Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Genes & Dev. 20 (18): 2527-2538

Copyright © 2006 by Cold Spring Harbor Laboratory Press.


The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1β

Ksenya Shchors1, Elena Shchors2, Fanya Rostker1, Elizabeth R. Lawlor1,3, Lamorna Brown-Swigart1,, and Gerard I. Evan1,4

1 Cancer Research Institute and Department of Cellular and Molecular Pharmacology, University of California at San Francisco Comprehensive Cancer Center, San Francisco, California 94143, USA;
2 Biotraces, Inc., Herndon, Virginia 20171, USA

Abstract: Although induction of blood vessel growth is acknowledged as a pivotal requirement for the evolution of macroscopic tumors, the events that trigger onset of tumor angiogenesis remain largely obscure. The pervasive Myc oncoprotein is itself a potent inducer of angiogenesis in a wide range of tissues. We have used a reversibly switchable mouse transgenic model of Myc-dependent β-cell carcinogenesis to delineate the kinetics and causal sequence of angiogenic processes following acute Myc activation. We show that onset of endothelial cell proliferation is induced shortly after Myc-induced cell cycle entry of β cells. Endothelial cell proliferation is not indirectly induced by local tissue hypoxia but instead via a diffusible angiogenic signal produced by Myc-expressing β cells. This signal triggers the release of pre-existing, sequestered VEGF from the islet extracellular matrix, that then homes to the endothelial compartment where it induces endothelial cell proliferation. Myc activation in β cells rapidly induces expression and release of the proinflammatory cytokine interleukin 1β (IL-1β). We show that IL-1β is the principal effector downstream of Myc responsible for triggering rapid onset of islet angiogenesis. Together, our data delineate a complete pathway in vivo by which the highly pleiotropic Myc oncoproteins elicits coexpansion of the vascular compartment during tumorigenic progression.

Key Words: Myc • angiogenesis • interleukin 1β • tumor

Received for publication June 6, 2006. Accepted for publication July 26, 2006.

3 Present address: University of Southern California Keck School of Medicine, Children's Hospital Los Angeles, Division of Hematology-Oncology, 4650 Sunset Blvd., Los Angeles, CA 90027-6016, USA

4 Corresponding author.

E-MAIL gevan{at}; FAX (415) 514-0878.

Supplemental material is available at

Article is online at

Critical role for IL-1{beta} in DNA damage-induced mucositis.
N. Kanarek, S. I. Grivennikov, M. Leshets, A. Lasry, I. Alkalay, E. Horwitz, Y. D. Shaul, M. Stachler, E. Voronov, R. N. Apte, et al. (2014)
PNAS 111, E702-E711
   Abstract »    Full Text »    PDF »
IL-32 Promotes Angiogenesis.
C. A. Nold-Petry, I. Rudloff, Y. Baumer, M. Ruvo, D. Marasco, P. Botti, L. Farkas, S. X. Cho, J. A. Zepp, T. Azam, et al. (2014)
J. Immunol. 192, 589-602
   Abstract »    Full Text »    PDF »
The Role of IL-1{beta} in the Early Tumor Cell-Induced Angiogenic Response.
Y. Carmi, S. Dotan, P. Rider, I. Kaplanov, M. R. White, R. Baron, S. Abutbul, M. Huszar, C. A. Dinarello, R. N. Apte, et al. (2013)
J. Immunol. 190, 3500-3509
   Abstract »    Full Text »    PDF »
Myc Posttranscriptionally Induces HIF1 Protein and Target Gene Expression in Normal and Cancer Cells.
M. R. Doe, J. M. Ascano, M. Kaur, and M. D. Cole (2012)
Cancer Res. 72, 949-957
   Abstract »    Full Text »    PDF »
Endogenous Myc maintains the tumor microenvironment.
N. M. Sodir, L. B. Swigart, A. N. Karnezis, D. Hanahan, G. I. Evan, and L. Soucek (2011)
Genes & Dev. 25, 907-916
   Abstract »    Full Text »    PDF »
The Myc-miR-17~92 Axis Blunts TGF{beta} Signaling and Production of Multiple TGF{beta}-Dependent Antiangiogenic Factors.
M. Dews, J. L. Fox, S. Hultine, P. Sundaram, W. Wang, Y. Y. Liu, E. Furth, G. H. Enders, W. El-Deiry, J. M. Schelter, et al. (2010)
Cancer Res. 70, 8233-8246
   Abstract »    Full Text »    PDF »
Hyperpolarized 13C Spectroscopic Imaging Informs on Hypoxia-Inducible Factor-1 and Myc Activity Downstream of Platelet-Derived Growth Factor Receptor.
H. Dafni, P. E. Z. Larson, S. Hu, H. A. I. Yoshihara, C. S. Ward, H. S. Venkatesh, C. Wang, X. Zhang, D. B. Vigneron, and S. M. Ronen (2010)
Cancer Res. 70, 7400-7410
   Abstract »    Full Text »    PDF »
MYC and Breast Cancer.
J. Xu, Y. Chen, and O. I. Olopade (2010)
Genes & Cancer 1, 629-640
   Abstract »    Full Text »    PDF »
Tumour Biology: Tumour-associated Inflammation versus Antitumor Immunity.
Anticancer Res 29, 4795-4805
   Abstract »    Full Text »    PDF »
Acute Overexpression of Myc in Intestinal Epithelium Recapitulates Some but Not All the Changes Elicited by Wnt/{beta}-Catenin Pathway Activation.
A. J. Finch, L. Soucek, M. R. Junttila, L. B. Swigart, and G. I. Evan (2009)
Mol. Cell. Biol. 29, 5306-5315
   Abstract »    Full Text »    PDF »
Estrogen regulation of vascular endothelial growth factor in breast cancer in vitro and in vivo: the role of estrogen receptor {alpha} and c-Myc.
M. Dadiani, D. Seger, T. Kreizman, D. Badikhi, R. Margalit, R. Eilam, and H. Degani (2009)
Endocr. Relat. Cancer 16, 819-834
   Abstract »    Full Text »    PDF »
Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.
F. Colotta, P. Allavena, A. Sica, C. Garlanda, and A. Mantovani (2009)
Carcinogenesis 30, 1073-1081
   Abstract »    Full Text »    PDF »
Absence of Caspase-3 Protects Pancreatic {beta}-Cells from c-Myc-induced Apoptosis without Leading to Tumor Formation.
A. Radziszewska, S. A. Schroer, D. Choi, P. Tajmir, N. Radulovich, J. C. Ho, L. Wang, N. Liadis, R. Hakem, M.-S. Tsao, et al. (2009)
J. Biol. Chem. 284, 10947-10956
   Abstract »    Full Text »    PDF »
B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver.
K. R. Reed, D. Athineos, V. S. Meniel, J. A. Wilkins, R. A. Ridgway, Z. D. Burke, V. Muncan, A. R. Clarke, and O. J. Sansom (2008)
PNAS 105, 18919-18923
   Abstract »    Full Text »    PDF »
c-myc in the hematopoietic lineage is crucial for its angiogenic function in the mouse embryo.
C. He, H. Hu, R. Braren, S.-Y. Fong, A. Trumpp, T. R. Carlson, and R. A. Wang (2008)
Development 135, 2467-2477
   Abstract »    Full Text »    PDF »
Critical Roles for Macrophages in Islet Angiogenesis and Maintenance During Pancreatic Degeneration.
J. S. Tessem, J. N. Jensen, H. Pelli, X.-M. Dai, X.-H. Zong, E. R. Stanley, J. Jensen, and J. DeGregori (2008)
Diabetes 57, 1605-1617
   Abstract »    Full Text »    PDF »
The world according to MYC: Conference on MYC and the Transcriptional Control of Proliferation and Oncogenesis.
B. Luscher and L.-G. Larsson (2007)
EMBO Rep. 8, 1110-1114
   Full Text »    PDF »
Hypoxia-Inducible Factor 1 and Dysregulated c-Myc Cooperatively Induce Vascular Endothelial Growth Factor and Metabolic Switches Hexokinase 2 and Pyruvate Dehydrogenase Kinase 1.
J.-w. Kim, P. Gao, Y.-C. Liu, G. L. Semenza, and C. V. Dang (2007)
Mol. Cell. Biol. 27, 7381-7393
   Abstract »    Full Text »    PDF »
Malignant astrocytic glioma: genetics, biology, and paths to treatment.
F. B. Furnari, T. Fenton, R. M. Bachoo, A. Mukasa, J. M. Stommel, A. Stegh, W. C. Hahn, K. L. Ligon, D. N. Louis, C. Brennan, et al. (2007)
Genes & Dev. 21, 2683-2710
   Abstract »    Full Text »    PDF »
Hypoxia Inducible Factor-1 Independent Pathways in Tumor Angiogenesis.
Y. Mizukami, Y. Kohgo, and D. C. Chung (2007)
Clin. Cancer Res. 13, 5670-5674
   Abstract »    Full Text »    PDF »
Tumor Angiogenesis: Cause or Consequence of Cancer?.
K. Shchors and G. Evan (2007)
Cancer Res. 67, 7059-7061
   Abstract »    Full Text »    PDF »
Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice.
I. Kim, K. Morimura, Y. Shah, Q. Yang, J. M. Ward, and F. J. Gonzalez (2007)
Carcinogenesis 28, 940-946
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882