2004Cancer Biology & Therapy2008; Vol. 7 Issue 12
[Cancer Biology & Therapy 7:12, 2004-2006; December 2008]; ©2008 Landes Bioscience
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Targeting tumor associated blood vessels is a way to at least
theoretically bypass tumor resistance mechanisms.1 However, there
are notable exceptions to this notion.2,3 Nevertheless, pharmaco-
logic agents directed against the vascular endothelial growth factor
(VEGF)-VEGF receptor 2 (VEGFR2) pathway have been shown to
be useful for the treatment of cancer. The anti-VEGF monoclonal
antibody bevacizumab (Avastin) when combined with chemotherapy
is clinically effective for the treatment of colon, lung and breast
tumors.4-6 Similarly, sunitinib (Sutent) and sorafenib (Nexavar) are
drugs that inhibit VEGFR1, VEGFR2, VEGFR3 and other protein
kinases that are effective in the treatment of solid tumors of kidney
and liver origin.7-9 Hence, treating tumors by inhibiting angiogenesis
has been a remarkably successful way to treat cancer.
The identification of biomarkers that allow evaluation of the
response to agents that target angiogenesis would be very useful.10
To date, serum biomarkers that have been described to predict the
response to anti-angiogenic therapy measuring cytokines/growth
factors11,12 or circulating endothelial cells (EC)/endothelial progen-
itor cells (EPC)13 have been somewhat unconvincing. Alternatively,
imaging technologies could possibly provide a novel approach for
interrogating the efficacy of anti-angiogenic therapies, but have
inherent limitations and are still mainly in development.14 Even the
histological examination of VEGF-VEGR2 targeted therapy has not
been necessarily reliable.14 Thus, there are currently no ideal methods
for pre-clinically or clinically evaluating anti-angiogenic therapies.
In this issue of Cancer Biology & Therapy, Lee and colleagues
present data that activated or phosphorylated signal transducers
and activators of transcription 3 (STAT3) may serve as a functional
molecular biomarker for endothelial VEGR2 activity.15 Downstream
signaling pathways mediating some functions of activated VEGFR2
have been described and include the mitogen-activated protein
kinase (MAPK)16 and phosphatidylinositol 3'-kinase (PI3K)-Akt17
pathways (Fig. 1). After the binding of ligands to their receptors,
STAT proteins are phosphorylated, dimerize and then translocate to
the nucleus where they function as sequence specific transcription
factors.18 A 10-fold increase in the numbers of ECs with activated
STAT3 in the nuclei of tumor vessels versus the ECs of most normal
mouse organs was observed. VEGF was shown to induce STAT3
activation via a VEGFR2- and Src-dependent mechanism in cultured
micro- and macro-vascular ECs. Activated STAT3 was then shown
to mediate survival of ECs in vitro in a VEGF-VEGFR2-dependent
fashion by upregulation of Bcl-2. Finally, this VEGF-VEGFR2-
STAT3 axis in ECs was demonstrated in vivo using transplanted
conditional VEGF expressing tumors treated using two different
anti-VEGF manipulations, VEGF Trap and SU5416.15
The study by Lee raises several interesting questions. A previous
study has shown VEGF activation of STAT3 promotes increased
cellular motility and tube formation in microvascular ECs.19
Could VEGF effects on EC vessel permeability, nitric oxide (NO)
production and proliferation also be coordinated in part through a
Src-STAT3 mechanism (Fig. 1)? Clearly additional work is required
to fully understand the VEGF-VEGFR2 downstream pathways
mediating functions in ECs. The potential significance could be
broad because activated STAT3 is implicated in the viability of many
tumor types.20 Hence, understanding this highly complex pathway
and its specific role in different cell types for the regulation of micro-,
macro-vascular ECs and tumor cells is important.19,21,22
The identification by Lee and colleagues of activated STAT3 as a
novel biomarker of EC VEGFR2 activity could be very useful. The
use of activated STAT3 as a tissue biomarker may be more easily
translated in the preclinical evaluation of novel anti-angiogenic
compounds or combinations.15 The measurement of activated
STAT3 in circulating EPCs and ECs may improve on the simple
enumeration of these cells and provide a much needed clinical
biomarker. It will be important to validate these results in clinical
The current STATe of biomarkers to predict the response to
Phuoc T. Tran1,2 and Dean W. Felsher2,*
1Department of Radiation Oncology; 2Departments of Medicine and Pathology; Division of Oncology; Stanford University School of Medicine; Stanford, California USA
Abbreviations: ECs, endothelial cells; VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2; EPC, endothelial progenitor
cells; STAT3, signal transducers and activators of transcription 3; NO, nitric oxide; MAPK, mitogen-activated protein kinase; PI3K,
Key words: VEGFR2, STAT3, Src, signaling, tissue biomarker, angiogenesis, anti-angiogenic
*Correspondence to: Dean W. Felsher; Departments of Medicine and Pathology;
Division of Oncology; Stanford University School of Medicine; CCSR Building;
Room 1120; 269 Campus Drive; Stanford, California 94305-5151 USA;
Tel.: 650.725.6454; Fax: 650.725.1420; Email: firstname.lastname@example.org
Submitted: 09/16/08; Accepted: 10/15/08
Previously published online as a Cancer Biology & Therapy E-publication:
Commentary to: Chen S-H, Murphy DA, Lassoued W, Thurston G, Feldman MD,
Lee WMF. Activated STAT3 is a mediator and biomarker of VEGF endothelial activa-
tion. Cancer Biol Ther 2008; This issue.
STAT3 biomarker for activated endothelial VEGFR2
11. DePrimo SE, Wong LM, Khatry DB, Nicholas SL, Manning WC, Smolich BD, et al.
Expression profiling of blood samples from an SU5416 Phase III metastatic colorectal
cancer clinical trial: A novel strategy for biomarker identification. BMC Cancer 2003; 3:3.
12. Drevs J, Zirrgiebel U, Schmidt-Gersbach CI, Mross K, Medinger M, Lee L, et al. Soluble
markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/
ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor
in patients with advanced colorectal cancer from two phase I trials. Ann Oncol 2005;
13. Duda DG, Cohen KS, di Tomaso E, Au P, Klein RJ, Scadden DT, et al. Differential CD146
expression on circulating versus tissue endothelial cells in rectal cancer patients: Implications
for circulating endothelial and progenitor cells as biomarkers for antiangiogenic therapy. J
Clin Oncol 2006; 24:1449-53.
14. Provenzale JM. Imaging of angiogenesis: Clinical techniques and novel imaging methods.
AJR Am J Roentgenol 2007; 188:11-23.
15. Chen S-H, Murphy DA, Lassoued W, Thurston G, Feldman MD, Lee WMF. Activated
STAT3 is a mediator and biomarker of VEGF endothelial activation. Cancer Biol Ther
16. Takahashi T, Yamaguchi S, Chida K, Shibuya M. A single autophosphorylation site on
KDR/Flk-1 is essential for VEGF-A-dependent activation of PLCgamma and DNA syn-
thesis in vascular endothelial cells. EMBO 2001; 20:2768-78.
17. Holmqvist K, Cross MJ, Rolny C, Hagerkvist R, Rahimi N, Matsumoto T, et al. The
adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF)
receptor-2 and regulates VEGF-dependent cellular migration. J Biol Chem 2004;
18. Yu H, Jove R. The STATs of cancer—new molecular targets come of age. Nat Rev 2004;
19. Yahata Y, Shirakata Y, Tokumaru S, Yamasaki K, Sayama K, Hanakawa Y, et al. Nuclear
translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-
induced human dermal microvascular endothelial cell migration and tube formation. J Biol
Chem 2003; 278:40026-31.
20. Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs 2005; 16:601-7.
21. Bartoli M, Platt D, Lemtalsi T, Gu X, Brooks SE, Marrero MB, et al. VEGF differentially
activates STAT3 in microvascular endothelial cells. Faseb J 2003; 17:1562-4.
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specimens, with careful consideration of the potential difficulties of
such analysis.23 Galvanized by recent clinical success, there has been a
surge of interest in anti-angiogenic targeted therapies [for anti-angio-
genic clinical trials (http://www.cancer.gov/cancertopics/factsheet/
Therapy/angiogenesis-inhibitors)]. To further expedite preclinical
and human investigation it will be important to develop and validate
biomarkers for angiogenesis such as described by Lee and colleagues
in this issue of Cancer Biology & Therapy.
1. Kerbel RS. Tumor angiogenesis. N Engl J Med 2008; 358:2039-49.
2. Hida K, Hida Y, Amin DN, Flint AF, Panigrahy D, Morton CC, et al. Tumor-associated
endothelial cells with cytogenetic abnormalities. Cancer Res 2004; 64:8249-55.
3. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev 2008;
4. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-
carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;
5. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevaci-
zumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357:2666-76.
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Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer.
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hepatocellular carcinoma. N Engl J Med 2008; 359:378-90.
8. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in
advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:125-34.
9. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, et al. Activity
of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and
platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J
Clin Oncol 2006; 24:16-24.
10. Gillick MR. Molecular medicine, the Medicare drug benefit and the need for cost control.
J Am Geriatr Soc 2006; 54:1442-6.
www.landesbioscience.comCancer Biology & Therapy 2005
Figure 1. Pathways facilitating downstream functions of VEGFR2. The binding of VEGF to VEGFR-2 leads to dimerization of the receptor, followed by
intracellular activation of different signaling pathways resulting in the regulation of genes involved in mediating endothelial permeability, NO production,
proliferation, survival and migration of ECs. Activation of the MAPK pathway initiates DNA synthesis and cell growth,16 whereas activation of the PI3K-Akt
pathway leads to increased endothelial cell survival and migration.1,24 FAK-dependent signaling has also been associated with facilitating EC migration.17
Chen et al. have described the involvement of a Src-STAT3 signaling pathway in mediating survival15 and a prior study has demonstrated STAT3 mediation
of cell migration.19
© 2009 LANDES BIOSCIENCE. DO NOT DISTRIBUTE.
STAT3 biomarker for activated endothelial VEGFR2 Download full-text
23. Helft PR, Daugherty CK. Are we taking without giving in return? The ethics of research-
related biopsies and the benefits of clinical trial participation. J Clin Oncol 2006; 24:4793-5.
24. Abedi H, Zachary I. Vascular endothelial growth factor stimulates tyrosine phosphorylation
and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial
cells. J Biol Chem 1997; 272:15442-51.
2006Cancer Biology & Therapy2008; Vol. 7 Issue 12
© 2009 LANDES BIOSCIENCE. DO NOT DISTRIBUTE.