent manner in SBC-1 clinical development. These TKIs include the vascular xenografts. Vandetanib inhibited the growth of MS-1-L endothelial growth factor (VEGF) receptor tyrosine kinase xenografts at a low dose (<12.5 mg/kg/day), but it did not inhibitors vandetanib, sorafenib and sunitinib (3). Sorafenib affect tumor size or change microvessel counts at a higher and sunitinib have progressed beyond clinical trials in some dose. Interestingly, secretion of VEGF increased significantly tumor types and are licensed therapies in some markets. In a in the MS-1-L cell line in the presence of a high dose of phase I study of patients with advanced solid tumors, daily vandetanib in vitro. The effects of vandetanib on tumor oral vandetanib was generally well tolerated at daily oral angiogenesis were different in SBC-1 and MS-1-L cell lines. doses of 300 mg/d or lower; notably, 4 of 9 Japanese Production of angiogenic factors such as VEGF by the patients with refractory non-small cell lung cancer (NSCLC) tumor potentially stimulates tumor angiogenesis and experienced objective tumor responses ranging from 90 to results in the acquisition of resistance to VEGFR TKI. 438 days (4,5). Vandetanib in combination with docetaxel, increased progression free survival (PFS) compared with docetaxel alone in a phase II study of 127 patients with pre- _________________________________________ treated advanced NSCLC. It was demonstrated that addition of vandetanib 100 mg improved median PFS from 12 weeks with docetaxel alone to 18.7 weeks in combination (HR=0.64, Correspondence to: Dr Yoshinobu Ohsaki, Respiratory Medicine, Asahikawa Medical College, 2-1-1-1 Midorigaoka Higashi, 95% CI 0.38-1.05; p=0.074). The combination therapy using Asahikawa 078-8510, Japan vandetanib (100 mg) and docetaxel was generally well- E-mail: [email protected] tolerated; common adverse events included rash, diarrhea and asymptomatic QTc prolongation, all of which responded Key words: small-cell lung cancer, vascular endothelial growth to a standard management (6). In that study, progression-free factor, VEGF receptor, tyrosine kinase inhibitor, anti-angiogenic survival of patients receiving vandetanib treatment was therapy/strategy, microvessel counts significantly longer than that of those receiving gefitinib treatment. SCLC is characterized by its rapid growth and tendency toward metastatic spread. SCLC cells have been reported to 525-532 1/8/08 14:28 Page 526 526 SASAKI et al: VANDETANIB INDUCES DRUG RESISTANCE OF SCLC express VEGF receptor 1 (VEGFR1), VEGFR2, and VEGFR3 10% heat-inactivated fetal calf serum. Cells were grown as (7). We previously reported that SCLC cell lines express suspension cultures at 37˚C in 95% air/5% CO2 and passaged large numbers of functional VEGFR2 receptors that play an twice weekly in complete medium with a simple dilution of important role in tumor growth and invasion (7). Previous 1:5. Hypoxic culture conditions (1% O2, 5% CO2 and 94% N2) studies have suggested that the VEGF/VEGFR system plays were achieved by using a sealed hypoxia chamber (Billups- an important role in tumor growth and metastasis. VEGF Rothenberg, Del Mar, CA, USA). has been reported to be a key growth factor in tumor angio- genesis (8-10). Therefore, inhibition of the VEGF/VEGFR Reverse transcription (RT)-PCR. Total cellular RNA was system seems to be a promising strategy for cancer therapy. extracted from the cell lines by using an RNeasy Mini Kit In fact, inhibition of the VEGF/VEGFR signaling pathway (Qiagen, Valencia, CA, USA) according to the manufacturer's disturbs tumor angiogenesis and inhibits tumor growth by instructions. Total RNA (1 μg) was transcribed into DNA decreasing the vascular density (11,12). Both endothelial and using a reverse transcriptase. The PCR program used to parenchymal cells in tumors were killed mainly by induction amplify VEGF, VEGFRs, EGFR and ß-actin genes consisted of apoptosis (13-18). Therefore, VEGFRs in human SCLC of one preliminary cycle of 5 min at 94˚C, 45 sec at 60˚C, and may be a target for therapy using small molecules. 45 sec at 72˚C, followed by 30 cycles of 1 min at 94˚C, Vandetanib is a once-a-day oral anticancer agent that 45 sec at 65˚C, 2 min at 72˚C, and concluded with 7 min at selectively inhibits VEGFR, epidermal growth factor 72˚C. The primers for VEGF, VEGFRs, EGFR and ß-actin receptor (EGFR), and RET (rearranged during transfection) gene amplification were: for VEGF, sense (5'-TCCAGGA signaling. Administration of vandetanib produced dose- GTACCCTGATGAG-3') and antisense (5'-CTTTCCTGG dependent inhibition of tumor growth in nude mice bearing TGAGAGATCTGG-3') representing the immediate flanking human NSCLC, prostate, breast, ovarian, colon and vulval region of the VEGF open reading frame involved in the tumors without SCLC (19-22). The IC50 of vandetanib alternative splicing of several exons; (27); for VEGFR1, sense against VEGFR2 tyrosine kinase activity was reported to be (5'-ATTTGTGATTTTGGCCTTGC-3') and antisense (5'-CA 40 nM, and vandetanib also inhibited VEGFR3 tyrosine GGCTCATGAACTTGAAAGC-3') (28); for VEGFR2, kinase activity, which binds VEGF-C and VEGF-D (IC50 of sense (5'-GTGACCAACATGGAGTCGTG-3') and antisense 110 nM) (14). In contrast, the IC50 of vandetanib against (5'-CCAGACATTCCATGCCACTT-3') (28); for VEGFR3, VEGFR1 tyrosine kinase activity was 1600 nM. Vandetanib sense (5'-CCCACGCAGACATCAAGACG-3') and antisense did not inhibit tyrosine kinase activity of other growth factor (5'-TGCAGAACTCCACGATCACC-3') (29); for EGFR, receptors, including platelet-derived growth factor receptor sense (5'-TGACTCCGTCCAGTATTGATCG-3') and ß, FGFR1, c-erbB-2, c-kit, and type-1 insulin-like growth antisense (5'-ATTCCTTACACACTTTGCGCC-3') (30); and factor receptor (21). Ciardiello et al reported that vandetanib for ß-actin, sense (5'-GGAAATCGTGCGTGACATT-3') inhibited cell growth and induced apoptosis in human NSCLC, and antisense (5'-CATCTGCTGGAAGGTGGACAG-3') colon, ovarian, breast and gastric cancer cell lines that express (30). RT-PCR was done using a one-step RT-PCR kit both EGFR and TGF-α but lack VEGFR1 and VEGFR2. (Qiagen). The bands were visualized by ethidium bromide They suggested that vandetanib inhibited cell-proliferation staining. in these cell lines by disturbing the transduction of the mito- genic signal from EGFR (23). Xenograft tumor model. SCLC cell lines, SBC-1 and MS-1-L, Among lung cancer patients treated with the EGFR were inoculated into the backs of 5-week-old female athymic TKI gefitinib, having the EGFR gene mutation, being a non- BALB/c-nu/nu mice (Charles River Laboratories Japan, Inc., smoker, female, Asian, and having adenocarcinoma have Yokohama, Japan). The mice were maintained for about 1 been reported to be favorable factors in terms of good drug week until xenografts reached 2 mm x 2 mm x 2 mm. Then response (24-26). To intelligently adapt molecular targeting the mice were randomly divided into 4 groups and treated with agents to cancer therapy, understanding the mechanism of vandetanib 12.5 mg/kg/day, 25 mg/kg/day, 50 mg/kg/day, anti-tumor activity is necessary. However, little is known or the vehicle only. Each group included 4 mice. Tumor about the effects of VEGFR2 TKIs on tumor angiogenesis. diameter and body weight were measured twice weekly. Therefore, in the present study we compared the effect of We measured tumor size with calipers, and the volume vandetanib on SCLC cell lines with and without VEGFR2 was calculated as: length x width2 x 0.5.
Load more

Recommended publications
  • Targeting FGFR/PDGFR/VEGFR Impairs Tumor Growth, Angiogenesis, and Metastasis by Effects on Tumor Cells, Endothelial Cells, and Pericytes in Pancreatic Cancer
    Published OnlineFirst September 1, 2011; DOI: 10.1158/1535-7163.MCT-11-0312 Molecular Cancer Preclinical Development Therapeutics Targeting FGFR/PDGFR/VEGFR Impairs Tumor Growth, Angiogenesis, and Metastasis by Effects on Tumor Cells, Endothelial Cells, and Pericytes in Pancreatic Cancer Johannes Taeger1, Christian Moser1, Claus Hellerbrand2, Maria E. Mycielska1, Gabriel Glockzin1, Hans J. Schlitt1, Edward K. Geissler1, Oliver Stoeltzing3, and Sven A. Lang1 Abstract Activation of receptor tyrosine kinases, such as fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and VEGF receptor (VEGFR), has been implicated in tumor progression and metastasis in human pancreatic cancer. In this study, we investigated the effects of TKI258, a tyrosine kinase inhibitor to FGFR, PDGFR, and VEGFR on pancreatic cancer cell lines (HPAF-II, BxPC-3, MiaPaCa2, and L3.6pl), endothelial cells, and vascular smooth muscle cells (VSMC). Results showed that treatment with TKI258 impaired activation of signaling intermediates in pancreatic cancer cells, endothelial cells, and VSMCs, even upon stimulation with FGF-1, FGF-2, VEGF-A, and PDGF-B. Furthermore, blockade of FGFR/PDGFR/VEGFR reduced survivin expression and improved activity of gemcitabine in MiaPaCa2 pancreatic cancer cells. In addition, motility of cancer cells, endothelial cells, and VSMCs was reduced upon treatment with TKI258. In vivo, therapy with TKI258 led to dose-dependent inhibition of subcutaneous (HPAF-II) and orthotopic (L3.6pl) tumor growth. Immunohistochemical analysis revealed effects on tumor cell proliferation [bromodeoxyuridine (BrdUrd)] and tumor vascularization (CD31). Moreover, lymph node metastases were significantly reduced in the orthotopic tumor model when treatment was initiated early with TKI258 (30 mg/kg/d).
    [Show full text]
  • The Role of Signaling Pathways in the Development and Treatment of Hepatocellular Carcinoma
    Oncogene (2010) 29, 4989–5005 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW The role of signaling pathways in the development and treatment of hepatocellular carcinoma S Whittaker1,2, R Marais3 and AX Zhu4 1Dana-Farber Cancer Institute, Boston, MA, USA; 2The Broad Institute, Cambridge, MA, USA; 3Institute of Cancer Research, London, UK and 4Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA Hepatocellular carcinoma (HCC) is a highly prevalent, malignancy in adults (Pons-Renedo and Llovet, 2003). treatment-resistant malignancy with a multifaceted mole- For the vast majority of patients, HCC is a late cular pathogenesis. Current evidence indicates that during complication of chronic liver disease, and as such, is hepatocarcinogenesis, two main pathogenic mechanisms often associated with cirrhosis. The main risk factors for prevail: (1) cirrhosis associated with hepatic regeneration the development of HCC include infection with hepatitis after tissue damage caused by hepatitis infection, toxins B virus (HBV) or hepatitis C virus (HCV). Hepatitis (for example, alcohol or aflatoxin) or metabolic influ- infection is believed to be the main etiologic factor in ences, and (2) mutations occurring in single or multiple 480% of cases (Anzola, 2004). Other risk factors oncogenes or tumor suppressor genes. Both mechanisms include excessive alcohol consumption, nonalcoholic have been linked with alterations in several important steatohepatitis, autoimmune hepatitis, primary biliary cellular signaling pathways. These pathways are of cirrhosis, exposure to environmental carcinogens (parti- interest from a therapeutic perspective, because targeting cularly aflatoxin B) and the presence of various genetic them may help to reverse, delay or prevent tumorigenesis.
    [Show full text]
  • Structural and Mechanistic Insights Into VEGF Receptor 3 Ligand Binding and Activation
    Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation Veli-Matti Leppänena,1, Denis Tvorogova,1, Kaisa Kiskob, Andrea E. Protab, Michael Jeltscha, Andrey Anisimova, Sandra Markovic-Muellerb, Edward Stuttfeldb,c, Kenneth N. Goldied, Kurt Ballmer-Hoferb, and Kari Alitaloa,2 aWihuri Research Institute and Translational Cancer Biology Program, Institute for Molecular Medicine Finland and Helsinki University Central Hospital, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland; bLaboratory of Biomolecular Research, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland; cStructural Biology and Biophysics, Biozentrum, University of Basel, CH-4056 Basel, Switzerland; and dCenter for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, CH-4056 Basel, Switzerland Edited by Napoleone Ferrara, University of California at San Diego, La Jolla, CA, and approved June 26, 2013 (received for review January 23, 2013) Vascular endothelial growth factors (VEGFs) and their receptors binding, VEGFRs use predominantly D2, with D3 providing ad- (VEGFRs) are key drivers of blood and lymph vessel formation in ditional binding affinity (16–18). In addition, D1 is required for development, but also in several pathological processes. VEGF-C VEGFR-3 ligand binding, but the exact role of this domain re- signaling through VEGFR-3 promotes lymphangiogenesis, which is mains elusive (19, 20). VEGFRs and the closely related type III a clinically relevant target for treating lymphatic insufficiency and RTKs are activated by ligand-induced dimerization of the extra- for blocking tumor angiogenesis and metastasis. The extracellular cellular domain, followed by tyrosine autophosphorylation of the domain of VEGFRs consists of seven Ig homology domains; intracellular kinase domain to generate downstream signaling domains 1–3 (D1-3) are responsible for ligand binding, and the (21).
    [Show full text]
  • (VEGF) Receptor Gene, KDR, in Hematopoietic Cells and Inhibitory Effect of VEGF on Apoptotic Cell Death Caused by Ionizing Radiation
    ICANCERRESEARCH55. 5687-5692. December I, 9951 Expression of the Vascular Endothelial Growth Factor (VEGF) Receptor Gene, KDR, in Hematopoietic Cells and Inhibitory Effect of VEGF on Apoptotic Cell Death Caused by Ionizing Radiation Osamu Katoh,' Hiroshi Tauchi, Kuniko Kawaishi, Akiro Kimura, and Yukio Satow Departments of Environment and Mutation 10. K., K. K., A. K., I'. S.J and Radiation Biology (H. TI, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima-shi 734, Japan ABSTRACT growth factors regulating hematopoiesis, including megakaryocyto poiesis. Several tyrosine kinase genes including KDR, FMS, KIT, and Vascular endothelial growth factor (VEGF) has been identified as a TIE were detected by RT-PCR using degenerated primers correspond peptide growth factor specific for vascular endothelial cells. In this study, ing to the catalytic domains of the tyrosine kinase family (2, 3, 9, 10). we demonstrated the expression of the KDR gene transcript, which en We also report here mRNA expression of the FLT-1 and VEGF genes codes a cell surface receptor for VEGF, in normal human hematopoietic stem cells, megakaryocytes, and platelets as well as in human leukemia cell (1 1, 12) in human leukemia cell lines, hematopoietic stem cells, and lines, HEL and CMKS6. Moreover, we showed the expression of VEGF megakaryocytes. The KDR gene product and the FLT-1 gene product gene transcript in these normal fresh cells and cell lines To elucidate belong to the VEGF receptor family (9, 13, 14). biological functions of VEGF on hematopoiesis, we determined whether VEGF has been identified as a peptide growth factor specific for this growth factor has mitogenic activity to hematopoietic cells or the vascular endothelial cells ( 11).
    [Show full text]
  • A Selective Inhibitor of Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase That Suppresses Tumor Angiogenesis and Growth
    Molecular Cancer Therapeutics 1639 KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth Kazuhide Nakamura,1 Atsushi Yamamoto,1 permeability. These data suggest that KRN633 might be Masaru Kamishohara,1 Kazumi Takahashi,1 useful in the treatment of solid tumors and other diseases Eri Taguchi,1 Toru Miura,1 Kazuo Kubo,1 that depend on pathologic angiogenesis. [Mol Cancer Ther Masabumi Shibuya,2 and Toshiyuki Isoe1 2004;3(12):1639–49] 1Pharmaceutical Development Laboratories, Kirin Brewery Co. Ltd., Takasaki, Gunma and 2Division of Genetics, Institute of Medical Science, University of Tokyo, Tokyo, Japan Introduction The formation of new blood vessels (angiogenesis) is es- sential for tumor progression and metastasis (1). This Abstract process is strictly controlled by positive angiogenic factors Vascular endothelial growth factor (VEGF) and its receptor and negative regulators; therefore, tumors without an VEGFR-2 play a central role in angiogenesis, which is angiogenic phenotype cannot grow beyond a certain size necessary for solid tumors to expand and metastasize. and remain in a state of dormancy. However, once tumors Specific inhibitors of VEGFR-2 tyrosine kinase are therefore become capable of angiogenesis due to somatic mutations thought to be useful for treating cancer. We showed that that alter the balance between angiogenic factors and neg- the quinazoline urea derivative KRN633 inhibited tyrosine ative regulators, they can grow rapidly and metastasize (2). Vascular endothelial growth factor (VEGF) is the an- phosphorylation of VEGFR-2 (IC50 = 1.16 nmol/L) in human umbilical vein endothelial cells. Selectivity profiling giogenic factor that is most closely associated with ag- with recombinant tyrosine kinases showed that KRN633 gressive disease in numerous solid tumors.
    [Show full text]
  • And Vascular Endothelial Growth Factor Receptor (VEGFR)
    molecules Review Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR) Nichole E. M. Kaufman 1, Simran Dhingra 1 , Seetharama D. Jois 2,* and Maria da Graça H. Vicente 1,* 1 Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA; [email protected] (N.E.M.K.); [email protected] (S.D.) 2 School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA * Correspondence: [email protected] (S.D.J.); [email protected] (M.d.G.H.V.); Tel.: +1-225-578-7405 (M.d.G.H.V.); Fax: +1-225-578-3458 (M.d.G.H.V.) Abstract: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are two extensively studied membrane-bound receptor tyrosine kinase proteins that are frequently overexpressed in many cancers. As a result, these receptor families constitute attractive targets for imaging and therapeutic applications in the detection and treatment of cancer. This review explores the dynamic structure and structure-function relationships of these two growth factor receptors and their significance as it relates to theranostics of cancer, followed by some of the common inhibition modalities frequently employed to target EGFR and VEGFR, such as tyrosine kinase inhibitors (TKIs), antibodies, nanobodies, and peptides. A summary of the recent advances Citation: Kaufman, N.E.M.; Dhingra, in molecular imaging techniques, including positron emission tomography (PET), single-photon S.; Jois, S.D.; Vicente, M.d.G.H. emission computerized tomography (SPECT), computed tomography (CT), magnetic resonance Molecular Targeting of Epidermal imaging (MRI), and optical imaging (OI), and in particular, near-IR fluorescence imaging using Growth Factor Receptor (EGFR) and tetrapyrrolic-based fluorophores, concludes this review.
    [Show full text]
  • Diagnostic Value of VEGF-A, VEGFR-1 and VEGFR-2 in Feline Mammary Carcinoma
    cancers Article Diagnostic Value of VEGF-A, VEGFR-1 and VEGFR-2 in Feline Mammary Carcinoma Catarina Nascimento 1 , Andreia Gameiro 1, João Ferreira 2, Jorge Correia 1 and Fernando Ferreira 1,* 1 CIISA—Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal; [email protected] (C.N.); [email protected] (A.G.); [email protected] (J.C.) 2 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; [email protected] * Correspondence: [email protected]; Tel.: +351-21-365-2800 (ext. 431234) Simple Summary: Feline mammary carcinoma (FMC) is the third most common neoplasia in the cat, showing a highly malignant behavior, with both HER2-positive and triple negative (TN) subtypes presenting worse prognosis than luminal A and B subtypes. Furthermore, FMC has become a reliable cancer model for the study of human breast cancer, due to the similarities of clinicopathological, histopathological, and epidemiological features among the two species. Therefore, the identification of novel diagnostic biomarkers and therapeutic targets is needed to improve the clinical outcome of these patients. The aim of this study was to assess the potential of the VEGF-A/VEGFRs pathway, in order to validate future diagnostic and checkpoint-blocking therapies. Results showed that serum VEGF-A, VEGFR-1, and VEGFR-2 levels were significantly higher in cats with HER2-positive and TN normal-like tumors, presenting a positive association with its tumor-infiltrating lymphocytes expres- sion, suggesting that these molecules may serve as promising non-invasive diagnostic biomarkers for these subtypes.
    [Show full text]
  • Implications for Combining Anti–VEGF and Anti–EGFR Agents
    Subject Review The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents Josep Tabernero Medical Oncology Service, Vall d’Hebron University Hospital, Barcelona, Spain Abstract faceted approach involving targeted inhibition of multiple Multiple cellular pathways influence the growth and signaling pathways may be more effective than inhibition of metastatic potential of tumors. This creates a single target and may help overcome tumor resistance by heterogeneity, redundancy, and the potential for tumors blocking potential ‘‘escape routes.’’ to bypass signaling pathway blockade, resulting in Two key elements in the growth and dissemination of tumors primary or acquired resistance. Combining therapies that are the vascular endothelial growth factor (VEGF) and the inhibit different signaling pathways has the potential to epidermal growth factor (EGF) receptor (EGFR). The VEGF be more effective than inhibition of a single pathway and and EGFR pathways are closely related, sharing common down- to overcome tumor resistance. Vascular endothelial stream signaling pathways (1). Furthermore, EGF, a key EGFR growth factor (VEGF) and epidermal growth factor ligand, is one of the many growth factors that drive VEGF receptor (EGFR) inhibitors have become key therapies in expression (2). VEGF and EGFR play important roles in tumor several tumor types. Close relationships between these growth and progression through the exertion of both indirect and factors exist: VEGF signaling is up-regulated by EGFR direct effects on tumor cells (1). Biological agents targeting the expression and, conversely, VEGF up-regulation VEGF and EGFR pathways have shown clinical benefit in independent of EGFR signaling seems to contribute to several human cancers, either alone or in combination with resistance to EGFR inhibition.
    [Show full text]
  • Blockade of Epha Receptor Tyrosine Kinase Activation Inhibits Vascular Endothelial Cell Growth Factor-Induced Angiogenesis
    2 Vol. 1, 2–11, November 2002 Molecular Cancer Research Blockade of EphA Receptor Tyrosine Kinase Activation Inhibits Vascular Endothelial Cell Growth Factor-Induced Angiogenesis Nikki Cheng,1 Dana M. Brantley,2 Hua Liu,3,4 Qin Lin,2 Miriam Enriquez,4 Nick Gale,5 George Yancopoulos,5 Douglas Pat Cerretti,3 Thomas O. Daniel,3,4 and Jin Chen1,2,6 Departments of 1Cancer Biology, 2Medicine, Division of Rheumatology, 4Division of Nephrology, and 6Cell Biology, Vanderbilt University School of Medicine, Nashville, TN; 3Immunex Corporation, Seattle, WA; and 5Regeneron Inc., Tarrytown, NY Abstract endothelial cell proliferation, migration, and assembly, as well Angiogenesis is a multistep process involving a diverse as recruitment of perivascular cells and extracellular matrix array of molecular signals. Ligands for receptor tyrosine remodeling. Three families of receptor tyrosine kinases (RTKs) kinases (RTKs) have emerged as critical mediators of have emerged as critical mediators of angiogenesis; these are the angiogenesis. Three families of ligands, vascular endo- vascular endothelial growth factor (VEGF), Tie, and Eph RTK thelial cell growth factors (VEGFs), angiopoietins, and families (1, 2). VEGF (VEGF-A/VEGF165) is a potent angio- ephrins, act via RTKs expressed in endothelial cells. genic factor in both embryonic development and in adult disease Recent evidence indicates that VEGF cooperates with states, such as cancer. VEGF and its RTKs, Flt-1/VEGFR1 and angiopoietins to regulate vascular remodeling and Flk-1/KDR/VEGFR2, are required for the development and angiogenesis in both embryogenesis and tumor remodeling of blood vessels during embryogenesis (3–8). neovascularization. However, the relationship between Moreover, VEGF signaling plays a crucial role in pathogenic VEGF and ephrins remains unclear.
    [Show full text]
  • VEGF Receptor Protein–Tyrosine Kinases: Structure and Regulation
    Biochemical and Biophysical Research Communications 375 (2008) 287–291 Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc Mini Review VEGF receptor protein–tyrosine kinases: Structure and regulation Robert Roskoski Jr. * Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116A, Box 19, Horse Shoe, NC 28742, USA article info abstract Article history: The human VEGF family consists of VEGF (VEGF-A), VEGF-B, VEGF-C, VEGF-D, and placental growth factor Received 6 July 2008 (PlGF). The VEGF family of receptors consists of three protein–tyrosine kinases (VEGFR1, VEGFR2, and Available online 3 August 2008 VEGFR3) and two non-protein kinase co-receptors (neuropilin-1 and neuropilin-2). These components participate in new blood vessel formation from angioblasts (vasculogenesis) and new blood vessel forma- tion from pre-existing vasculature (angiogenesis). Interaction between VEGFR1 and VEGFR2 or VEGFR2 Keywords: and VEGFR3 alters receptor tyrosine phosphorylation. Angiogenesis Ó 2008 Elsevier Inc. All rights reserved. Flt-1 Flk-1/KDR Lymphangiogenesis Protein–tyrosine kinase Vasculogenesis . VEGF is one of the key regulators of angiogenesis, vasculogene- minal tail (Fig. 1 and Table 1). These enzymes catalyze the sis, and developmental hematopoiesis [1]. VEGF is a mitogen and following reaction: survival factor for vascular endothelial cells while also promoting MgATP1À protein-OH Protein-OPO2À MgADP Hþ vascular endothelial cell and monocyte motility. VEGF-B also pro- þ ! 3 þ þ motes angiogenesis in an ill-defined manner. VEGF-C participates where -OH is a tyrosyl hydroxyl group. Moreover, there are two in lymphangiogenesis during embryogenesis and in the mainte- non-enzymatic VEGF family co-receptors (neuropilin-1 and neuro- nance of differentiated lymphatic endothelium in adults.
    [Show full text]
  • HER2/Neu: an Increasingly Important Therapeutic Target
    Clinical Trial Outcomes NELSON HER2/neu: an increasingly important therapeutic target. Part 1 4 Clinical Trial Outcomes HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium Clin. Invest. This is the first of a comprehensive three-part review of the foundation for and Edward L Nelson therapeutic targeting of HER2/neu. No biological molecule in oncology has been more University of California, Irvine, extensively or more successfully targeted than HER2/neu. This review will summarize School of Medicine; Division of Hematology/Oncology; Department the pertinent biology of HER2/neu and the EGF receptor family to which it belongs, of Medicine; Department of Molecular with attention to the biological foundation for the design and clinical development Biology & Biochemistry; Sprague Hall, of the entire range of HER2/neu-targeted therapies, including efforts to mitigate Irvine, CA 92697, USA resistance mechanisms. In conjunction with the subsequent two parts (HER2/neu tissue [email protected] expression and current HER2/neu-targeted therapeutics), this comprehensive survey will identify opportunities and promising areas for future evaluation of HER2/neu- targeted therapies, highlighting the importance of HER2/neu as an increasingly important therapeutic target. Keywords: c-erbB2 • EGF receptor • EGFR • EGFR ligand • expression modulation • HER2/neu • monoclonal antibody • signaling network • targeted therapeutic • tyrosine kinase inhibitor • vaccine The history of the molecule known as c-erbB2 = neu, c-erbB3 = EGFR-3, and HER2/neu dates back to the earliest stud- eventually, c-erbB4 = EGFR-4) were estab- 10.4155/CLI.14.57 ies of virus-associated oncogenes. In 1979, lished [13] . The fact that the neu molecule studies of avian erythroblastosis virus iden- and coding sequence was originally identi- tified two putative viral oncogenes, v-erbA fied in the rat species and only recently has and v-erbB [1–3] .
    [Show full text]
  • Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor
    Pharmacological Research 120 (2017) 116–132 Contents lists available at ScienceDirect Pharmacological Research j ournal homepage: www.elsevier.com/locate/yphrs Invited Review Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas ∗ Robert Roskoski Jr. Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742-8814, United States a r t i c l e i n f o a b s t r a c t Article history: One Von Hippel-Lindau (VHL) tumor suppressor gene is lost in most renal cell carcinomas while the Received 14 March 2017 nondeleted allele exhibits hypermethylation-induced inactivation or inactivating somatic mutations. As Accepted 15 March 2017 a result of these genetic modifications, there is an increased production of VEGF-A and pro-angiogenic Available online 19 March 2017 growth factors in this disorder. The important role of angiogenesis in the pathogenesis of renal cell carcinomas and other tumors has focused the attention of investigators on the biology of VEGFs and Chemical compounds studied in this article: VEGFR1–3 and to the development of inhibitors of the intricate and multifaceted angiogenic pathways. Axitinib: (PubMED CID: 6450551) VEGFR1–3 contain an extracellular segment with seven immunoglobulin-like domains, a transmembrane Bevacizumab: (PubMED CID: 24801580) segment, a juxtamembrane segment, a protein kinase domain with an insert of about 70 amino acid Pozantinib: (PubMED CID: 25102847) residues, and a C-terminal tail. VEGF-A stimulates the activation of preformed VEGFR2 dimers by the Lenvatinib: (PubMED CID: 9823820) Pazopanib (PubMED CID: 10113978) auto-phosphorylation of activation segment tyrosines followed by the phosphorylation of additional Sorafenib: (PubMED CID: 216239) protein-tyrosines that recruit phosphotyrosine binding proteins thereby leading to signalling by the Sunitinib: (PubMed CID: 5329102) ERK1/2, AKT, Src, and p38 MAP kinase pathways.
    [Show full text]