Current
Volume 3, Number 7, 2003
Contents
Cancer
Executive
Editor: Barid B. Mukherjee
Genomic Instability and Cancer Pp.589-596
George
S. Charames and Bharati Bapat
Aberrant Regulation of Translation Initiation
in Tumorigenesis Pp.597-603
Mark
Stoneley and Anne E. Willis
The Quest for a Tumor Suppressor Gene
Phenotype Pp.605-629
Nadege
Presneau, Emily N. Manderson and
Patricia N. Tonin
The Role of Apoptosis in Tumor Progression
and Metastasis Pp.631-642
Jason
L. Townson, George N. Naumov and
Ann F. Chambers
Fundamental Concepts of the Angiogenic
Process Pp.643-651
Judah
Folkman
Role of Maspin in Tumor Metastasis and
Angiogenesis Pp.653-658
Jeremy S. Schaefer and Ming Zhang
Molecular Mechanisms of Tumor Invasion and
Metastasis: An Integrated View
Pp.659-671
R.A.
Cairns, R. Khokha and R.P. Hill
Abstracts
[Back to top] Genomic Instability and Cancer
George
S. Charames and Bharati Bapat
Tumorigenesis can
be viewed as an imbalance between the mechanisms of cell-cycle control and
mutation rates within the genes. Genomic instability is broadly classified into
microsatellite instability (MIN) associated with mutator phenotype, and
chromosome instability (CIN) recognized by gross chromosomal abnormalities.
Three intracellular mechanisms are involved in DNA damage repair that leads to
mutator phenotype. They include the nucleotide excision repair (NER), base
excision repair (BER) and mismatch repair (MMR). The CIN pathway is typically
associated with the accumulation of mutations in tumor suppressor genes and
oncogenes. Defects in DNA MMR and CIN pathways are responsible for a variety of
hereditary cancer predisposition syndromes including hereditary non-polyposis
colorectal carcinoma (HNPCC), Bloom syndrome, ataxia-telangiectasia, and
Fanconi anaemia. While there are many genetic contributors to CIN and MIN, there
are also epigenetic factors that have emerged to be equally damaging to
cell-cycle control. Hypermethylation of tumor suppressor and DNA MMR gene
promoter regions, is an epigenetic mechanism of gene silencing that contributes
to tumorigenesis. Telomere shortening has been shown to increase genetic
instability and tumor formation in mice, underscoring the importance of
telomere length and telomerase activity in maintaining genomic integrity. Mouse
models have provided important insights for discovering critical pathways in
the progression to cancer, as well as to elucidate cross talk among different
pathways. This review examines various molecular mechanisms of genomic
instability and their relevance to cancer.
[Back to top] Aberrant Regulation of Translation Initiation
in Tumorigenesis
Mark
Stoneley and Anne E. Willis
Altering the rate
of translation initiation of a specific gene can tightly regulate the synthesis
of the corresponding polypeptide and is an important mechanism in the control
of gene expression. For some time it has been known that many genes involved in
cell proliferation, cell growth and apoptosis have atypical 5' untranslated
regions (UTRs) containing a high degree of RNA secondary structure, upstream open
reading frames and internal ribosome entry segments. These features play a key
role in the regulation of protein synthesis. In this review we discuss how the
rate of translation initiation of proto-oncogenes and tumour suppressor genes
is affected by elements in their 5' and 3' UTRs and we focus on how changes in
the control of gene expression at this level can contribute towards
tumorigenesis.
[Back to top] The Quest for a Tumor Suppressor Gene
Phenotype
Nadege
Presneau, Emily N. Manderson and
Patricia N. Tonin
Our current
definitions of the tumor suppressor gene (TSG) have been guided by the
identification of the prototypical gene, RB1, a TSG that is implicated in the
development of both the inherited and sporadic forms of retinoblastoma. The
hallmark feature of this TSG is loss of function in tumoral cells, which can be
restored by reintroduction of a normally functioning protein with concomitant
reversion of tumorigenicity. Key to this discovery was that loss of function is
often achieved by deletion of a normal copy of the TSG and retention of a
mutated allele, which was either inherited or acquired. Suppression of
tumorigenicity and the loss-of-function concept of TSGs was also demonstrated
in early studies where normal cellular growth was achieved when tumorigenic
cells were fused with normal cells. Thus loss of genetic content and
restoration of gene function has guided studies aimed at the discovery of novel
TSGs. Here we review the successes of TSG discovery using three approaches that
are based on the genetic analysis of inherited predisposition to cancer, tumors
that display chromosome loss, and tumorigenic cells that display a suppression
of tumorigenicity as a result of transfer of normal chromosomes. Based on a
review of the literature we conclude that the discovery of TSGs has been highly
successful in the genetic analysis of inherited predisposition to cancer with a
dominant mode of inheritance. In contrast, the latter two approaches have
yielded a paucity of TSGs that exhibit features similar to the prototypical RB1
in that they are rarely inactivated by somatic mutations in tumors displaying
LOH, although decreased gene expression is observed. Nevertheless, some of
these genes have been shown to suppress tumorigenicity when normal function is
restored in tumorigenic cells consistent with the loss-of-function concept.
These observations continue to challenge our current definition of TSG.
[Back to top] The Role of Apoptosis in Tumor Progression
and Metastasis
Jason
L. Townson, George N. Naumov and
Ann F. Chambers
Metastasis, the
process by which cancer spreads from a primary to a secondary site, is
responsible for the majority of cancer related deaths. Yet despite the detrimental
effects of metastasis, it is an extremely inefficient process by which very few
of the cells that leave the primary tumor give rise to secondary tumors.
Metastasis can be considered as a series of sequential steps that begins with a
cell leaving a primary tumor, and concludes with the formation of a metastatic
tumor in a distant site. During the process of metastasis cells are subjected
to various apoptotic stimuli. Thus, in addition to genetic changes that promote
unregulated proliferation, successful metastatic cells must have a decreased
sensitivity to apoptotic stimuli. As many cancer cells exhibit aberrations in
the level and function of key apoptotic regulators, exploiting these
alterations to induce tumor cell apoptosis offers a promising therapeutic
target. This review will examine the apoptotic regulators that are often
aberrantly expressed in metastatic cells; the role that these regulators may
play in metastasis; the steps of metastasis and their susceptibility to
apoptosis; and finally, current and future cancer prognostics and treatment
targets based on apoptotic regulators.
[Back to top] Fundamental Concepts of the Angiogenic
Process
Judah Folkman
The process of
angiogenesis encompasses the growth and regression of capillary blood vessels.
Angiogenesis is finely regulated at the molecular and genetic levels, not
unlike other physiologic processes such as coagulation, glucose metabolism, and
blood pressure. During the development of the field of angiogenesis research
over the past three decades, fundamental concepts have been introduced along
the way in an attempt where possible, to unify new data from a variety of
different laboratories. I have assembled here the major concepts which underlie
the angiogenic process as we currently understand it. Many of these are now
taken for granted, but this was not always the case, and I have tried to show
how they were developed. My goal is to provide a conceptual framework for those
basic scientists or clinicians who may enter this rapidly expanding field. Each
concept discussed here is accompanied by a few key references as a guide to the
pertinent literature.
[Back to top] Role of Maspin in Tumor Metastasis and
Angiogenesis
Jeremy
S. Schaefer and Ming Zhang
Cancer is one of
the leading causes of mortality in developed countries such as the USA. In
1998, there were more than 280,000 and 250,000 cancer related deaths in males
and females, respectively. In males, lung and prostate cancers accounted for
almost half of these deaths, whereas in females, lung and breast cancers were
the leading causes of cancer mortalities. Therefore, the study of cancer has
been of the utmost importance to patients, doctors, and researchers alike. A
variety of cellular processes occur in the precancerous cells that contribute
to the development and progression to cancer. Not surprisingly, all of these
cellular processes have been targeted for anticancer therapy. A novel serpin,
maspin, has demonstrated a robust effect on a variety of these cancer
progression steps. A number of studies have shown that maspin inhibits
angiogenesis and tumor cell growth and invasion both in vitro and in vivo. In
addition, maspin promotes cell adhesion to the basement membrane and extracellular
matrix components. Efforts underway to understand the molecular mechanisms
involved in the diverse functions influenced by maspin have yielded promising
results and shed light on the cancer pathways.
[Back to top] Molecular Mechanisms of Tumor Invasion and
Metastasis: An Integrated View
R.A.
Cairns, R. Khokha and R.P. Hill
As tumors progress
to increased malignancy, cells within them develop the ability to invade into
surrounding normal tissues and through tissue boundaries to form new growths
(metastases) at sites distinct from the primary tumor. The molecular mechanisms
involved in this process are incompletely understood but those associated with
cell-cell and cell-matrix adhesion, with the degradation of extracellular
matrix, and with the initiation and maintenance of early growth at the new site
are generally accepted to be critical. This article discusses current knowledge
of molecular events involved in these various processes. The potential role of
adhesion molecules (eg. integrins and cadherins) has undergone a major
transition over the last ten years, as it has become apparent that such
molecules play a major role in signaling from outside to inside a cell, thereby
controlling how a cell is able (or not) to sense and interact with its local
environment. Similarly the roles of proteolytic enzymes and their inhibitors
(eg. matrix metalloproteinases and TIMPs) have also expanded as it has become
apparent that they not only have the abilities to break down the components of
the extracellular matrix but also are involved in the release of factors which
can affect the growth of the tumor cells positively or negatively. Recent work
has highlighted the importance of the later, post-extravasational stages of
metastasis, where adhesion and proteolysis are now known to play a role along
with other processes such as apoptosis, dormancy, growth factor-receptor
interactions and signal transduction. Recent work has also demonstrated that
not only the immediate cellular microenvironment, in terms of specific
cell-cell and cell-matrix interactions, but also the extended cellular
microenvironment, in terms of vascular insufficiency and hypoxia in the primary
tumor, can modify cellular gene expression and enhance metastasis. Mechanisms
of metastasis appear to involve a complex array of genetic and epigenetic
changes many of which appear to be specific both for different types of tumors
and for different sites of metastasis. Our improved understanding of the
expanded roles of the individual molecules involved has resulted in a
mechanistic blurring of the previously described discrete stages of the
metastatic process.