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2163
COMMUNICATION
Union Internationale
Contre le Cancer
Reprinted from Int J Cancer 1997;73:461–3 with
minor editorial clarification but no substantive
changes.
UICC Study Group on Basic and
Clinical Cancer Research
UICC Study Group on Basic and Clinical Cancer
Research, Woods Hole, Massachusetts, June 18–
21, 1997.
Mechanisms of Growth Factor and Hormone
Insensitivity
This meeting was sponsored by Novartis, Inc., Basel, Switzerland. The Tumor Biology Program of
UICC (Dr. K. Höffken) and the participants express
their gratitude for the unselfish support and lowkey presence of the sponsor.
List of Participants: Attisano, L., Department of
Anatomy and Cell Biology, University of Toronto,
Toronto, Canada, Benjamin, T.L., Department of
Pathology, Harvard Medical School, Boston, MA,
USA, Buchdunger, E., Oncology Research, Novartis, Inc., Basel, Switzerland, Burger, M.M.,
Friedrich Miescher-Institut, Basel, Switzerland, De
Lange, T., Laboratory of Cell Biology and Genetics,
Rockefeller University, New York, NY, USA,
Doetschman, T., Department of Molecular Genetics, University of Cincinnati, Cincinnati, OH, USA,
Gelbart, W.M., Biological Laboratories, Harvard
University, Cambridge, MA, USA, Hamy, F., Oncology Research, Novartis, Inc., Basel, Switzerland,
Katzenellenbogen, B.S., Department of Molecular
and Integrative Physiology, University of Illinois,
Urbana, IL, USA, Korsmeyer, S.J., HHMI Research
Laboratories, Washington University, School of
Medicine, St. Louis, MO, USA, Levine, A.J., Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA,
Markowitz, S., Ireland Cancer Center Laboratories,
Western Reserve University, Cleveland, OH, USA,
Mendelsohn, J., MD Anderson Cancer Center,
Houston, TX, USA, Moses, H.L., Department of Cell
Biology, Vanderbilt Cancer Center, Nashville, TN,
USA, Pietenpol, J.A., Department of Biochemistry,
Vanderbilt Cancer Center, Nashville, TN, USA,
Scher, H.I., Genito-urinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York,
NY, USA, Serra, R., Department of Cell Biology,
Vanderbilt Cancer Center, Nashville, TN, USA, Shay,
J.W., Department of Cell Biology, UT Southwestern
Medical Center, Dallas, TX, USA, Weinberg, R.A.,
Whitehead Institute for Biomedical Research, MIT,
Cambridge, MA, USA, Whitman, M., Department
of Cell Biology, Harvard Medical School, Cambridge, MA, USA, Wrana, J.L., Program in Developmental Biology and Division of Gastroenterology,
Hospital for Sick Children, Toronto, Canada.
Address for reprints: Max M. Burger, M.D.,
Friedrich Miescher-Institut, P.O. Box 2543, CH4002 Basel, Switzerland.
Received July 18, 1997; revision received August
19, 1997.
Max M. Burger1
Harold L. Moses2
1
Friedrich Miescher-Institut, Basel, Switzerland.
2
Department of Cell Biology, Vanderbilt Cancer Center, Nashville, TN.
I
t is the purpose of these Study Group Meetings, which are organized
by the Tumor Biology Program of the UICC, to establish a basis for
possible clinical applications founded on molecular concepts. For this
purpose, a few clinicians, pathologists and epidemiologists are invited
together with a core group of cell and molecular biologists. The meetings are of a particularly informal nature, to foster exchanges of ideas
rather than discuss data. It is for this reason that no book is published
as a follow-up but, instead, the following short report. More detailed
data can be requested from the participants directly.
Many recent meetings in this series dealt indirectly either with ‘‘receptorology’’ in general, or with signaling from receptors (oncogenes, 1988;
tumor-suppressor genes, 1990 and 1992; angiogenesis, 1993; apoptosis,
1994; the cell cycle, 1995; multigene effects influencing each other, 1996).
It was therefore timely to have a closer look at receptors and their signaling
paths. The key issue from the clinical point of view is the gradual loss of
ligand dependence of these receptors and their signaling path and thus
escape from local growth control. These points were dealt with in more
depth at this meeting, and individual views are summarized below. Stimulating discussions followed the individual presentations.
General Survey and Some Thoughts on Telomers
Dr. Robert Weinberg opened the meeting with a summary of some
of the main discussion concepts. The evolution of a tumor depends
upon changes in a specific and apparently limited spectrum of cell
physiologic phenotypes. Included among these are changes in the
responsiveness of cells to cellular signals, including acquired independence from growth-factor stimulation, and in acquired refractoriness
to growth-inhibiting signals such as those conveyed by TGF-b. In
addition, the evolving tumor-cell clone must overcome an intrinsic
limitation to its proliferation-the generational clock that determines
cell mortality, and that is deranged during tumor progression by the
resurrection of telomerase expression. The human telomerase gene
has now been cloned, making it possible to understand how expression of telomerase is achieved late in tumor progression.
Dr. Jerry Shay described experiments indicating that the shortening of telomere length may be causal and not just correlative in the
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CANCER December 1, 1997 / Volume 80 / Number 11
regulation of human cell proliferative lifespan, also,
experiments showing that the introduction of single
chromosomes into telomerase-positive tumor cells resulted in inhibition of telomerase activity, progressive
telomere shortening, and finally inhibition of cell proliferation. There is mounting evidence that knowledge
of telomerase activity and RNA will be useful in the
early diagnosis of cancer and may be a marker of residual disease following chemotherapy.
Recent progress in this field was summarized by
Dr. Titia de Lange. She showed that telomeres contain
several types of telomere-binding proteins regulating
telomerase. In mammalian cells, the duplex TTAGGG
repeats at chromosome ends are bound to 2 Mybrelated factors, TRF1 and TRF2. TRF1 was found to be
a negative regulator of telomere maintenance, proposed as acting in cis to limit the activity of telomerase
at individual telomere ends.
While research on the telomere/telomerase field
is still young, and surprises are likely in the future, the
basic studies and those on clinical cancer and aging
already performed are highly encouraging.
TGF-b, Smads, Signaling and Cancer
Dr. Harold L. Moses then introduced the TGF-b signaling pathway, its homologue in insects and reviewed
the critical issues of its relationship with cancer. The
TGF-bs signal through heteromeric transmembrane
serine/threonine kinase receptors that interact with
intracellular signaling molecules related to the Drosophila Mothers Against Decapentaplegic (Mad,
Smad) gene products. Genes encoding members of
this signaling pathway have been shown to be tumorsuppressor genes. Additional evidence for the TGF-b
pathway having tumor-suppressive activity comes
from transgenic studies in Dr. Moses’ laboratory in
which over-expression of TGF-b1 in mammary epithelial cells was shown to suppress mammary-tumor formation. Once carcinoma cells have lost the growthinhibitory response to TGF-b, over-expression frequently ensues, with enhancement of tumorigenicity
and metastatic spread. Possible mechanisms for TGFb promotion of tumor progression include suppression of immune surveillance and/or direct autocrine
effect of TGF-b on tumor cells, increasing plasticity
through effects on Rho signaling and integrin redistribution.
Dr. Jeffrey L. Wrana then dissected the signaling
pathway. TGF-b signaling through Smads is initiated
when the activated receptor phosphorylates Smad2,
which then associates with Smad4, followed by nuclear translocation of the complex. Our current understanding of this pathway suggests that TGF-b and activin specifically regulate Smad2 and 3, while BMPs
regulate Smad1 and 5. Loss of TGF-b signaling can
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occur through mutation of Smads. Dr. Wrana has now
identified Smad7 as an intracellular antagonist of the
TGF-b receptor that blocks activation of Smad2, providing a novel mechanism to suppress TGF-b signaling.
Smad2, which is centrally involved in TGF-b signaling, is located, according to Dr. Liliana Attisano, at
18 q 21, a region that displays LOH in many human
tumors. Mis-sense mutations identified in sporadic
colorectal carcinoma disrupt phosphorylation of
Smad2 by the receptor and its association with Smad4,
but not interaction with the nuclear target FAST-1. She
proposes that the gene dosage effects caused by LOH
at 18 q 21, in the absence of mis-sense mutations, may
be sufficient to suppress TGF-b signaling during tumor
progression.
TGF-b induces epithelial-cell apoptosis and
growth suppression in colon in vitro. Dr. Sanford Markowitz has focused his interest on human tumors. Mutations in type II of the TGF-b receptor (RII) have been
demonstrated in a sub-set of human colon cancers
that show the defect of microsatellite instability. In
these cancers, a microsatellite-like polyadenine coding
sequence in RII is mutated on both alleles over 90%
of the time. Restoring wild-type RII blocks tumorigenicity of these cells.
In view of the expression patterns of TGF-b1, 2
and 3, also the fact that all 3 may signal through a
common type-II receptor, and bearing in mind the
lack of phenotypic overlap in the 3 knock-out mice,
Dr. Tom Doetschman proposes that an important aspect of ligand specificity may lie in ligand activation.
Furthermore, the fact that TGF-b1-deficient platelets
have an aggregation defect which is eliminated by preincubation in TGF-b1 suggests that activity is not mediated by transcriptional control. Finally, analysis of
intestinal-tumor formation in TGF-b1-deficient mice
indicates that its role in preventing these tumors is
immunoprotective (protection against inflammationinduced damage) rather than immunosuppressive.
FAST-1 was identified by Dr. Malcolm Whitman
as a transcription factor mediating activin/TGF-b responses in early amphibian embryos. FAST-1 associates with the TGF-b signal transducer Smad2 and
Smad4. His group has identified a 126-amino-acid domain of FAST-1 which is necessary and sufficient for
interaction with Smads. This isolated domain is a potent inhibitor of activin/Smad2 signaling.
The Drosophila decapentaplegic (Dpp) and vertebrate BMP2/4 pathways were shown by Dr. William
M. Gelbart to be conserved in terms of cellular components and probably also in terms of developmental
roles in the establishment of complex pattern. The
issue of how a graded Dpp signal might lead to different cell fates was discussed. A more general issue
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UICC Study Group on Basic and Clinical Cancer Research/Burger and Moses
raised was how bio-informatics might be used to make
relevant Drosophila genetic and developmental information more accessible to the cancer-biology community.
Hormone Resistance and Possible Therapeutic
Approaches via Receptors
Dr. Benita S. Katzenellenbogen discussed structureactivity relationships in the estrogen receptor, current
interest in the possible role of a second estrogen receptor, called ER-b, in hormonal responsiveness and resistance in breast cancer, as well as work towards the
development of even more tissue-selective anti-estrogens. Hormonal resistance is multifactorial, involving
changes in the estrogen receptor, as well as alterations
at post-receptor points in the ligand-receptor-effectorresponse pathway, including changes in phosphorylation and growth-factor production/sensitivity that
may render breast-cancer cells unresponsive to hormones (estrogen/antiestrogen). An important aspect
is that anti-estrogen resistance is often reversible, suggesting cellular adaptational changes, not genetic alteration, in many cases; moreover, different anti-estrogens work through somewhat different mechanisms,
so that resistance to anti-estrogen need not mean
cross-resistance to others.
Dr. Howard Scher reviewed data showing that the
progression of prostate cancers from hormone-responsive primary tumors to androgen-independent
metastases is associated with increased frequency of
mutations in the androgen receptor. The mutations
that develop are influenced by the specific hormone
therapy administered, and include mutations across
all exons and amplification of the wild-type receptor.
All are associated with a gain of function and may
explain, in part, the lack of cross-resistance between
casodex and flutamide. An alternative strategy, currently under investigation by his group, is focussed on
blocking androgen-receptor signaling through selective degradation of the receptor.
One of the serious problems with the use of ligands designed as antagonists is the fact that they
often unpredictably act as agonists, particularly in the
steroid field; but similar unexpected results have occurred earlier, with antibodies against receptors. The
monoclonal antibody (MAb) which Dr. John Mendelsohn has shown to block the EGF receptors can prevent ligand-induced activation of receptor tyrosine kinase, and this results in elevation of p27 and slowing
or arrest of cell-cycle traversal in the G1 phase. Treatment of a number of well-established human tumor
xenografts with a systemic MAb can reduce tumor
growth, and treatment with a MAb combined with
chemotherapy (doxorubicin, cisplatin, or paclitaxel, at
maximally tolerated but non-curative doses) can erad-
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2165
icate the tumors. The results suggest that an active
growth-factor-mediated signal-transduction pathway
can become essential for survival or recovery in cells
damaged by chemotherapy, and this approach to cancer therapy is being explored in clinical trials.
Signaling for Cyto-Architecture, the Cytoskeleton, Cell
Cycle and Apoptosis
Dr. Rosa Serra reminded the participants that expression and function of integrins and integrin-signaling
molecules are altered in tumorigenic cells, and that
restoration of normal integrin profile is sufficient to
suppress the tumorigenic phenotype of many transformed cells. TGF-b can regulate cell shape and tissue
architecture by regulating integrin function by a pathway independent of pRb and myc. Regulation of cell
shape and tissue architecture is one possible mechanism of TGF-b action in morphogenesis and tumorigenesis.
The recently unraveled Wnt-1-APC (adenomatous
polyposis coli) pathway was presented by Dr. Arnold
J. Levine. It coordinates cell division, cytoskeleton architecture and adhesion junctions in epithelial cells.
The pathway coordinates the level of beta catenin. A
number of components (beta and alpha catenin, cadherins, APC, Wnt) are found to be mutated in human
cancers. Restoration of wild-type alpha catenin in a
cell with mutant alpha catenins restores growth regulation, and diminishes the tumorigenic potential of
these cells.
Recent studies suggest that epithelial tumor cells
undergo G2 /M checkpoint arrest following exposure
to genotoxic agents. Manipulation of this checkpoint
through direct or indirect modulation of cdc2 kinase
activity was shown by Dr. Jennifer Pietenpol to result
in increased rates of apoptosis. In fact, microtubulemodifying agents, such as taxol, may exert their anticancer effects, in part, through activation of cdc2 kinase and override of G2 /M transition.
The last speaker, Dr. Stanley Korsmeyer, addressed some points in signaling in apoptosis. The
BCL-2 family has both anti-apoptotic (e.g., BCL-2) and
pro-apoptotic (e.g., BAX) molecules with an ability to
dimerize; however, genetic, mutational and localization studies indicate that they can function independently of one another. Distant members, BID and BAD,
possess only the BH3 helix that binds to membranebased members and represent ligands connecting the
BCL-2 checkpoint to signal transduction. BAX can kill
without another signal, activating caspases as well as
mitochondrial dysfunction that may reflect the ionconductive pore activity of these molecules.
Discussion, formal as well as informal, centered
mainly on 2 topics. The first, as expected, was the
mechanisms of signaling and the rapid increase of in-
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CANCER December 1, 1997 / Volume 80 / Number 11
formation on assignable molecular alterations in these
pathways, including resistance to hormones and
growth factor, and analogous drug resistance.
The second, less expected, topic began to capture
the attention of participants during the meeting: the
possibility that the loss in tissue architecture in cancer
may be closely associated not only with extracellularmatrix alteration but also with cytoskeleton rearrangements. These may influence many neoplastic phenomena, such as de-differentiation, invasiveness, and
deformability, all of their cell biological parameters for
which only descriptive molecular data have accumulated. Consequently, the absence of convincing functional molecular explanations is even more painful,
but may stimulate further research.
2.
3.
4.
5.
6.
7.
REFERENCES
1.
Burger MM, Barbacid M, Stiles CD. UICC Study Group on
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basic and clinical cancer research: growth factors, receptors
and oncogenes. Int J Cancer 1988;41:1–4.
Burger MM, Croce CM. UICC Study Group on basic and
clinical cancer research: cancer-suppressing genes. Int J
Cancer 1990;45:221–3.
Burger MM, Folkman J. UICC Study Group on basic and
clinical cancer research: tumor angiogenesis. Int J Cancer
1993;56:311–3.
Burger MM, Friend S. UICC Study Group on basic and clinical cancer research: multigene effects influencing each
other. Int J Cancer 1996;68:273–5.
Burger MM, Harlow E. UICC Study Group on basic and clinical cancer research: cell-cycle control: a target for therapy?
Int J Cancer 1995;63:321–3.
Burger MM, Harris C. UICC Study Group on basic and clinical cancer research: apoptosis in normal and tumor cells.
Int J Cancer 1994;60:590–2.
Levine AJ, Burger MM. UICC Study Group on basic and
clinical cancer research: genotypes and phenotypes of tumor suppressors. Int J Cancer 1992;53:883–5.
W: Cancer
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