Current
Cancer Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 8, Number 6, September 2008
Contents
Targeting Tumor Stroma
Guest Editors: Marc G. Achen and Steven A.
Stacker
Editorial Pp. 446
Tumor Stroma as a Target in Cancer Pp. 447-453
F. Ahmed, J.C. Steele, J.M.J. Herbert, N.M. Steven and
R. Bicknell
[Abstract]
Importance of Wnt Signaling in the Tumor Stroma
Microenvironment Pp. 454-465
Maria L. Macheda and Steven A. Stacker
[Abstract]
Role of TGF—β
in the Tumor Stroma Pp. 466-472
H.P.H. Naber, P. ten Dijke and E. Pardali
[Abstract]
Eph/Ephrin Signalling and Function in Oncogenesis:
Lessons from Embryonic Development Pp. 473-489
Peter W. Janes, Samantha Adikari and Martin Lackmann
[Abstract]
Prostatic Tumor Stroma: A Key Player in Cancer Progression
Pp. 490-497
R.A. Taylor and G.P. Risbridger
[Abstract]
Clinical Use of Therapies Targeting Tumor Vasculature
and Stroma Pp. 498-508
Ian D. Davis and Jayesh Desai
[Abstract]
General Articles
Epigenetic Aberrations and Targeted Epigenetic Therapy
of Esophageal Cancer Pp.509-521
Ronghua Zhao and Alan G. Casson
[Abstract]
The Heat Shock Protein 90 Chaperone Complex:
An Evolving Therapeutic Target Pp. 522-535
M.F. Barginear, C. Van Poznak, N. Rosen, S. Modi, C.A.
Hudis, and D.R. Budman
[Abstract]
Targeting Apoptosis Resistance in Rhabdomyosarcoma
Pp. 536-544
Simone Fulda
[Abstract]
Abstracts
[Back to top]
Editorial
Many of the currently available anti-cancer therapeutics are
based on the concept of targeting tumor cells. However, the
tumor stroma has also become a major focus of attention as
a therapeutic target. An early attempt to target stromal components,
in the 1990s, involved the matrix metalloproteinases (MMPs),
that can be expressed by various cell types in the tumor stroma.
MMPs were targeted in human cancer with synthetic inhibitors,
however, these compounds failed in clinical trials, in part
because the complex mechanisms-of-action of MMPs, and the
biology of the tumor stroma, were not well understood. Typically,
the tumor stroma can consist of extracellular matrix as well
as a range of cell types, including fibroblasts, the endothelial
cells of blood vessels and lymphatic vessels, and immune cells
such as monocytes and macrophages. The cells of the tumor
stroma can be important for sustaining or promoting the growth
and metastatic spread of solid tumors. For example, tumor
angiogenesis, that gives rise to tumor blood vessels, promotes
tumor growth and presumably facilitates metastatic spread
via the blood-stream. Moreover, tumor lymphangiogenesis,
that increases the abundance and possibly the size of peritumoral
or intratumoral lymphatics, may facilitate metastatic spread
of tumor cells to regional lymph nodes and possibly to more
distant sites in the body. Recent studies have indicated that
components of inflammatory infiltrate in solid tumors, particularly
macrophages, can play a role in recruiting blood vessels thereby
facilitating tumor growth.
The communication between tumor cells and stromal components
is facilitated by a range of growth factors, growth factor
receptors and proteases. Members of the VEGF family of glycoproteins
are important for recruitment of tumor blood vessels and lymphatics,
Wnt signaling pathways are involved in signaling between epithelial
cells and stromal cells, TGF-β
is thought to play a role in the tumor-promoting activities
of cancer-associated fibroblasts, and the Eph receptors and
their ephrin ligands may be important for migration of stromal
cells associated with tumors. Each of these signaling systems
is examined by an article in this issue. The growth factors
and receptors that are essential for such signaling pathways
are potential therapeutic targets in cancer – some,
including VEGF-A and VEGF receptors, have already been exploited
for development of anti-cancer therapeutics. The emerging
technologies of “systems biology” will surely
prove useful for defining the circuitry of biological signal
transduction pathways that control the interaction of tumor
cells with components of the tumor stroma. This information
will be essential for understanding how distinct signaling
pathways can influence each other to determine outcomes in
terms of tumor biology.
The targeting of the tumor stroma will undoubtedly become
a more prominent theme for anti-cancer therapeutics in future.
We trust that this issue, which explores i) the biology of
the tumor stroma, ii) specific signaling pathways involved
in communication between tumor cells and stromal components,
and iii) therapeutic strategies for targeting stromal components,
will provide a useful overview of current activities in this
rapidly developing area.
Marc G. Achen and Steven A. Stacker
Melbourne Tumour Biology Branch,
Ludwig Institute for Cancer Research,
Royal Melbourne Hospital,
Victoria, Australia
Tel: (61-3) 9341 3155
Fax: (61-3) 9341 3107
E-mail: Marc.achen@ludwig.edu.au
Steven.stacker@ludwig.edu.au
[Back to top]
Tumor Stroma as a Target in Cancer
F. Ahmed, J.C. Steele, J.M.J. Herbert, N.M. Steven and
R. Bicknell
Solid tumors are composed of the malignant cell itself
(most commonly a carcinoma) and supporting cells that comprise
the stroma. Significant stromal components include the extracellular
matrix, supporting fibroblasts, vessels comprised of endothelium,
pericytes and in some cases vascular smooth muscle, lymphatics
and usually a major leukocyte infiltration. Indeed, macrophages
may constitute up to 50% of the viable cells within the tumor.
For many years, researchers have concentrated almost exclusively
on the malignant carcinoma and looked for ways to either selectively
kill or restrict its growth. In recent years the frustrating
lack of advances in cytotoxic cancer therapy provoked a search
for more novel strategies and foremost amongst these were
anti-angiogenesis and vascular targeting. The purpose of this
article is to illustrate how the stroma is now being pursued
as an anti-cancer target. The article will briefly touch on
anti-angiogenics that are now entering the clinic but concentrate
on recent studies looking at vascular disrupting agents, stromal
tumor fibroblasts and macrophages. Target identification is
illustrated by the search for tumor endothelial markers. Finally,
we draw attention to efforts to develop a cancer vaccine.
The genetic instability and variation found in carcinoma cells
made vaccination in the past a near impossibility. In contrast,
genetically stable tumor endothelium with its unique accessibility
to blood borne agents, together with recent advances in immunotherapy
means that the possibility of a cancer vaccine now takes on
a reality not previously recognised.
[Back to top]
Importance of Wnt Signaling in the Tumor Stroma
Microenvironment
Maria L. Macheda and Steven A. Stacker
Wnt signaling plays an important role in cancer. Signaling
is initiated by binding of Wnt ligands to Frizzled cell surface
receptors and results in signaling via one of three pathways,
the canonical Wnt pathway, which is the best characterized
in both normal tissues and in cancer, and two non-canonical
Wnt pathways, the Ca2+-dependent
and the PCP pathways. Canonical Wnt signaling results in β-catenin
accumulation in the cytoplasm, translocation into the nucleus
and activation of transcription of Wnt target genes including
the c-Myc oncogene. Some cancer types, including colorectal
cancer, have mutations in APC and Axin, which are involved
in β-catenin
phosphorylation, such that the canonical pathway is constitutively
active. Few studies have investigated the role non-canonical
Wnt signaling in cancer, or of Wnt signaling on tumor stromal
cells. Wnt overexpression is observed in tumor stroma, as
is overexpression of the Wnt pathway inhibitors, secreted
Frizzled-related proteins and Dickkopf proteins. Interactions
between epithelial cells and stromal cells have been observed
to activate Wnt signaling in both cell types. Wnt signaling
is also observed in tumor blood vessels and is likely to be
activated by signals from tumor cells. Current cancer therapies
focus on interfering with canonical Wnt signaling in the tumor
cells. Future therapeutic targets for interfering with Wnt
signaling include cell surface receptors such as the RYK and
Ror2 receptors and secreted signaling molecules, which mediate
signaling between cancer cells and the stromal environment.
[Back to top]
Role of TGF—β
in the Tumor Stroma
H.P.H. Naber, P. ten Dijke and E. Pardali
Recent findings have demonstrated that the tumor stroma
actively contributes to tumorigenesis. The communication of
malignant cells and tumor stromal components is orchestrated
in part by a network of growth factors. One of these growth
factors is transforming growth factor-β
(TGF-β),
a secreted multifunctional protein that acts in a highly cellular
contextual manner. TGF-β
can either stimulate or inhibit the tumor-promoting effects
of the different components of the tumor stroma. In this review,
we discuss our current understanding on how TGF-β
influences different stromal compartments.
[Back to top]
Eph/Ephrin Signalling and Function in Oncogenesis:
Lessons from Embryonic Development
Peter W. Janes, Samantha Adikari and Martin Lackmann
Eph receptors and their membrane-bound ephrin ligands
are developmental cell guidance cues that direct cell migration
and orchestrate patterning processes by modulating adhesive
or repulsive cell properties. During the past two decades,
an exponentially growing interest in their function has resulted
in a considerably advanced understanding of the cellular and
molecular principles of Eph function in normal and oncogenic
development. Ephs not only accurately guide the path of migrating
cells, but also facilitate contact and communication between
neighbouring cell populations, in particular at epithelial/mesenchymal
boundaries. Precise cell positioning not only relies on accurately-graded
expression of individual Eph/ephrin pairs, but on the sum
of interactions within particular expression domains and their
modulation through crosstalk with a range of other signalling
systems. There is little doubt that Eph and ephrins provide
exciting new targets for anti-cancer therapies, but in appreciation
of the complexity of their signals and biological functions
it is perhaps not surprising that the development of Ephspecific
therapeutics is only emerging.
[Back to top]
Prostatic Tumor Stroma: A Key Player in Cancer Progression
R.A. Taylor and G.P. Risbridger
Although it is evident that prostatic epithelial stem
cells are responsible for maintaining normal and malignant
tissues, it is well recognized that epithelial cells do not
exist independently, but act in concert with the stromal microenvironment.
Prostatic stroma is pivotal for normal development and homeostasis.
The genetic and morphological changes that occur in prostatic
epithelial cells, as they progress from a normal to malignant
phenotype, have been well described. However, it is evident
that the surrounding microenvironment also plays a major role
in cancer cell growth, survival, invasion and metastatic progression.
Prostatic tumor stroma provides a niche environment for cancer
stem cells and therefore contributes to self-renewal and differentiation.
In order to target the tumor microenvironment and develop
new therapeutics for prostate cancer, we must understand the
role of the tumor stroma, specifically the events mediating
the interactions between the cancer stem cell and its immediate
microenvironment during cancer initiation and progression.
This article presents the rationale and discusses the challenges
to targeting prostatic tumor stroma in cancer therapies that
will potentially treat prostate cancer.
[Back to top]
Clinical Use of Therapies Targeting Tumor Vasculature
and Stroma
Ian D. Davis and Jayesh Desai
Many recent advances in cancer therapy have been based
on an understanding of the basic biology of the cancer cell
itself, particularly with respect to abnormalities in various
signalling pathways. It has become increasingly apparent that
malignant cells exist in a complex cellular and extracellular
microenvironment, which can play key roles in the initiation
and maintenance of the malignant phenotype. These interactions
can provide therapeutic targets that are now being exploited
in the clinic. Much attention has been paid to agents that
disrupt angiogenesis or existing tumor vasculature, however
other cellular and non-cellular components of the tumor mass
mediate critical functions and can also be useful treatment
targets. Treatments directed at these interactions bring new
challenges in terms of how best to develop these strategies,
and require approaches that differ in many ways from conventional
anticancer therapies.
[Back to top]
Epigenetic Aberrations and Targeted Epigenetic Therapy
of Esophageal Cancer
Ronghua Zhao and Alan G. Casson
Squamous cell carcinoma of the esophagus is one of the
ten most frequent malignancies worldwide, characterized by
a striking geographic variation in incidence. In North America
and Europe, there has recently been a marked change in the
epidemiology of this disease, where incidence rates for primary
esophageal adenocarcinoma have increased in excess of any
other human solid tumor. Although the reasons for this are
largely unknown, several molecular genetic alterations have
been associated with esophageal tumor progression. In recent
years, epigenetic aberrations have been increasingly recognized
as an important alternative mechanism of carcinogenesis and
it is anticipated that substantial progress in the treatment
of esophageal malignancy will likely only be made with a clearer
understanding of esophageal tumor biology. Whereas genetic
mutations, deletions, or allelic losses are fixed and irreversible,
epigenetic abnormalities can potentially be corrected without
interfering with the fundamental sequence of the target gene.
Our current understanding of epigenetics in esophageal cancer,
and the potential for targeted epigenetic therapy, will be
the subject of this review.
[Back to top]
The Heat Shock Protein 90 Chaperone Complex:
An Evolving Therapeutic Target
M.F. Barginear, C. Van Poznak, N. Rosen, S. Modi, C.A.
Hudis, and D.R. Budman
Hsp90 (heat shock protein 90) is a molecular chaperone
that modulates the stability and/or transport of a diverse
set of critical cellular regulatory, metabolism, organization,
and signaling proteins. Binding to Hsp90 is required for normal
function of many proteins. In addition, Hsp90 has an extra-cellular
function. It is found in two isotypes: α
which is inducible and β
which is constitutive. Tumor cells frequently over express
Hsp90β,
and Hsp90 is implicated in cancer progression. Hence Hsp90
has emerged as a potential target for cancer treatment. A
variety of agents have been found to interfere with Hsp function,
mainly by binding to an ATP binding site on the molecule.
More recent agents interfere with protein binding or the dimerization
of Hsp90 needed for function. Preclinical studies have demonstrated
that disruption of the many client proteins chaperoned by
Hsp90 is achievable and associated with significant growth
inhibition, both in vitro and in tumor xenografts.
As a result, agents which interfere with this protein’s
function are being tested in the clinic as a targeted method
of interfering with malignant growth. We review the current
clinical status of therapeutic efforts to perturb this pathway
and discuss future directions.
[Back to top]
Targeting Apoptosis Resistance in Rhabdomyosarcoma
Simone Fulda
Resistance of human cancers to current treatment approaches
remains a challenge in oncology. Therefore, there has been
much interest in identifying molecular pathways that are responsible
for primary or acquired resistance of cancers. Since most
anticancer therapies, i.e. chemotherapy or radiotherapy, primarily
act by triggering programmed cell death (apoptosis) in cancer
cells, defects in apoptosis programs may confer resistance.
Evasion of apoptosis in rhabdomy-osarcoma may be caused by
the dominance of cell survival pathways, for example aberrant
activation of the PI3K/Akt/mTOR cascade, or alternatively,
by defective expression or function of critical mediators
of apoptosis, i.e. components of the TRAIL signaling system.
In addition, signaling to apoptosis can be blocked under hypoxia,
a characteristic feature of most solid tumors including rhabdomyosarcoma
that has been associated with poor treatment response. Thus,
molecular targeted therapies that are specifically directed
to the defects in apoptosis programs, open novel perspectives
to restore apoptosis sensitivity in rhabdomyosarcoma.
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