Table Of ContentEXS 74
Epithelial-Mesenchymal
Interactions in Cancer
Edited by I.D. Goldberg
E.M. Rosen
Birkhauser Verlag
Basel . Boston . Berlin
Editors
Dr. I.D. Goldberg
Dr. E.M. Rosen
Long Island Jewish
Medical Center
Institute of Oncology
New Hyde Park
N.Y. 11042
USA
Library of Congress Cataloging-in-Publication Data
Epithelial-mesenchymal interactions in cancer I edited by I.D.
Goldberg, E.M. Rosen.
p. cm. - (Exs; 74)
Includes bibliographical references and index.
1. Epithelium-Tumors. 2. Mesenchyme-Pathophysiology. 3. Cancer
invasiveness. 4. Carcinogenesis. 5. Fibroblasts. 6. Transforming
growth factors. I. Goldberg, I.D. (ltzhak David), 1948-
II. Rosen, E.M. (Eliot M.) III. Series: Experientia. Supplementum; v. 74.
[DNLM: 1. Epithelium-physiology. 2. Mesoderm-physiology.
3. Stromal Cells-physiology. 4. Cell Transformation, Neoplastic.
5. Neoplasm Metastasis. 6. Neoplasm Invasiveness. EX23 v. 74 1995
I QZ 365 E64 1995]
RC280.E66E65 1995
616.99'4071-dc20
DNLM/DLC
for Library of Congress
Deutsche Bibliothek Cataloging-in-Publication Data
EXS. - Basel; Boston; Berlin: Birkhauser.
Friiher Schriftenreihe
Fortlaufende Bei!. zu: Experientia
74. Epithelial-mesenchymal interactions in cancer. - 1995
Epithelial-mesenchymal interactions in cancer I ed. by I.D. Goldberg; E.M. Rosen. - Basel;
Boston; Berlin: Birkhauser, 1995
(EXS; 74)
NE: Goldberg, Itzak D. [Hrsg.]
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© 1995 Birkhauser Verlag, P.O. Box 133, CH-4010 Basel, Switzerland
Softcover reprint of the hardcover 1st edition 1995
Printed on acid-free paper produced from chlorine-free pulp. TCF
00
ISBN-13: 978-3-0348-9893-5 e-ISBN-13: 978-3-0348-9070-0
DOl: 10.1007/978-3-0348-9070-0
987654321
Dedicated to the memory of Gertrude Kurz,
whose character, devotion and courage
were an inspiration to all who knew her.
Itzhak D. Goldberg
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX
W. Birchmeier and C. Birchmeier
Epithelial-mesenchymal transitions in development and tumor
progresSIon. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
E.M. Rosen and I.D. Goldberg
Regulation of scatter factor (hepatocyte growth factor) production
by tumor-stroma interaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
R. Zarnegar
Regulation of HGF and HGFR gene expression. . . . . . . . . . . . . . 33
PJ. Polverini and BJ. Nickoloff
The role of scatter factor and the c-met proto-oncogene in angio-
gemc responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
A. Nusrat and l.L. Madara
Modulation of intercellular junctions of epithelia by scatter factor
(hepatocyte growth factor) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
l. Cortner, G.F. Vande Woude and S. Rong
The Met-HGF/SF autocrine signaling mechanism is involved in
sarcomagenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
G.L. Nicolson
Tumor cell interactions with the vascular endothelium and their
role in cancer metastasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 123
M.D. Levine, L.A. Liotta and M.L. Stracke
Stimulation and regulation of tumor cell motility in invasion and
metastasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 157
B.M. Kacinski
Tumor-stromal cytokine interactions in ovarian neoplasms. . . . . 181
l.S. Rubin, D.P. Bottaro, M. Chedid, T. Miki, D. Ron, G.R. Cunha
and P. W. Finch
Keratinocyte growth factor as a cytokine that mediates mesenchy
mal-epithelial interaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 191
Y.E. Shi and Y. Liu
Stromal-epithelial interaction in type IV collagenase expression
and activation: The role in cancer metastasis. . . . . . . . . . . . . . . .. 215
VIII Contents
D.S. Grant, R. Wesley Rose, 1.K. Kinsella and M.e. Kibbey
Angiogenesis as a component of epithelial-mesenchymal interac-
tions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 235
A.E. Hornby and K.J. Cullen
Mammary tumor fibroblasts are phenotypically distinct from non
tumor fibroblasts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 249
S.L. Schor
Fibroblast subpopulations as accelerators of tumor progression:
The role of migration stimulating factor . . . . . . . . . . . . . . . . . . . .. 273
Su~ect index ............................................. 297
Epithelial-Mesenchymal Interactions in Cancer
ed. by I.D. Goldberg & E.M. Rosen
© 1995 Birkh,user Verlag Basel/Switzerland
Introduction
The idea that interactions between malignant epithelia and surrounding
stromal cells might contribute to neoplasia is not new. The contribution
of the stroma to tumor development and progression has been recognized
in the past. Stromal cells actively interact with tumor epithelia and
actively support malignant growth. In addition, tumor stromal cells (eg.,
fibroblasts) are phenotypically distinct from their non-tumor counter
parts; these tumor fibroblasts may phenotypically resemble embryonic
fibroblasts more than normal adult fibroblasts (see van den Hooff, A.
(1988) Stromal involvement in malignant growth. Adv. Cancer Res. 50:
159-196). The implication is that tumor-associated fibroblasts, while not
'malignant' in the usual sense of the word, are somehow 'activated' or
'stimulated'. Within the last six years, considerable progress has been
made in identifying some of the molecular mechanisms through which
tumor cells interact with stroma. Some of the recent advances in this field
and their potential relevance to cancer invasion and metastasis are
highlighted in this book.
The importance of epithelial-mesenchyme interaction in embryogene
sis and tissue formation was suspected even before its significance in
malignancy came to be appreciated. Indeed, recent progress in decipher
ing the molecular signals that mediate the exchange between epithelia
and mesenchyme suggests intriguing parallels between the processes of
normal development and malignant growth. Some of the same cytokines,
growth factors, proteolytic enzymes, cell adhesion molecules, and struc
tural proteins of the extracellular matrix (ECM) have been implicated in
both processes. Epithelia-mesenchyme signalling relevant to develop
ment is discussed in the chapter by Birchmeier and in some of the other
chapters.
Scatter factor (SF, aka. hepatocyte growth factor) is a cytokine that
is synthesized and secreted predominantly by mesenchymal cells; its
canonical receptor, the protein product of the c-met proto-oncogene, is
expressed predominantly on epithelial cells. SF is over-produced within
tumors; and an increasing body of circumstantial evidence suggests that
SF may mediate tumor-stroma interactions that contribute to tumor
progression. Different aspects of these interactions are discussed in this
volume. Rosen and Goldberg discuss potential mechanisms that may
account for the accumulation of large quantities of SF within tumors.
Evidence is presented that malignant tumor cells secrete proteins (SF-in
ducing factors) that stimulate stromal cells to produce more SF. Zarne-
x Introduction
gar discusses recent studies of the SF gene promoter that may be relevant
to understanding the detailed molecular mechanism(s) by which soluble
factors regulate SF production.
Polverini and Nickoloff discuss another mechanism by which SF may
enhance tumor growth, ie., stimulation of angiogenesis, the formation
of new blood vessels from pre-existing microvessels. Angiogenesis is
required for continued growth of most solid tumors, and provides a
mechanism by which the stroma may continue to grow along with the
tumor cells. Although endothelial cells are stromal cells, they express a
number of epithelial characteristics including (i) epithelial-like tight
junctions and junctional proteins; (ii) the ability to organize into flat
tened tubular structures; (iii) the c-met receptor protein; and (iv) biologic
responsiveness to SF. It is, perhaps, not surprising that vascular endothe
lial cells may both produce and respond to SF in different situations.
'Epithelialness' may be defined in two ways: (i) expression of generic
epithelial structures and proteins (eg., specialized junctions, junctional
proteins [eg., cadherins, ZOl], cytokeratins); and (ii) production of
specific differentiated products (eg., milk proteins by mammary epithelia,
renin by renal tubular epithelia of the juxtaglomerular apparatus).
Recent studies suggest that SF Ic-met signalling may mediate epithelia
mesenchyme interconversion, in part by modifying some of the generic
epithelial characteristics. Nusrat discusses the effects of SF on the
epithelial junctional apparatus. Relatively little is known about whether
and how SF regulates cell-specific differentiation.
The contributions of paracrine and autocrine SF/c-met signalling to
the tumorigenic phenotype of NIH/3T3-derived tumors in an in vivo
animal model is discussed by Cortner and colleagues. These studies may
be relevant to mechanisms of human sarcomagenesis, the process by
which tumors of mesenchymal origin are formed. The authors have
shown that over-expression of both ligand and receptor are required for
maximal tumorigenesis. Thus, mechanisms that normally repress c-met
receptor expression in fibroblasts may be important in the prevention of
spontaneous development of sarcomas. The authors suggest that the p53
anti-oncoprotein is one possible regulator of c-met expression, providing
possible linkage between p53 mutation and c-met over-expression.
A variety of other growth factors, cytokines, and motility factors that
accumulate within the tumor microenvironment contribute to tumor
growth, invasion, and metastasis. Some of these factors are described in
the chapters by Drs. Nicolson, Stracke, Kacinski, and Rubin. Stracke
describes a group of factors originally thought to primarily mediate
tumor cell motility, although in some cases, various other activities have
been documented. Some of these factors are autocrine factors, ie., act
upon the same cells that produce them. The designation of a factor as
autocrine may be somewhat artificial, since a soluble factor produced by
one tumor cell may diffuse to and stimulate a neighboring tumor
Introduction XI
cell. Autotaxin, a tumor cell-derived motility factor related to certain
ectoenzymes (ie., phosphodiesterases) is described in detail in the chap
ter by Stracke. Nicolson describes paracrine interactions between mi
crovascular endothelial cells and tumor cells that may explain why
certain tumor types metastasize exclusively or selectively to specific
organs. Some of the molecular mediators of organ specific colonization
and growth of tumor cells which have been isolated and characterized
are discussed in this chapter.
Kacinski reviews some new data relating to tumor-stromal interactions
that may promote the growth of ovarian carcinomas, including studies
from his own laboratory. Colony-stimulating factor-l (CSF-I) and its
receptor (the c-fms proto-oncogene product) may be of particular interest.
CSF-I simulates proliferation and invasion of ovarian carcinoma cells in
vitro, and its expression in vivo is correlated with prognosis. Moreover,
CSF-l expression may be regulated in part by a paracrine mechanism
involving production of inducing factors by tumor cells leading to
production of CSF-I by stromal cells. The recently discovered kerati
nocyte growth factor (KGF ), a member of the heparin-binding family of
fibroblast growth factors, stimulates epithelial cell proliferation through
its receptor, a tyrosine kinase isoform encoded by thefgfr-2 gene. Studies
of the distribution and activity ofKGF and its receptor suggest that KGF
may act as a paracrine mediator of mesenchymal-epithelial communica
tion. These findings are described, and their possible contribution to
malignancy are discussed in the chapter by Rubin.
In addition to growth-stimulating and invasogenic cytokines, other
factors may promote the invasive tumor phenotype, including proteases
that degrade basement membrane and other forms of ECM. Accumu
lating evidence indicates that members of the family of matrix metallo
proteinases (MMPs) contribute to the invasive behavior of tumor cells.
Enzymes of particular interest in this respect are MMP-2 and MMP-9,
two distinct forms of type IV collagenase. Molecular interactions be
tween invading tumor cells and adjacent stroma contributory to the
expression and activation of these enzymes have recently been identified.
As described by Shih, it now appears that type IV procollagenase is
produced by stromal fibroblasts in response to factors secreted by
tumor cells at the leading edge of an invading tumor. Moreover,
procollagenase IV may be activated by proteins located on the tumor
cell membrane. Some of these same mechanisms may also be relevant to
angiogenesis, during which endothelial cells transiently become proteo
lytically active and invade through basement membrane of the parent
vessel. Endothelium-stroma interactions that may regulate the angio
genic phenotype are discussed in the chapter by Grant.
Studies of potential differences between tumor-associated versus nor
mal adult fibroblasts have been pursued at the molecular level. Two
chapters on this subject have been provided by Drs. Hornby and Schor.
