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Graham
S. Baldwin and Arthur Shulkes, Department of Surgery, University
of Melbourne, Austin and Repatriation Medical Centre, Melbourne,
Victoria, Australia
Correspondence to: Graham S. Baldwin Department of Surgery,
A&RMC, Austin Campus, Studley Rd., Heidelberg,
Victoria 3084, Australia.
Telephone:
(613) 9496 5592, Fax. (613) 9458 1650
E-mail: g.baldwin＠surgeryaustin.
unimelb. edu. au
Received: 1998-10-28
Subject
headings: stomach; corrosion casts;
lymphatics; three-dimensional structure
Graham
S. Baldwin and Arthur Shulkes. Gastrin as an autocrine growth factor
in colorectal carcinoma: implications for therapy World
J Gastroenterol,1998;4(6):461-463
There is now considerable experimental support for the hypothesis
that progastrinderived peptides stimulate proliferation of the
normal colonic mucosa［1］,
and act as autocrine growth factors in colorectal carcinoma (CRC).
In a previous review［2］
we summarized the evidence for
the presence of progastrin-derived peptides and their receptors in
CRC, and presented a model in which amidated and non-amidated
progastrin-derived peptides stimulate proliferation of CRC cells via
distinct receptor classes. In this editorial we will consider the
various strategies available to interfere with the individual
components of the autocrine loop, and the potential of the
strategies to yield novel diagnostic and therapeutic agents.
AUTOCRINE LOOPS
In the autocrine model (Figure 1) a cell synthesises its own growth
factor, which is released into the surrounding medium. Binding of
the growth factor to cell surface receptors then results in the
transmission of a mitogenic signal to the cell nucleus, with a
consequent increase in cell proliferation. In principle, autocrine
loops could be disrupted in at least 3 ways:
1. By reduction of growth factor mRNA by introduction of
antisense RNA or oligonucleotides,
2. By reduction of the concentration of extracellular growth
factor by treatment with specific antibodies, or
3. By blockade of growth factor receptors with selective
antagonists.
In addition the presence of elevated concentrations of tumour-derived
growth factors in the sera of patients with CRC
may offer a sensitive method of tumour detection, via the
development of anti growth factor antibodies suitable for
radioimmunoassay. CRC cells synthesise progastrin mRNA, translate
the message into progastrin, and process the progastrin into
progastrin-derived peptides, which are released into the surrounding
medium. Binding of progastrin derived peptides to a specific
receptor then results in an increase in cell proliferation. In
principle the loop could be blocked by expression of antisense
gastrin mRNA, by antibodies against the appropriate progastrin-derived
peptides, or by selective receptor antagonists (Figure 1).
Figure 1(PDF)
An autocrine
growth loop involving progastrin-derived peptides.
ANTISENSE mRNA EXPRESSION
Antisense experiments have provided clear evidence for the
involvement of progastrinderived peptides in an autocrine loop in
some cell lines of colonic origin. Expression of antisense gastrin
mRNA reduced in vitro growth of the CRC cell lines Colo 320
and HCT 116［3］.
and of the conditionally immortalized mouse colon cell line YAMC［4］.
The ability of HCT 116 cells to grow as tumours in nude mice was
also reduced by antisense gastrin mRNA expression［3］.
In control experiments in vitro and in vivo growth of
the CRC cell line Colo 205A, which expressed negligible amounts of
gastrin mRNA prior to transfection, was unaffected by expression of
antisense gastrin mRNA［3］.
However the inherent difficulty of selectively targeting antisense
constructs to tumour cells may delay development of related clinical
therapies.
ANTIBODIES
Diagnosis
The question of whether or not CRCs produce progastrin-derived
peptides has been controversial, at least partly because of the
large number of potential products of the gastrin gene［2］.
Progastrin is processed to amidated gastrin via a number of
intermediates which include glycine-extended gastrins. Some early
reports were confined to measurement of amidated forms of gastrin
only, and the variable extent of postranslational processing of
progastrin in peptide-producing tumours may explain some of the
negative findings reported in the literature. Progastrin or
progastrin-derived peptides are now detected in 80%-100% of CRCs［2］.
The concentrations of progastrin-derived peptides in the serum of
patients with CRC are also elevated between 2.3-fold (H. pylori negative)
and 5.2-fold (H. pylori positive)［5］.
The availability of a panel of antibodies recognizing different
regions of intact progastrin, and of antibodies selective for
individual progastrin derived peptides, may permit the early
diagnosis of CRC by radioimmunoassay of serum samples. In this
context a large prospective study has recently indicated that
hypergastrinaemia was associated with a 3.9-fold increase in the
risk of later development of CRC［6］.
Therapy
Antibodies against progastrin-derived peptides may also be useful
for treatment of CRC. The proliferation of some, but not all, CRC
cell lines was inhibited by antibodies recognizing the C-terminal
amidated tetrapeptide of gastrin［2］.
On the other hand, proliferation of the mouse colon cell line YAMC
was inhibited by antibodies recognizing glycine extended, but not
amidated, gastrins［4］.
A promising approach to future therapy has been provided by the
observation that preimmunization of rats with Gastrimmune (a
conjugate of amino acids 1-9 of gastrin17 and diphtheria
toxoid which recognises both gastrin17 and gastrin17-gly)
reduced the in vivo growth of the rat CRC cell line DHDK12,
either alone or in conjuction with 5-fluorouracil and leucovorin［7］.
ANTAGONISTS
Gastrin/CCK receptor antagonists
At least four receptors exist for the gastrin/CCK family of peptides2.
The CCK A and gastrin/CCK-B receptors are specific for amidated
peptides, while the glycine-extended gastrin receptor is selective
for non-amidated forms of gastrin. The low affinity gastrin/CCK-C
receptor binds amidated and non-amidated forms of gastrin with equal
affinity. While the nonselective antagonists proglumide and
benzotript inhibit the binding to gastrin/CCK-A, B and C receptors,
antagonists selective for either-A or -B receptors have also been
developed［2］.
The non-selective antagonists proglumide and benzotript
inhibit proliferation of many gastrointestinal carcinoma cell lines
both in vitro and in vivo［8］.
Comparison of the inhibitory potencies of proglumide, benzotript and
other selective gastrin/CCK receptor antagonists with receptor
affinities suggests that the gastrin/CCK-C receptor is the probable
target［9］.
However a clinical trial of proglumide in patients with gastric
carcinoma did not reveal any benefits, perhaps because the
concentrations achieved were not sufficient to saturate gastrin/CCK
receptors. Gastrin/CCK-B receptor antagonists have also been shown
to inhibit the growth of some CRC cell lines in vitro, and of
primary human CRCs in vitro and in vivo, but have not
yet been subjected to clinical trials. However the observation that
most CRCs do not express gastrin/CCK B receptors indicates that it
will be unlikely that gastrin/CCK-B receptorselective antagonists
will be a general treatment for CRC［2］.
Non-steroidal anti-inflammatory drugs
Epidemiological studies have revealed that non-steroidal
anti-inflammatory drugs (NSAIDs), and in particular aspirin, reduce
by approximately 50% the risk of CRC and other cancers of the
gastrointestinal tract［10］.
The NSAID sulindac also reduces the size and number of colorectal
polyps in patients with familial adenomatous polyposis, and inhibits
the development of chemically-induced CRC in rodents. Although
selective antagonists have indicated that the inducible isozyme
cyclooxygenase2 is one of the targets for the inhibitory
effects of NSAIDs on CRC growth in vivo, several lines of
evidence suggest that other targets may contribute to the anti-proliferative
effects in vitro［10］.
The gastrin/CCK-C
receptor may be one such alternative target. All of a panel of 17
NSAIDs tested inhibited the binding of gastrin to the gastrin/CCK-C
receptor with affinities which correlated well with their potencies
as inhibitors of the proliferation of CRC cell lines［11］.
The most potent antagonist of gastrin binding to date is sulindac
sulphide, which has an IC50 value of 40μM, and more
potent antagonists of the gastrin/CCK-C receptor may well be of use
in the treatment of CRC.
CONCLUSIONS
This editorial has summarized several promising avenues for future
research into the effects of progastrin-derived peptides as
autocrine growth factors in CRC. In particular the development of
antibodies against progastrin-derived peptides, and of antagonists
selective for progastrin-derived peptide receptors, may provide new
opportunities for diagnosis and therapy of CRC.
REFERENCES
1
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Dockray GJ. Processing and proliferative effects of human
progastrin
in transgenic mice, J Clin Invest 1996;98:1918-1929
2 Baldwin
GS and Shulkes A, Gastrin, gastrin receptors and colorectal
carcinoma. Gut,1998;42:581-584
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Owlia A, Varro A, Dai B, Rajaraman S, Wood T. Gastrin gene
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and
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F, Imdahl A, Mantamadiotis T, Ciccotosto GD, Shulkes A, Baldwin GS.
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CM, Friedman GD, Dickinson, CJ, Vogelman, JH, Orentreich N and
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A prospective study.Gastroenterology,1998;115:275-280
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SA, Michaeli D, Grimes S, Morris TM, Robinson G, Varro A et al.
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and glycine-extended gastrin-17 and inhibit the growth of colon
cancer.Cancer Res, 1996;56:880-885
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9 Baldwin
GS. Antiproliferative gastrin/cholecystokinin receptor antagonists
target the 78-kda gastrin-binding protein.
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NatlAcad SciUSA,1994;91:7593-7597
10 Gupta RA and DuBois RN. Aspirin, NSAIDs and colon cancer
prevention: Mechanisms. Gastroenterology,
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11 Baldwin GS, Murphy VJ, Yang Z and Hashimoto T. Binding of
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