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web page was produced as an assignment for an undergraduate course at Davidson College.
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My favorite gene in the
popular press
My
favorite gene in the popular press is Ad-VEGF(165), the gene encoding vascular
endothelial growth factor, or VEGF.
Ad-VEGF(165) has never per se been called “the gene for” something in
the popular press, and so is somewhat outside the specifications for this
assignment, though, I believe it fall within the spirit of the assignment. VEGF, or rather the inhibition of VEGF, was for a time seen as the magic bullet cure
for all cancer. As anyone who has
studied genomics would imagine, things did not quite pan out. The study of angiogenesis, and inhibition
thereof has produced many exciting results nonetheless.
chime
image of VEGF, obtained by Y.A.Muller & A.M.De Vos, 8-Apr-97. This file was downloaded from pubmed, a government site.
Basics
The
gene map locus of Ad-VEGF(165) is 6p12.1 The protein encoded, VEGF, is an extremely
important factor in both vasculogenesis(the formation of blood vessels), and
angiogenesis(the sprouting of blood vessels and the remodeling of vascular
beds).2 VEGF acts
exclusively on endothelial cells, on whose cell surface it’s receptor, Flk1, is
located. VEGF has been shown to be a
factor in the permeability, proliferation, migration, and
maintenance/protection of endothelial cells.
Media Buzz
Judah
Folkman studied the process of angiogenesis for decades in relative anonymity,
with the hope of using angiogenesis inhibitors to cure cancer. The idea was that for tumors to grow beyond
a relatively innocuous size, they would need to recruit their own blood supply. Dr. Folkman discovered that many tumors
accomplish this using VEGF. He believed
that if this process was disallowed, tumors would cease to grow. In 1998 he found what appeared to be his
answer, when he demonstrated the efficacy of angiostatin, a naturally occurring
protein, in fighting cancer in mice. Not only did the protein stop tumor growth by ceasing new vascular
formation, it completely eliminated the cancer from the mice. His research entered the limelight when Dr.
James Watson(yes, the Watson) was quoted in the New York Times as stating
that “Judah is going to cure cancer in two years.” This turned out to be a sensationalist claim, but the seed was
planted in the mind of the public.3
Angiogenesis Inhibitors
Dr.
William Li, and expert in the field, states that more than 300 potential blood
vessel blockers have been discovered, with at least 40 reaching the stage of
human cancer testing. Eighteen
antiangiogenesis compounds have entered phase III FDA trials since May 2001. As of May 2002, seven of those were halted
prematurely because of poor interim results.
Dr. Li notes three particularly promising drugs still in phase III. The first of these is Avastin, developed by Genentech. Avastin is a monoclonal antibody to VEGF,
given by injection. Thalidomide was
originally developed by Celgene Corp to
counteract morning sickness in pregnant women, but was taken off the market
after hundreds of children were born with massive birth defects as a
result. Thalidomide inhibits VEGF, TNF,
and bFGF, as well as COX2, which is known to upregulate VEGF. Nevostat, developed by Aeterna Laboratories, blocks VEGF, in
addition to a number of other proteins involved in the proliferation of cancer.4
Complications
There
is currently not a clear picture of what the signaling pathway may be, though
many of the proteins involved have been identified. Recently the transcription factors nuclear factor kB(NFkB)
and activator protein-1(AP-1) were shown to promote expression of VEGF and
another angiogenesis factor interleukin-8(IL-8) after being coactivated by
interleukin-1a. However, in June of this year, the same lab
determined that expression of IL-1 receptor antagonist incompletely blocked
expression of VEGF. Epidermal growth
factor receptor(EGFR) has been shown to activate PI3K and MEK pathways, which
can modulate activation of NF-kB and AP-1, though
the pathway by which EGFR activates these pathways is unknown.5 VEGF has been shown to induce biphasic
prolonged phosphorylation of p44/42 MAPK and Akt, which has been shown to be
necessary for neovessel sprouting.
Angiopoietin-1(Ang-1) was shown to potentiate VEGF-induced neovessel sprouting,
but was not sufficient to do this in the absence of VEGF.6 A number of other molecules have been shown
to upregulate VEGF production, including securing pituitary tumor transforming
gene(PTTG), Cyr61, interleukin-18, H2O2, vitamin-D, and
estrogen.
Other Possible Clinical Applications
In
addition to the cancer therapies this research was initiated for, many other
promising applications are surfacing.
Angiogenesis factors have already proven to be tremendously useful as
gene therapy for patients with severe coronary heart disease.7 Angiogenesis inhibitors are being tested as
therapies for certain forms of blindness as well, and have seen promising early
results.
1
Online Mendelian Inheritance
in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. 192240: { 192240}: { 7/31/2002 }:
World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/
2 Developmental
Biology
- by Scott F. Gilbert. (ISBN 0-87893-243-7; published by Sinauer Associates,
Inc.: 2000)
3 Haney, D.: Celebrated idea for curing cancer proves hard to translate from mouse to man. AP Worldstream 05/29/2002.
4 Friend,
T.: Beating tumors at their own game.
USA Today, 05/16/2002.
5 Bancroft-Caren;
et al.: Effects of pharmacologic antagonists of epidermal growth factor
receptor, PI3l and MEK signal kinases on NF-kB
and AP-1 activation and IL-8 and VEGF expression in human head and neck
squamous cell carcinoma lines. Int. J. Cancer. June, 2002; 99(4): 538-548.
6
Zhu, W.H.: Regulation of angiogenesis by vascular endothelial growth factor
and angiopoietin-1 in the rat aorta model: distinct with temporal patterns of
intracellular signaling correlate with induction of angiogenic sprouting. Am
J Pathol. Sept, 2002;161(3):823-30
7 Chapman, J.; Hope, J.: Half-hour
heart ‘cure’: gene injection could end need for bypass. Daily Mail
11/13/2001.
Send comments, questions and suggestions to edhaas@davidson.edu
Many thanks to Dr. A. Malcolm Campbell for his guidance in this endeavor as well as others.