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The precise timing of the angiogenic switch in colorectal cancer development is still
unclear. The simultaneous expression of Endoglin (CD105), transforming growth
factor (TGF)-beta1 and TGF-beta receptor (R) II were quantified in surgical
specimens comprising normal human colon, pre-malignant dysplastic tissue, in situ,
and invasive colon cancer specimens, at mRNA and protein levels, respectively by
real-time PCR and immunohistochemistry. Serum concentrations of soluble
Endoglin and TGF-beta1 were evaluated. mRNA and CD105+-microvessel density
(MVD) increased significantly in dysplastic colon and carcinoma versus normal
tissues; values correlated respectively with dysplasia degree and Dukes' stages.
TGF-beta1 expression was significantly upregulated in most severe dysplastic
adenoma specimens, while TGF-beta1 transcript and protein signals were intense in
carcinoma, positively-correlated with tumor progression. TGF-beta1 RII was
overexpressed in adenoma and carcinoma versus normal samples, but unrelated
with dysplasia or Dukes' stage. Soluble Endoglin serum levels were equivalent in
adenoma and normal tissues; in carcinoma the highest levels were in invasive
tumor. Circulating TGF-beta1 levels were increased in severe dysplasia and
progressed with tumor progression. Correlations between adenoma dysplasia
degree and TGF-beta RII and CD105+-MVD, and between tumor Dukes' staging
and TGF-beta1 and CD105+-MVD, were significant. TGF-beta1 and Endoglin and
TGF-beta1 serum levels, TGF-beta1 staining and CD105+-MVD were significantly
and inversely associated with disease-free survival. TGF-beta1 levels were an
independent and significant prognostic factor of disease-free survival. These
findings suggest active angiogenesis occurs in many pre-malignant colon cases and
supports more careful evaluation of different chemopreventive agents.
Endometriosis dan endoglin 2011.enl Page 5
Journal: BJOG
Volume: 117
Issue: 3
Pages: 321-30
Journal: Br J Surg
Volume: 97
Issue: 6
Pages: 892-901
Issue: 5
Pages: 703-8
Journal: Breast
Volume: 19
Issue: 6
Pages: 493-8
Volume: 38
Issue: 1
Pages: 43-51
detection rate for a 10% false-positive rate was 46.7% for sEng alone and 96.3% for
a combination of maternal factors, sEng, PlGF and uterine artery L-PI.
CONCLUSIONS: Effective screening for early PE can be provided by a combination
of maternal factors, sEng, PlGF and uterine artery L-PI at 11-13 weeks' gestation.
Year: 2010
Journal: Oncogene
The periodontal ligament (PDL), a connective tissue located between the cementum
of teeth and the alveolar bone of mandibula, plays a crucial role in the maintenance
and regeneration of periodontal tissues. The PDL contains fibroblastic cells of a
heterogeneous cell population, from which we have established several cell lines
previously. To analyze characteristics unique for PDL at a molecular level, we
performed cDNA microarray analysis of the PDL cells versus MC3T3-E1
osteoblastic cells. The analysis followed by validation by reverse
transcription-polymerase chain reaction and immunochemical staining revealed that
endoglin, which had been shown to associate with transforming growth factor
(TGF)-beta and bone morphogenetic proteins (BMPs) as signaling modulators, was
abundantly expressed in PDL cells but absent in osteoblastic cells. The knockdown
of endoglin greatly suppressed the BMP-2-induced osteoblastic differentiation of
PDL cells and subsequent mineralization. Interestingly, the endoglin knockdown did
not alter the level of Smad-1/5/8 phosphorylation induced by BMP-2, while it
suppressed the BMP-2-induced expression of Id1, a representative BMP-responsive
gene. Therefore, it is conceivable that endoglin regulates the expression of
BMP-2-responsive genes in PDL cells at some site downstream of Smad-1/5/8
phosphorylation. Alternatively, we found that Smad-2 as well as Smad-1/5/8 was
Endometriosis dan endoglin 2011.enl Page 19
phosphorylated by BMP-2 in the PDL cells, and that the BMP-2-induced Smad-2
phosphorylation was suppressed by the endoglin knockdown. These results, taken
together, raise a possibility that PDL cells respond to BMP-2 via a unique signaling
pathway dependent on endoglin, which is involved in the osteoblastic differentiation
and mineralization of the cells.
Journal: Am J Cardiol
Volume: 106
Issue: 12
Pages: 1770-6
Year: 2011
Pages: H959-74
OBJECTIVES: To evaluate soluble endoglin (sEng) and the soluble fms-like tyrosine
kinase 1 (sFlt1) to placental growth factor (PlGF) ratio for the prediction of
preeclampsia in high-risk women, and to evaluate differences in sEng between
women with high-risk singleton and multiple gestation pregnancies. STUDY
DESIGN: We collected serial serum specimens from 119 women at high
preeclampsia risk. sEng, sFlt1 and PlGF were measured by ELISA. RESULTS:
Among subjects who did not develop preeclampsia, mean serum sEng was
significantly higher in those with multiple gestation pregnancies vs. high-risk
singletons. Among women with singleton gestations, mean serum sEng was higher
in subjects who developed early-onset (<34 weeks) and late-onset (>or= 34 weeks)
preeclampsia, as compared with subjects without preeclampsia, from 22 weeks and
28 weeks gestation onward, respectively. The within-woman rate of change of sEng
was also higher in women who later developed preeclampsia. CONCLUSIONS:
sEng is higher in women with multiple gestations vs. high-risk singleton
pregnancies. In high-risk women, serum sEng is increased prior to preeclampsia
onset.
Endometriosis dan endoglin 2011.enl Page 26
Journal: Oncogene
Volume: 30
Issue: 3
Pages: 334-45
Tumor cell plasticity enables certain types of highly malignant tumor cells to
dedifferentiate and engage a plastic multipotent embryonic-like phenotype, which
enables them to 'adapt' during tumor progression and escape conventional
therapeutic strategies. This plastic phenotype of aggressive cancer cells enables
them to express endothelial cell-specific markers and form tube-like structures, a
phenotype that has been linked to aggressive behavior and poor prognosis. We
demonstrate here that the transforming growth factor (TGF)-beta co-receptor
endoglin, an endothelial cell marker, is expressed by tumor cells and its expression
correlates with tumor cell plasticity in two types of human cancer, Ewing sarcoma
and melanoma. Moreover, endoglin expression was significantly associated with
worse survival of Ewing sarcoma patients. Endoglin knockdown in tumor cells
interferes with tumor cell plasticity and reduces invasiveness and
anchorage-independent growth in vitro. Ewing sarcoma and melanoma cells with
reduced endoglin levels showed reduced tumor growth in vivo. Mechanistically, we
provide evidence that endoglin, while interfering with TGF-beta signaling, is required
for efficient bone morphogenetic protein, integrin, focal adhesion kinase and
phosphoinositide-3-kinase signaling in order to maintain tumor cell plasticity. The
present study delineates an important role of endoglin in tumor cell plasticity and
progression of aggressive tumors.
Journal: Am J Hypertens
Endometriosis dan endoglin 2011.enl Page 28
Volume: 23
Issue: 8
Pages: 911-6
Journal: ScientificWorldJournal
Volume: 10
Pages: 2367-84
Journal: ScientificWorldJournal
Volume: 10
Pages: 2367-84
Journal: APMIS
Volume: 119
Issue: 2
Pages: 103-10
The aim of this study was to investigate the midkine and endoglin expression in
breast carcinomas with five different immunohistochemical profiles and their
relevance to histopathologic and clinicopathologic features. We analyzed 161
archival tissues immunohistologically. The level of midkine expression in breast
cancer significantly correlated with lymph node metastasis (p = 0.001) and TNM
staging (p = 0.003). High microvessel density (MVD) was associated with higher
midkine reactivity group (p = 0.036). Although the basal-like subtype had higher
midkine expression level and MVD, no significant difference with the other breast
cancer subtypes was found. In conclusion, midkine was a promising target for tumor
prognosis in clinical diagnosis and treatment. This study found no significant
differences in tumor angiogenesis in different molecular subtypes of breast cancer.
Journal: Carcinogenesis
Volume: 31
Issue: 3
Pages: 435-41
angiogenesis has not been defined. Here, we investigate the role of the cytoplasmic
domain of endoglin and its phosphorylation by ALK5 in regulating endoglin function
in endothelial cells. We demonstrate that the cytoplasmic domain of endoglin is
basally phosphorylated by ALK5, primarily on serines 646 and 649, in endothelial
cells. Functionally, the loss of phosphorylation at serine 646 resulted in a loss of
endoglin-mediated inhibition of Smad1/5/8 signaling in response to TGF-beta and
endothelial cell migration, whereas loss of phosphorylation at both serines 646 and
649 resulted in a loss of endoglin-mediated inhibition of Smad1/5/8 signaling in
response to bone morphogenetic protein-9. Taken together, these results support
endoglin phosphorylation by ALK5 as an important mechanism for regulating
TGF-beta superfamily signaling and migration in endothelial cells.
Journal: Carcinogenesis
Volume: 31
Issue: 3
Pages: 359-66
Journal: Neoplasma
Volume: 57
Issue: 6
Pages: 590-3
Journal: Carcinogenesis
Volume: 31
Issue: 12
Pages: 2145-54
Endometriosis dan endoglin 2011.enl Page 35
Year: 2010
J Oral Pathol Med (2010) Background: The pyogenic granuloma (PG) is a common
localized hyperplastic lesion of the oral cavity. The purpose of the present study was
to investigate the immunohistochemical expression of endothelial nitric oxide
synthases (eNOS) and CD105/endoglin in oral PGs, to evaluate their involvement in
the angiogenetic pathways of the lesion. Materials and Methods: Ninety-three PGs
were included in the study. Sixteen tumors were further sub-classified as pregnancy
tumors (PT) and seventeen as pyogenic granulomas with fibrosis (PGFM).
Immunohistochemical expression of eNOS and CD105/endoglin was quantified by
computerized image analysis with a semi-automated system. Percentage of staining
and number of objects (positive vessels) were recorded for each case. Results:
Intense eNOS expression was seen in 92 of 93 lesions. A statistically significant
association was found between eNOS percentage of staining/eNOS positive
vascular spaces (objects) and age of the patients (9% increase per decade of life).
Approximately 40% less eNOS positive objects were recorded in PGFM compared
with PGs. Intense membranous CD105/endoglin expression was seen in all cases.
The percentage of CD105/endoglin staining was statistically increased in PGs
compared with PT. Approximately 40% less CD105/endoglin objects were found in
PGFM compared with PGs; 56% more CD105/endoglin objects were found in
tongue lesions, compared with gingival lesions. There was no statistically significant
correlation considering percentage of staining and number of objects between
CD105/endoglin and eNOS. Conclusions: It is suggested that eNOS and CD105
endoglin are involved in the angiogenetic pathways of PG.
Bicuspid Aortic Valve (BAV) is a highly heritable congenital heart defect. The low
frequency of BAV (1% of general population) limits our ability to perform
genome-wide association studies. We present the application of four a priori SNP
selection techniques, reducing the multiple-testing penalty by restricting analysis to
SNPs relevant to BAV in a genome-wide SNP dataset from a cohort of 68 BAV
probands and 830 control subjects. Two knowledge-based approaches, CANDID
and STRING, were used to systematically identify BAV genes, and their SNPs, from
the published literature, microarray expression studies and a genome scan. We
additionally tested Functionally Interpolating SNPs (fitSNPs) present on the array;
the fourth consisted of SNPs selected by Random Forests, a machine learning
approach. These approaches reduced the multiple testing penalty by lowering the
fraction of the genome probed to 0.19% of the total, while increasing the likelihood
Endometriosis dan endoglin 2011.enl Page 42
of studying SNPs within relevant BAV genes and pathways. Three loci were
identified by CANDID, STRING, and fitSNPS. A haplotype within the AXIN1-PDIA2
locus (p-value of 2.926x10(-06)) and a haplotype within the Endoglin gene (p-value
of 5.881x10(-04)) were found to be strongly associated with BAV. The Random
Forests approach identified a SNP on chromosome 3 in association with BAV
(p-value 5.061x10(-06)). The results presented here support an important role for
genetic variants in BAV and provide support for additional studies in well-powered
cohorts. Further, these studies demonstrate that leveraging existing expression and
genomic data in the context of GWAS studies can identify biologically relevant
genes and pathways associated with a congenital heart defect.
Journal: Circulation
Volume: 121
Issue: 3
Pages: 436-44