INTESTINAL
TREFOIL FACTOR AND [beta]-CATENIN PHOSPHORYLATION:
Cadherins are calcium-dependent, homotypic, intercellular adhesion molecules
central to embryonic development, tissue morphogenesis, and the maintenance
of epithelial cell polarity and differentiation. The loss of E-cadherin
function, either by mutation or post-translational regulation, enhances
the propensity of tumor cells to metastasize. Other components of the cadherin
adhesion complex include the proteins [alpha]-catenin and [beta]-catenin
(or [gamma]-catenin). A prerequisite for effective cadherin function is
linkage to the cortical spectrin-actin skeleton, mediated by [alpha]- and
[beta]-catenin. The tyrosine phosphorylation of [beta]-catenin correlates
with a reduction in cellular adhesion and the liberation of [beta]-catenin
from the membrane adhesion complex. In other roles, [beta]-catenin associates
with the gene responsible for adenomatosis polyposis coli, APC, which sequesters
it. Alternatively, it directly interacts with the transcription factor LEF-1/XTCF-3
and thereby modulates transcription. An exactly analogous signaling cascade,
called Wnt, links membrane signaling to transcriptional control throughout
the animal kingdom. Given these understandings, a central question remains
as to what mechanisms, other than direct cadherin engagement between cells,
regulate this signaling system. The close linkage of certain receptor tyrosine
kinases, such as the epidermal growth factor receptor (EGF-R), to the cadherin
complex suggests one pathway of regulation. In this month's Laboratory Investigation,
Pignatelli and coworkers report another. The recently recognized trefoil
family of peptides are mucin-associated molecules sharing a unique three-loop
structure formed by intrachain disulfide bonds between six conserved cysteine
residues. Three trefoil peptides are known, TFF1 to 3 (also known as pS2,
ITF, and SP, respectively). Largely found in gastrointestinal tissues, these
peptides enhance the integrity of the gastrointestinal mucosa and facilitate
its repair. In vitro, TFFs enhance the migration of epithelial cells. Examining
four colorectal carcinoma-derived cell lines, Liu et al find that either
TFF3 or EGF dynamically regulates the association of EGF-R and [beta]-catenin
with cadherin; moreover, they show that this effect is at least partially
mediated by the direct tyrosine phosphorylation of [beta]-catenin in response
to TFF3. This is an important result that highlights similarities in action
between TFF3 and other growth/motogenic factors that enhance cell migration
(or tumor invasion) by modulating intercellular adhesion. Examples of such
factors include epidermal growth factor and hepatocyte growth factor. Although
the mechanisms of how TFF3 effects its control over [beta]-catenin remain
to be fully elucidated, an attractive hypothesis is that [beta]-catenin
represents a point of convergence between signaling cascades activated by
either EGF or TFF, and acts as a common regulator of E-cadherin function.
TISSUE FACTOR PATHWAY INHIBITOR
IN SEPSIS:
A characteristic feature of the sepsis syndrome is disseminated intravascular
coagulation (DIC). The pathogenesis of DIC involves an imbalance between
prothrombotic and antithrombotic pathways. Previous animal model studies,
including work in non-human primates, have suggested that there are two
key events that tilt the balance toward thrombosis. The first of these events
is the induction of tissue factor, a membrane protein that initiates the
extrinsic coagulation pathway by binding factor VII or VIIa, thereby accelerating
the factor VII/VIIa-mediated proteolytic activation of factors IX to IXa
and X to Xa. Intravascular tissue factor protein is largely expressed by
blood monocytes in response to lipopolysaccharide (LPS), but may also be
induced on vascular endothelial cells either by LPS or by cytokines (eg,
TNF or IL-1) released by LPS-activated monocytes. The procoagulant complex
of tissue factor-factor VIIa-factor X, which assembles on the activated
monocyte or endothelial cell surface, may be inhibited by the binding of
a regulatory protein called tissue factor pathway inhibitor (TFPI). The
second event leading to DIC is the shut-off of synthesis and expression
of thrombomodulin by vascular endothelial cells in response to LPS or by
the same cytokines that induce tissue factor. Thrombomodulin normally functions
to bind intravascular thrombin, thereby altering the specificity of thrombin
from proteolytic conversion of fibrinogen to fibrin, a prothrombotic action,
to proteolytic activation of protein C. Activated protein C is a potent
antithrombotic agent that works by proteolytic inactivation of certain key
clotting factors. Loss of thrombomodulin removes this important breaking
system, allowing procoagulant thrombin to go more or less unchecked. (The
other major antithrombin system, namely antithrombin III, is simply overwhelmed
by the quantities of thrombin generated in response to the tissue factor-initiated
extrinsic pathway.) Because the tissue factor pathway is critical for DIC,
an unanswered question is why does the TFPI system fail? In the present
issue of the journal, Hara and colleagues provide the first clue. Like thrombomodulin,
it appears that TFPI synthesis and expression are shut-off, at least in
the lung endothelial cells of LPS-treated rats, the same vessels where thrombi
develop. Although it remains to be seen how general this response is and
what the molecular mechanisms behind TFPI loss are, these data do provide
new justification for the use of TFPI as a potential therapy for DIC of
sepsis and perhaps other conditions.
TYPE II COLLAGEN GENE MUTATION
DISTURBS SPINAL DEVELOPMENT:
A variety of vertebral column abnormalities have been observed in patients
with different chondrodysplasias. These abnormalities include retarded ossification,
abnormal vertebral shapes, and curvature of the vertebral column. Several
of the chondrodysplasias are known to be caused by mutations of the collagen
type II gene that, because of the complexity of vertebral development, have
remained largely uncharacterized. In several murine studies, Hox and Pax
genes were found to define the shapes of vertebral structures as were transforming
growth factor-[beta] superfamily members. In this issue of the journal,
Savontaus et al demonstrate that a mutation in the type II collagen gene
(the major structural element of cartilage) results in retardation in ossification
centers and abnormal shapes and proportions of the vertebral columns of
Del1 transgenic mice, which express six copies of a shortened type II collagen
transgene. Thus, the expression of an abnormal structural element gives
rise to a phenotype that has been observed following perturbations of Hox,
Pax, and transforming growth factor-[beta] family gene expression. The presence
of this structurally abnormal collagen retards endochondral bone formation
and causes abnormal appositional growth patterns of cartilage along the
peripheries of vertebral bodies, resulting in vertebral shape and size abnormalities.
The Del1 transgenic mice should be a useful model to study maldevelopment
of the vertebral column and to better understand the vertebral column abnormalities
observed in a variety of chondrodysplasias, including thanatophoric dysplasia,
achondrogenesis, type II spondyloepiphyseal dysplasia congenita, and Kniest
dysplasia.
MICROSATELLITE INSTABILITY
IN GASTRIC LYMPHOMA:
The development and growth of tissues, as well as the maintenance of adult
tissue functions, require high-fidelity replication of the genome of each
cell. The semireplicative doubling of DNA and the existence of a complex
DNA repair machinery are two strategies that have been shaped by evolution
for maintaining genomic integrity. The cells making up malignant tumors
show a variegated and polymorphic array of genetic alterations, and their
study has lead to the isolation of tumor genes and, even before that, to
the concept of genetic instability as a fundamental characteristic of tumor
cells. Genetic instability can indeed be regarded as the mechanism underlying
the transition from a normal to neoplastic state and as the basis for tumor
progression. Instability also underlies clonal evolution. In the present
issue of Laboratory Investigation, Chong and colleagues report on microsatellite
instability (MI) and loss of heterozygosity in gastric lymphoma, and suggest
that genetic instability may be an important mechanism for the development
and progression of gastric lymphoma. The finding that two of four cases
of MALT-type and four of five cases of diffuse B-cell lymphoma showed regional
heterogeneity of the MI pattern indicates that clonal evolution can be witnessed.
Perhaps, as Shibata and others have suggested, heterogeneity in different
regions of the tumor is indicative of rapid evolution, whereas homogeneity
across the tumor tissue reflects the dominance of a clone and thus a period
of evolutionary calm in the life of a tumor. The paper by Chong et al supports
the intriguing notion that, perhaps, in a not-too-distant future, we will
be able to assess not only the stage of tumor progression by molecular means,
but also the rate of tumor progression in real time.
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