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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 14, Number 36, 2008
Contents
Angiogenesis in Tumor Growth and
Metastasis
Executive Editor: Riichiro Abe
Editorial: Pp.
3779
The Circulating Endothelial Cell in Cancer: Towards Marker
and Target Identification Pp.
3780-3789
I. Martin-Padura and F. Bertolini
[Abstract] [Purchase
Article] [PMID: 19128231 PubMed - indexed for MEDLINE]
Tumor Growth-Promoting Properties of
Macrophage Migration Inhibitory Factor Pp.
3790-3801
C. Bifulco, K. McDaniel, L. Leng and
R. Bucala
[Abstract] [Purchase
Article] [PMID: 19128232 PubMed - indexed for MEDLINE]
Pigment Epithelium-Derived Factor Prevents
Melanoma Growth via Angiogenesis Inhibition Pp.
3802-3809
R. Abe, Y. Fujita and S.-i. Yamagishi and
H. Shimizu
[Abstract] [Purchase
Article] [PMID: 19128233 PubMed - indexed for MEDLINE]
Color-Coded Fluorescent Protein Imaging
of Angiogenesis: The Angiomouse®
Models Pp. 3810-3819
Y. Amoh, K. Katsuoka and R.M. Hoffman
[Abstract] [Purchase
Article] [PMID: 19128234 PubMed - indexed for MEDLINE]
Clinical Approaches Toward Tumor Angiogenesis:
Past, Present and Future Pp. 3820-3834
Y. Fujita, R. Abe and H. Shimizu
[Abstract] [Purchase
Article] [PMID: 19128235 PubMed - indexed for MEDLINE]
General Articles
Tracking Stem Cell Therapy in the Myocardium: Applications
of Positron Emission Tomography Pp. 3835-3853
Y. Zhang, M. Ruel, R.S.B. Beanlands, R.A. deKemp, E.J.
Suuronen and J.N. DaSilva
[Abstract] [Purchase
Article] [PMID: 19128236 PubMed - indexed for MEDLINE]
Subtype Selectivity in Phosphodiesterase
4 (PDE4): A Bottleneck in Rational Drug Design Pp.
3854-3872
P. Srivani, D. Usharani, E.D. Jemmis and
G.N. Sastry
[Abstract] [Purchase
Article] [PMID: 19128237 PubMed - indexed for MEDLINE]
Potentials of ES Cell Therapy in Neurodegenerative
Diseases Pp. 3873-3879
A.S. Srivastava, R. Malhotra, J. Sharp and
T. Berggren
[Abstract] [Purchase
Article] [PMID: 19128238 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
Editorial: Angiogenesis in Tumor Growth and Metastasis
In this decade, novel strategy against cancer, antiangiogeneic
therapy, was attempted. A major microenvironmental event in
tumor growth and expansion is the ‘angiogenic switch’,
an alteration in the balance of pro-angiogenic and anti-angiogenic
molecules that leads to tumor neovascularization. Angiogenesis,
a process by which new vascular networks are formed from pre-existing
capillaries or circulating endothelial ceslls, is required
for tumors to grow, invade and metastasize. Tumor vessels
are genetically quite stable, and less likely to accumulate
mutations that allow them to develop drug resistance in a
rapid manner. Therefore, targeting vasculature that supports
tumor growth, rather than cancer cells themselves, is considered
the most promising approach to cancer therapy. In this issue,
we describe the possible antiangiogenesis basis of this therapeutic
strategy.
Circulating endothelial cell (CEC) and progenitor (CEP) number
and viability are modulated in various pathological conditions
including cancer. Martin-Padura and Bertolini [1] described
CEC and CEP play an important role in cancer progression and
metastasis. Indeed, emerging clinical data support that CEC
and CEP kinetics and viability might predict the efficacy
on anticancer drug combinations that include antiangiogenic
agents. On the basis of these observations, CEC and CEP measurements
have attractive potential diagnostic and therapeutic applications
for malignant diseases.
Among ‘angiogeneic cytokine’, macrophage migration
inhibitor factor (MIF) is a highly conserved and evolutionarily
ancient mediator with pleiotropic effects that has been implicated
in tumor growth and progression. Bifulco et al. [2]
reviewed MIF’s function in multiple processes fundamental
to tumorigenesis such as tumor proliferation, evasion of apoptosis,
angiogenesis and invasion. These pleiotropic functional aspects
are paralleled by MIF’s unique signaling properties,
which involve activation of the ERK-1/2 and AKT pathways.
These properties reflect features central to growth regulation,
apoptosis and cell cycle control than is typical for an immune
cytokine. The significance of these pro-tumorigenic properties
has found support in several in vitro and in
vivo models of cancer and in the positive association
between MIF production and tumor aggressiveness and metastatic
potential in a variety of human tumors.
Pigment epithelium-derived factor (PEDF) has recently been
shown to be the most potent inhibitor of angiogenesis in the
mammalian eye, and is involved in the pathogenesis of angiogenic
eye disease such as proliferative diabetic retinopathy. Abe
et al. [3] reviewed a functional role for PEDF in
tumor growth and angiogenesis. Recent studies reported the
antitumor potential of PEDF in various cancer based on its
antiangiogenic properties and PEDF direct inhibitory effect
via tumor cell apoptosis.
The discovery and evaluation of antiangiogenic substances
initially relied on methods such as various models that use
the cornea to assess blood vessel growth. Although they are
important for understanding the mechanisms of blood vessel
induction, these models do not represent tumor angiogenesis
and are poorly suited to drug discovery. Amoh et al.
[4] have utilized multicolored fluorescent proteins to develop
imaging models of tumor angiogenesis, which are clinically-relevant
imageable models to visualize and quantify angiogenesis and
efficacy of inhibitors.
Angiogenesis is a complex process which is critical for the
growth, invasion, and metastasis of tumors. Fujita et
al. [5] reviewed recent progress in this clinical filed.
In the past ten years numerous new agents have been developed
as angiogenesis inhibitors. Angiogenesis inhibitors can be
classified by their targeted area of the angiogenic process;
(1) VEGF and its receptors VEGFR (e.g. Bevacizumab); (2) tyrosine
kinases within endothelial cells (Sunitinib); (3) proliferation
of endothelial cells (Endostatin); (4) MMPs (Marimastat);
(5) intercellular interactions via integrins (Cilengitide)
and (6) combinations of the above mechanisms (Thalidomide).
Some show anti-tumor effects with objective responses and
stable disease, and some disappeared from clinical use due
to unexpected side effects or insufficient efficacies. Further
investigations of combined therapies including angiogenesis
inhibitors will shed light on the treatment of advanced and
metastasized malignancies.
This issue is dedicated to my wife Yukiko, and to my son Shuya.
References
[1] Martin-Padura I, Bertolini F. The circulating endothelial
cell in cancer: towards marker and target identification.
Curr Pharm Des 2009; 14(36): 3780-3789.
[2] Bifulco C, McDaniel K, Leng L, Bucala R. Tumor growth-promoting
properties of macrophage migration inhibitory factor. Curr
Pharm Des 2009; 14(36): 3790-3801.
[3] Abe R, Fujita Y, Yamagishi S, Shimizu H. Pigment epithelium-derived
factor prevents tumor growth via angiogenesis inhibition.
Curr Pharm Des 2009; 14(36): 3802-3809.
[4] Amoh Y, Katsuoka K, Hoffman RM. In vivo imaging
of tumor angiogenesis. Curr Pharm Des 2009; 14(36): 3810-3819.
[5] Fujita Y, Abe R, Shimizu H. Clinical approaches toward
angiogenesis; past, present and future. Curr Pharm Des 2009;
14(36): 3820-3834.
Riichiro Abe
Department of Dermatology
Hokkaido University Graduate School of Medicine
N 15 W 7, Kita-ku,
Sapporo 060-8638
Japan
[Back to top]
[Purchase
Article] [PMID: 19128231 PubMed - indexed for MEDLINE]
The Circulating Endothelial Cell in Cancer: Towards Marker
and Target Identification
I. Martin-Padura and F. Bertolini
Circulating endothelial cell (CEC) and progenitor (CEP)
number and viability are modulated in various pathological
conditions including cancer. There is increasing evidence
showing that CEC and CEP play a role in cancer progression
and metastasis in different animal models. At the clinical
level, emerging data support that CEC and CEP kinetics and
viability might predict the efficacy on anticancer drug combinations
that include antiangiogenic agents. On the basis of these
observations, CEC and CEP measurements have attractive potential
diagnostic and therapeutic applications for malignant diseases.
[Back to top]
[Purchase
Article] [PMID: 19128232 PubMed - indexed for MEDLINE]
Tumor Growth-Promoting Properties
of Macrophage Migration Inhibitory Factor
C. Bifulco, K. McDaniel, L. Leng and
R. Bucala
Macrophage migration inhibitor factor (MIF) is a highly
conserved and evolutionarily ancient mediator with pleiotropic
effects that has been implicated in tumor growth and progression.
MIF’s function is unique among cytokines and its effects
extend to multiple processes fundamental to tumorigenesis
such as tumor proliferation, evasion of apoptosis, angiogenesis
and invasion. These pleiotropic functional aspects are paralleled
by MIF’s unique signaling properties, which involve
activation of the ERK-1/2 and AKT pathways and the regulation
of JAB1, p53, SCF ubiquitin ligases and HIF-1. These properties
reflect features central to growth regulation, apoptosis and
cell cycle control than is typical for an immune cytokine.
The significance of these pro-tumorigenic properties has found
support in several in vitro and in vivo models
of cancer and in the positive association between MIF production
and tumor aggressiveness and metastatic potential in a variety
of human tumors.
[Back to top]
[Purchase
Article] [PMID: 19128233 PubMed - indexed for MEDLINE]
Pigment Epithelium-Derived Factor Prevents Melanoma Growth
via Angiogenesis Inhibition
R. Abe, Y. Fujita and S.-i. Yamagishi and
H. Shimizu
Pigment epithelium-derived factor (PEDF) has recently
been shown to be the most potent inhibitor of angiogenesis
in the mammalian eye, and is involved in the pathogenesis
of angiogenic eye disease such as proliferative diabetic retinopathy.
However, a functional role for PEDF in tumor growth and angiogenesis
remains to be determined. Melanoma is one of the most highly
invasive and metastatic tumors. Malignant Melanoma is an increasingly
common malignancy and also one the most invasive and metastatic
tumors, and its mortality rates have been rapidly increasing
above those of any other cancer in recent years. Surgical
resection and systemic chemotherapy are the main therapeutic
strategies for the treatment of malignant melanoma. However,
these approaches are insufficiently effective and may be associated
with significant adverse effects. Angiogenesis, a process
by which new vascular networks are formed from pre-existing
capillaries, is required for tumors to grow, invade and metastasize.
Tumor vessels are genetically stable, and less likely to accumulate
mutations that allow them to develop drug resistance in a
rapid manner. Therefore, targeting vasculatures that support
tumor growth, rather than cancer cells, is currently considered
the most promising approach to malignant melanoma therapy.
Now, novel anti-angiogenic agents with tolerable side effects
are actually desired for the treatment of patients with malignant
melanoma. In this paper, we review the current understanding
of anti-angiogenic therapy for malignant melanoma, especially
focusing on PEDF, which was recently identified as the most
potent endogenous inhibitor of angiogenesis in the mammalian
eye.
[Back to top]
[Purchase
Article] [PMID: 19128234 PubMed - indexed for MEDLINE]
Color-Coded Fluorescent Protein Imaging of Angiogenesis: The
Angiomouse®
Models
Y. Amoh, K. Katsuoka and R.M. Hoffman
We have utilized multicolored fluorescent proteins to
develop three imaging models of tumor angiogenesis. In one
model, the nonluminous induced capillaries are clearly visible
by contrast against the very bright tumor green fluorescent
protein (GFP) fluorescence examined either intravitally or
by whole-body imaging in real time. Intravital images of an
orthotopic model of human pancreatic tumors expressing GFP
visualized angiogenic capillaries at both primary and metastatic
sites. Whole-body optical imaging showed that blood vessel
density increased linearly over a 20-week period in an orthotopic
model of human breast cancer expressing GFP. Opening a reversible
skin-flap in the light path markedly reduces signal attenuation,
increasing detection sensitivity many-fold and enables vessels
to be externally visualized in GFP-expressing tumors growing
on internal organs. In another model, dual-color fluorescence
imaging was effected by using red fluorescent protein (RFP)-expressing
tumors growing in GFP-expressing transgenic mice that express
GFP in all cells. This dual-color model visualizes with great
clarity the details of the tumor-stroma interaction, especially
tumor-induced angiogenesis. The GFP-expressing tumor vasculature,
both nascent and mature, are readily distinguished interacting
with the RFP-expressing tumor cells. The third model involves
a transgenic mouse in which the regulatory elements of the
stem cell marker nestin drive GFP (ND-GFP). The ND-GFP mouse
expresses GFP in nascent blood vessels. RFP-expressing tumors
transplanted to nestin-GFP mice enable specific visualization
of nascent vessels. The ND-GFP mouse was utilized to develop
a rapid in vivo/ex vivo fluorescent angiogenesis
assay by implanting Gelfoam which was vascular-ized by fluorescent
nascent blood vessels. This process could be markedly stimulated
or inhibited by specific compounds. We also observed, using
ND-GFP mice, that the hair follicle is angiogenic and that
the hair-follicle vascular network is a prime target for chemotherapy
drugs which cause hair loss (chemotherapy-induced alopecia).
These fluorescent models, generally termed AngioMouse®,
can quantitatively determine efficacy of antiangiogenesis
compounds.
[Back to top]
[Purchase
Article] [PMID: 19128235 PubMed - indexed for MEDLINE]
Clinical Approaches Toward Tumor Angiogenesis: Past, Present
and Future
Y. Fujita, R. Abe and H. Shimizu
Angiogenesis is a complex process which is critical for
the growth, invasion, and metastasis of tumors. In the past
ten years numerous new agents have been developed as angiogenesis
inhibitors. Angiogenesis inhibitors can be classified by their
targeted area of the angiogenic process; (1) VEGF and its
receptors VEGFR (e.g. Bevacizumab); (2) tyrosine
kinases within endothelial cells (Sunitinib); (3) proliferation
of endothelial cells (Endostatin); (4) MMPs (Marimastat);
(5) intercellular interactions via integrins (Cilengitide)
and (6) combinations of the above mechanisms (Thalidomide).
Some showed anti-tumor effects with objective responses and
stable disease, and some disappeared from clinical use due
to unexpected side effects or insufficient efficacies. Further
investigations of combined therapies including angiogenesis
inhibitors will shed light on the treatment of advanced and
metastasized malignancies.
[Back to top]
[Purchase
Article] [PMID: 19128236 PubMed - indexed for MEDLINE]
Tracking Stem Cell Therapy in the Myocardium: Applications
of Positron Emission Tomography
Y. Zhang, M. Ruel, R.S.B. Beanlands, R.A. deKemp, E.J.
Suuronen and J.N. DaSilva
The introduction of stem cells and/or progenitor cells
into damaged myocardium has promising therapeutic potential
in ischemic heart diseases and dilated cardiomyopathy. However,
understanding the biologic mechanisms and the outcomes of
transplanted cells during cardiac regenerative therapy remains
mostly limited to histological assessment. Positron emission
tomography (PET) is a sensitive molecular imaging modality
that can non-invasively assess stem cell retention, survival,
and function after transplantation. Two radiolabel approaches
have been explored to implement PET: 1) direct cell labeling
with a radionuclide; and 2) reporter gene-based cell labeling.
Direct cell labeling has previously been used for early tracking
of transplanted stem cells into the myocardium in several
therapeutic clinical trials. Stem cells can also be labeled
after transfection with a reporter gene, which can subsequently
be visualized by using a PET reporter probe that binds to
the reporter gene, therefore allowing serial in vivo
evaluation of cell viability and proliferation in long-term
follow-up studies. Recently, some studies successfully used
this method to visualize implanted stem cells by PET imaging
in animals. With the projected rapid growth of cell therapy
for heart disease, PET is expected to play a major role in
monitoring relevant changes that occur at every stage in cardiac
regenerative therapy. These two cell tracking approaches used
for PET imaging are reviewed here and compared against other
imaging modalities.
[Back to top]
[Purchase
Article] [PMID: 19128237 PubMed - indexed for MEDLINE]
Subtype Selectivity in Phosphodiesterase 4 (PDE4): A Bottleneck
in Rational Drug Design
P. Srivani, D. Usharani, E.D. Jemmis and
G.N. Sastry
Subtype selectivity of phosphodiesterase 4 (PDE4) has
been proposed to be the most salient feature for the development
of drugs for asthma and inflammation. The present review provides
an account of various strategies to overcome the side effects
of the PDE4 inhibitors. Subtype selectivity and recent developments
of molecular modeling approaches towards PDE4 were addressed
using QSAR and docking, followed by a detailed structural
analysis of more than three dozen available X-ray structures
of PDE4B and PDE4D. Usually, the lack of a 3-dimensional structure
of a target protein is a bottleneck for rational drug design
approaches. However, in this case the availability of 39 X-ray
structures along with co-crystals has not improved the therapeutic
ratio of drugs through rational drug design approaches. The
investigation of structures led to find significant variations
in the M-loop region, which is the integral part of the active
site of PDE4B and PDE4D. These differences can be accounted
for by varying conformation of the Pro430
residue and a Thr436/Asn362
mutation in the M-loop that causes variations in adjacent
residue properties and also the pattern of hydrogen-bonding
interactions. The impact of the M-loop region on inhibitor
binding has been further scrutinized by MOLCAD surfaces and
hydrophobicity. These have shown that PDE4B is more hydrophobic
in nature than PDE4D in the M-loop region. A review of the
above aspects given the emphasis on a new PDE4 inhibitor which
can access both metal and solvent pockets may possibly lead
to ligands with enhanced potency. The lining of the Q2 pocket
that involves the M-loop region may be considered for the
design of potent subtype-selective inhibitors.
[Back to top]
[Purchase
Article] [PMID: 19128238 PubMed - indexed for MEDLINE]
Potentials of ES Cell Therapy in Neurodegenerative Diseases
A.S. Srivastava, R. Malhotra, J. Sharp and
T. Berggren
Neurodegenerative diseases comprise a heterogeneous spectrum
of neural disorders that cause severe and progressive cognitive
and motor deficits. A histological hallmark of these disorders
is the occurrence of disease-specific cell death in specific
regional subpopulations of neurons, such as the loss of dopaminergic
neurons in the substantia nigra in Parkinson’s disease.
Neurodegenerative disease can also possibly occur from the
loss or dysfunction of selected glial cell subsets, such as
the dysfunction of supportive glial cells around somatic motor
neurons in amyotrophic lateral sclerosis. The central nervous
system (CNS), unlike many other tissues, has a very limited
capacity for self-repair. Mature nerve cells lack the ability
to regenerate, although endogenous neural stem cells exist
in the adult brain that do have very limited ability to generate
new functional neurons in response to injury. Rapid advances
in stem cell biology have opened an alternative, fascinating
perspective of neurogenesis by activation of endogenous neural
stem cells and/or transplantation of in vitro-expanded
stem cells and/or their neuronal- or glial-differentiated
progeny. Embryonic stem (ES) cells, because of their ability
to provide seemingly unlimited supply of specific cell types,
their amenability to genetic engineering manipulations, and
their broad developmental potential, are expected to become
a cell source and biological delivery system for use in a
variety of neurodegenerative diseases, and are likely to play
a role in the development of novel cell-based therapies for
these indications. However, before the full potential of ES
cells can be realized for regenerative medicine, we need to
understand mechanisms regulating their proliferation, differentiation
into therapeutically relevant cells, and most importantly
in the case of neuronal and glial lineages, to characterize
their functional properties. In the present review we will
be focusing on the factors and methodologies responsible for
differentiation of ES cell into different neural precursors
and neural cell lineages with particular emphasis on the potential
research and clinical applications of ES cells in the field
of neurodegenerative disease.
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