Current
Volume 3, Number 8, 2003
Contents
The Quest for Surrogate Markers of
Angiogenesis: A Paradigm for Translational Research in Tumor Angiogenesis and
Anti- Angiogenesis Trials
Pp.673-691
Curzio
Rüegg, Jean-Yves Meuwly, Robert Driscoll, Patricia Werffeli, Khalil Zaman and
Roger Stupp
Naturally Arising CD25+CD4+
Regulatory T Cells in Maintaining Immunologic Self-Tolerance and Preventing
Autoimmune Disease
Pp.693-706
Takeshi
Takahashi and Shimon Sakaguchi
A Conceptual View on Glucocorticoid-Induced
Apoptosis, Cell Cycle Arrest and Glucocorticoid Resistance in Lymphoblastic
Leukemia Pp.707-717
K.
Renner, M.J. Ausserlechner and R.
Kofler
Bone Marrow Derived Cells for Brain Repair:
Recent Findings and Current Controversies Pp.719-725
Y.
Long and K.Y. Yang
TRAIL: A Potential Agent for Cancer Therapy Pp.727-736
Juan
Shi, Dexian Zheng, Kwan Man, Sheung-tat Fan and Ruian Xu
Molecular and Genetic Mechanisms of
Osteoporosis: Implication for Treatment Pp.737-757
H. Shen, R.R. Recker and H.-W. Deng
Regulation of Dendritic Cell Function Through
Toll-Like Receptors
Pp.759-771
Tsuneyasu Kaisho and Shizuo Akira
Vaccination Against Angiogenesis-Associated
Antigens: A Novel Cancer Immunotherapy Strategy Pp.773-100%
Yiwen Li, Peter Bohlen and Daniel J. Hicklin
Abstracts
[Back to top] The Quest for Surrogate Markers of
Angiogenesis: A Paradigm for Translational Research in Tumor Angiogenesis and Anti-
Angiogenesis Trials
Curzio
Rüegg, Jean-Yves Meuwly, Robert Driscoll, Patricia Werffeli, Khalil Zaman and
Roger Stupp
Inhibition of
tumor angiogenesis suppresses tumor growth and metastatic spreading in many
experimental models, suggesting that anti-angiogenic drugs may be used to treat
human cancer. During the past decade more than eighty molecules that showed
anti-angiogenic activity in preclinical studies were tested in clinical cancer
trials, but most of them failed to demonstrate any measurable anti-tumor
activity and none have been approved for clinical use. Recent results stemming
from trials with anti-VEGF antibodies, used alone or in combination with
chemotherapy, suggest that systemic anti-angiogenic therapy may indeed have a
measurable impact on cancer progression and patient survival. From the clinical
studies it became nevertheless clear that the classical endpoints used in
anti-cancer trials do not bring sufficient discriminative power to monitor the
effects of anti-angiogenic drugs. It is therefore necessary to identify and
validate molecular, cellular and functional surrogate markers of angiogenesis
to monitor activity and efficacy of anti-angiogenic drugs in patients.
Availability of such markers will be instrumental to re-evaluate the role of
tumor angiogenesis in human cancer, to identify new molecular targets and
drugs, and to improve planning, monitoring and interpretation of future
studies. Future anti-angiogenesis trials integrating biological endpoints and
surrogate markers or angiogenesis will require close collaboration between
clinical investigators and laboratory-based researchers.
Here we review and
discuss critical issues and emerging paradigms relevant to tumor angiogenesis
and anti-angiogenic drugs and to the monitoring of tumor angiogenesis and
anti-angiogenic effects in patients.
[Back to top] Naturally Arising CD25+CD4+
Regulatory T Cells in Maintaining Immunologic Self-Tolerance and Preventing
Autoimmune Disease
Takeshi
Takahashi and Shimon Sakaguchi
A large body of
evidence indicates that T cell-mediated dominant suppression of selfreactive T
cells is indispensable for maintaining immunologic unresponsiveness to
self-constituents (i.e., self-tolerance) and preventing autoimmune disease.
CD25+CD4+ regulatory T cells naturally present in normal
animals, in particular, engage in this function, as their reduction or
functional abnormality leads to the development of autoimmune disease in
otherwise normal animals. They are at least in part produced by the normal
thymus as a functionally mature and distinct subpopulation of T cells. Recent
studies have demonstrated that CD25+CD4+ regulatory T
cells control not only autoimmune reactions but also other immune responses,
including tumor immunity, transplantation tolerance and microbial infection.
Thus, this unique population of regulatory T cells can be exploited to control
pathological as well as physiological immune responses.
[Back to top] A Conceptual View on Glucocorticoid-Induced
Apoptosis, Cell Cycle Arrest and Glucocorticoid Resistance in Lymphoblastic
Leukemia
K.
Renner, M.J. Ausserlechner and R.
Kofler
Glucocorticoids
(GC) control cell cycle progression and induce apoptosis in cells of the
lymphoid lineage. Physiologically, these phenomena have been implicated in
regulating immune functions and repertoire generation. Clinically, they form
the basis of inclusion of GC in essentially all chemotherapy protocols for
lymphoid malignancies. In spite of their significance, the molecular mechanisms
underlying the anti-leukemic GC effects and the clinically important phenomenon
of GC resistance are still unknown. This review summarizes recent findings
related to GC-induced apoptosis, cell cycle arrest, and GC resistance with
particular emphasis on acute lymphoblastic leukemia (ALL). We hypothesize that
under conditions of physiological Bcl-2 expression, GC might induce classical
programmed cell death by directly perturbing the Bcl-2 rheostat. In the
presence of anti-apoptotic Bcl- 2 proteins, cell death might result from
accumulating catabolic and/or other detrimental GC effects driven by, and
critically dependent on, GC receptor (GR) autoinduction. Although still
controversial, there is increasing evidence for release of apoptogenic factors
through pores in the outer mitochondrial membrane, rather than DΨloss-dependent membrane rupture, with
maintenance of mitochondrial function at least in the early phase of the death
response. GC-induced cell cycle arrest in ALL cells appears to be independent
of apoptosis induction and vice versa, and critically depends on repression of
both cyclin-D3 and c-myc followed by increased expression of the
cyclin-dependent kinase inhibitor, p27Kip1. Since development of
GC-resistant clones requires both cell cycle progression and survival, GC
resistance might frequently result from structural or regulatory defects in GR
expression, perhaps the most efficient means to target both pathways
concurrently.
[Back to top] Bone Marrow Derived Cells for Brain Repair:
Recent Findings and Current Controversies
Y.
Long and K.Y. Yang
Adult stem cells
were once thought to produce only the cell lineages characteristic of the tissues
in which they reside. Recent studies suggest that cells derived from one adult
tissue can be reprogrammed to change into cellular phenotypes not normally
found in that tissue. Bone marrow (BM) derived cells have been demonstrated to
differentiate into multiple lineages, including glial cells and neurons, both
in vivo and in vitro. This unexpected plasticity of BM cells occurs not only
under experimental conditions, but also in humans following BM transplantation.
As a result, BM transplantation has emerged as a novel approach to enhance
neural regeneration and restore injured brain tissue. Several research teams
have reported that transplanted BM cells can differentiate into neural
derivatives; indeed, some of these cells were capable of integration into the
host brain, where they promoted functional recovery after brain injury. Other
researchers conducting similar studies were unable to find any evidence of
neural differentiation, concluding that differentiation ‘from marrow to brain’
is not a common phenomenon. More recently, two papers in Nature also cast doubt
on the plasticity of adult stem cells, suggesting that the acquisition of
different identities by grafted BM cells may merely reflect their fusion with
host cells. Reasons for the wide discrepancies among findings in current BM
stem cell research are unclear, making it difficult to understand the
mechanisms by which transplanted marrow stem cells provide therapeutic benefit.
Here, we summarize recent findings on this subject, and address some of the
major controversies that have marked the evolution of adult stem cell research.
[Back to top] TRAIL: A Potential Agent for Cancer Therapy
Juan Shi, Dexian Zheng, Kwan Man, Sheung-tat Fan and Ruian Xu
Induction of apoptosis
in cancer cells with chemotherapy and radiation treatment is a major strategy
in cancer therapy at present. Nevertheless, innate or acquired resistance has
been an obstacle for conventional clinical therapy. TNF-related apoptosis
inducing ligand (TRAIL/Apo-2L) is a ntypical member of the TNF ligand family
that induces apoptosis through activating the death receptors. In recent years,
considerable attention has been focused on the potential benefits of TRAIL in
cancer therapy, as the majority of cancer cells are sensitive to TRAIL-induced
apoptosis, while most normal cells are TRAIL-resistant. Furthermore, the use of
TRAIL in combination with chemotherapeutic agents or irradiation strengthens
its apoptotic effects. In this review, we will discuss the regulation mechanism
of TRAIL-induced apoptosis and the molecular basis of the synergies created by
its use in combination with chemotherapeutic agents and irradiation. We also
analyze in detail that TRAIL may be cytotoxic, as this is a potential obstacle
to its development for being used in cancer therapy.
[Back to top] Molecular and Genetic Mechanisms of
Osteoporosis: Implication for Treatment
H.
Shen, R.R. Recker and H.-W. Deng
Osteoporosis is a
leading public health problem in our rapidly growing, aging population. It is
characterized by reduced bone mass and microarchitectural deterioration of bone
tissue, with a consequent increase in bone fragility and susceptibility to
fracture risk. Osteoporosis is a complex multifactorial disease, determined by
genetic and environmental factors as well as their interactions. A large number
of molecular, genetic and environmental factors underlying osteoporosis have
been identified in past decades. In this article, we review 1) the molecular
mechanisms of several principal systemic and local factors regulating bone
metabolism; and 2) the current status of genetic studies searching for genes
underlying osteoporosis. Further, we attempt to integrate knowledge from those
two fields, and their potential implications for osteoporosis treatment.
[Back to top] Regulation of Dendritic Cell Function Through
Toll-Like Receptors
Tsuneyasu
Kaisho and Shizuo Akira
Higher animals establish
host defense by orchestrating innate and adaptive immunity. This is mediated by
professional antigen presenting cells, i.e. dendritic cells (DCs). DCs can
incorporate pathogens, produce a variety of cytokines, maturate, and present
pathogen-derived peptides to T cells, thereby inducing T cell activation and
differentiation. These responses are triggered by microbial recognition through
type I transmembrane proteins, Toll-like receptors (TLRs) on DCs. TLRs consist
of ten members and each TLR is involved in recognizing a variety of
microorganism-derived molecular structures. TLR ligands include cell wall
components, proteins, nucleic acids, and synthetic chemical compounds, all of
which can activate DCs as immune adjuvants.
Each TLR can
activate DCs in a similar, but distinct manner. For example, TLRs can be
divided into subgroups according to their type I interferon (IFN) inducing
ability. TLR2 cannot induce IFN-α or IFN- β, but TLR4 can lead to IFN-β
production. Meanwhile, TLR3, TLR7, and TLR9 can induce both IFN-α and IFN-β.
Recent evidences suggest that cytoplamic adapters for TLRs are especially
crucial for this functional heterogeneity. Clarifying how DC function is
regulated by TLRs should provide us with critical information for manipulating
the host defense against a variety of diseases.
[Back to top] Vaccination Against Angiogenesis-Associated
Antigens: A Novel Cancer Immunotherapy Strategy
Yiwen
Li, Peter Bohlen and Daniel J. Hicklin
Therapeutic
vaccines represent an attractive approach to cancer treatment. Traditionally,
cancer immunotherapy targets antigens expressed by the tumor cells. Although
numerous clinical trials studying different cancer vaccines have been conducted
during the past twenty years, very limited clinical responses have been
observed. The inefficient anti-tumor immunity is thought to be due, in major
part, to the escape mechanisms exerted by the genetically unstable tumor cells,
e.g., emergence of antigen-loss mutants, downregulation of MHC molecules and
lack of expression of costimulatory molecules. Recently, a novel vaccine
strategy has been developed to circumvent these obstacles. Taking advantage of
the importance of angiogenesis in tumor growth and the genetic stability of
endothelial cells, this immunotherapy strategy targets antigens (e.g.,
angiogenic growth factor receptors) overexpressed by the tumor neo-vasculature
rather than the tumor cells per se. For example, active immunization against
vascular endothelial growth factor receptor-2 (VEGFR-2) has been shown to
generate strong cellular and humoral immune responses, which lead to the
inhibition of angiogenesis and tumor growth and metastasis. This review
provides an outline of this emerging field and discusses the advantages and potential
pitfalls of such a vaccine strategy.