| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From INSERM U.314,*
IFR 53, Unité de Biologie
Cellulaire, Laboratoire Pol Bouin, CHU, Reims, France; and the
Department of Molecular Biology,
Molecular
Cell Biology Unit, VIB-University of Ghent, Ghent, Belgium
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-catenin, and ß-catenin in four human bronchial cancer
cell lines with different invasive abilities and in 44 primary
bronchopulmonary tumors. Although invasive bronchial cell lines did not
express E-cadherin and -catenin, complete down-regulation of
cadherin-catenin complex expression was a rare event in
vivo in bronchopulmonary carcinomas. Nevertheless,
a spotty and cytoplasmic pattern of E-cadherin and catenins was
observed in 32 primary tumors, only in invasive tumor clusters.
Immunoprecipitation experiments showed that this redistribution was not
related to a disruption of cadherin-catenin interaction but to
down-regulated tyrosine phosphorylation of E-cadherin. We conclude that
loss of E-cadherin and/or catenins is not a prominent early event in
the invasive progression of human bronchopulmonary carcinomas in
vivo. The decreased tyrosine phosphorylation of E-cadherin may
reflect a loss of functionality of the complex and implicates a
major role in tumor invasion.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-, ß-, and 
-catenin, and are able to
form at least two different trimeric adhesion complexes that include
both E-cadherin and -catenin and either ß-catenin or -catenin
(plakoglobin) in a mutually exclusive manner.6-8
The full adhesive function of E-cadherin depends on the integrity of
the entire cadherin-catenin-actin network. Indeed, decrease of adhesive
properties of cadherin-catenin complex has been shown to be related to
the loss of differentiation and the subsequent acquisition of a higher
motility and invasiveness of epithelial cells.9
The dysfunction in E-cadherin-mediated adhesion can be generated by
several mechanisms, including decrease or lack of E-cadherin or catenin
expression, mutations and deletions in the genes encoding E-cadherin or
catenins, and posttranslational alterations such as aberrant tyrosine
phosphorylation of the E-cadherin-catenin
complex.6,7 Consequently, it has been suggested that the cadherin-catenin complex function plays a critical role in the pathogenesis of human carcinomas.2,7,9 Several in vitro studies have demonstrated an invasion-suppressor role for E-cadherin and catenins by showing a strong correlation between the defect of cadherin-catenin complex expression and both loss of the epithelial phenotype and increase of the invasive phenotype.10-13 Moreover, restoration of E-cadherin or catenins levels by cDNA transfection experiments leads to the recovery of the epithelial phenotype, decrease of invasiveness, and tumorigenic and metastatic capability of cultured tumor cells.14-18 In vivo results are not so clear-cut. Indeed, the bulk of morphological studies have suggested an inverse correlation between E-cadherin or catenin expression and dedifferentiation, malignancy, tumor aggressivity, metastasis, or a poor survival rate in several tumor types including breast,19,20 gastric,21,22 liver,23 bladder,24 prostate,25 lung,26 and colon27 carcinomas. However, in some other cases, the lack of cadherin-catenin complex expression could not be correlated to any histopathological criteria of epithelial carcinomas.9,28
To investigate the involvement of E-caherin-catenin complex in the
pathophysiology of human bronchopulmonary carcinomas, we performed
immunolocalization studies of E-cadherin, -catenin, and ß-catenin
on several primary tumors and compared their in vivo pattern
to in vitro results on four human bronchial cell lines with
different invasive capacities. This study was completed by an
E-cadherin immunoprecipitation experiment to check the integrity and
the tyrosine phosphorylation state of the E-cadherin-catenin complex in
tumors as compared to nontumoral control lung parenchyma.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Fresh tissue samples were obtained from 44 lungs resected for
primary tumors including 26 squamous cell carcinomas (9 stage I, 6
stage II, 11 stage III), 6 adenocarcinomas (3 stage I, 3 stage
III), 4 bronchioloalveolar carcinomas (4 stage I), 4 neuroendocrine
tumors (1 stage I, 2 stage II, 1 stage III), 2 large cell carcinomas
(2 stage III), and 1 carcinoid (stage II) and 1 metastasis from
mammary carcinoma. Tumors were histologically classified according to
the World Health Organization classification and staged according to
the TNM classification. Nonneoplastic pulmonary parenchyma counterparts
taken from sites adjacent to the tumor were also used for
immunoprecipitation study.
Bronchial Cell Lines
The human bronchial cell lines used in this study, 16HBE14o, Beas2B, BZR, and BZR-T33, display different invasive potential in vitro and tumorigenicity and metastatic ability in athymic nude mice.29-31 16HBE14o and Beas2B were derived from normal human bronchial cells immortalized after transfection with SV40 large T-antigen gene. BZR cell line was established from Beas2B cells by transfection with v-Ha-ras oncogene, while the BZR-T33 cell line derived from a tumor formed by BZR cells injected subcutaneously into an athymic nude mouse.29,30 The cells were cultured at 37°C and 5% CO2 in Dulbecco modified Eagle's medium (DMEM) supplemented with penicillin, streptomycin, ascorbic acid (50 ng/ml), and 10% fetal calf serum (Gibco BRL, Grand Island, NY).
Antibodies
The antibodies used were mouse monoclonal anti-human E-cadherin-1
(dilutions of 1/200 and 1/250 for immunohistochemistry and Western
blotting, respectively) (R&D Systems, Abingdon, UK), anti-human
-catenin (dilution of 1/200 for immunohistochemistry and Western
blotting) (Camfolio/Becton Dickinson, San Jose, CA), anti-human
ß-catenin (dilutions of 1/500 and 1/1000 for immunohistochemistry and
Western blotting, respectively) (Transduction Laboratories, Lexington,
KY) and anti-phosphotyrosine (PY20) (dilution of 1/250 for Western
blotting) (Transduction Laboratories).
Immunohistochemistry
Tissue cryosections 5 µm thick were rehydrated in
phosphate-buffered saline (PBS) and nonspecific binding was blocked
with 3% bovine serum albumin-PBS for 30 minutes. Slides were incubated
for 1 hour with anti-E-cadherin, anti--catenin, or anti-ß-catenin
antibodies. Negative controls were carried out by replacing the primary
antibody with nonimmune IgG. After three 5-minute washes in PBS, tissue
sections were treated with a biotinylated secondary antibody for 1 hour
(1/50) (goat anti-mouse antibody) (Amersham, Aylesbury, UK), followed
by streptavidin fluorescein complex (30 minutes, 1/50) (Amersham). All
slides were counterstained with Mayer's hematoxylin, mounted in
Citifluor (UKC Chemistry Lab, Canterbury, UK) and examined under a
Zeiss Axiophot microscope.
Human bronchial cells grown on four-well chamber slides (Lab-Tek, Nunc, Naperville, IL) were fixed for 10 minutes with -20°C methanol before they were subjected to immunostaining as described above.
Staining was recorded as strong (+++) when all tumor cells showed reactivity, as moderate (++) and faint (+) when reactivity was lacking in a fraction of tumor cells (50 to 90% and 10 to 49%, respectively), and as negative (-) when there was no reactivity. Localization of the staining (membranous and cytoplasmic pattern) was also evaluated.
Immunolocalizations of E-cadherin and catenins were also observed using an MRC 600 Biorad confocal laser scanning microscope, which allows the observation of 0.2-µm-thick optical sections.
Immunoprecipitation
Proteins in lung samples were extracted in 1 ml of lysis buffer (1% Triton X-100, 1% Nonidet P-40, 0.2 mmol/L leupeptin, 10 mmol/L Pefablock, 2.77 nmol/L aprotinin, 10 mmol/L NaF and 1 mmol/L NaVO3 in PBS) per 20 mg of tissue. Lysates were cleared by spinning at 12,500 x g for 10 minutes. Protein concentrations were determined with the BCA protein assay reagent (Pierce, Rockford, IL). Five hundred µg of each protein sample were preincubated with protein G-Sepharose CL-4B beads (Pharmacia Biotech AB, Uppsala, Sweden), by rocking 1 hour at 4°C. These beads were discarded and the supernatants were incubated with either 1 µg of human E-cadherin-1 or 4 µg of PY20 antibody for 3 hours on a rotating wheel at 4°C. Protein G-Sepharose beads were then added and the samples incubated for 1 hour at 4°C. Immunoprecipitates were washed six times in lysis buffer and boiled in 30 µl of Laemmli sample buffer before they were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions.
Western Blotting
Proteins from human bronchial cell lines were solubilized in Laemmli sample buffer, separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (7.5% phastgels), and subsequently transferred to a polyvinylidene difluoride membrane (Millipore, Bedford, MA) using the Phast system (Pharmacia Biotech AB).
For tissue samples, immunoprecipitates were separated on 8% sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels under reducing conditions and transferred to immobilon polyvinylidene difluoride membrane (Millipore) using the Biorad miniprotean II electrophoresis and the mini-trans-blot electrophoretic systems, respectively (Biorad, Hercules, CA). To visualize protein transfer, blots were reversibly stained with 0.2% Ponceau-S in 3% trichloroacetic acid. All subsequent incubations were done on a rotary platform. Blots were treated for 1 hour in blocking buffer (5% low-fat milk powder, 0.1% Tween-20 in PBS), then incubated with primary antibodies in blocking buffer overnight at 4°C. Next, biotin-conjugated second antibodies were applied, followed by streptavidin-horseradish peroxidase in blocking buffer and in PBT (0.1% Tween-20 in PBS), respectively. After each incubation, blots were washed three times with blocking buffer and also twice in PBT before the ECL detection (Amersham, Buckinghamshire, UK).
Statistical Analyses
Statistical analyses of E-cadherin and catenins expression
patterns were made using the 
2
test (with
Yates' correction for adjustment of the continuity of the
2
distribution when necessary). Differences
between two populations were considered significant when confidence
intervals were >95% (P < 0.05).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Immunohistochemistry
By immunohistochemistry, adhesion molecule expression correlated
with the cell morphology. Indeed, whereas noninfiltrating 16HBE cells,
which displayed a polygonal epithelial phenotype, expressed E-cadherin,
-catenin and ß-catenin, the moderately infiltrating Beas2B cell
line and the highly infiltrating BZR and BZR-T33 cell lines, all
displaying an elongated fibroblastoid shape, did not express E-cadherin
or -catenin (data not shown). Only ß-catenin was always
detected in all cell lines. The spatial distribution study by confocal
microscopy revealed a strong membranous E-cadherin, -catenin, and
ß-catenin expression pattern in 16HBE cells (Figure 1A
-C). On the contrary, ß-catenin was
distributed in a spotty cytoplasmic pattern in Beas2B, BZR, and BZR-T33
invasive cell lines (Figure 1D)
.
|
The immunohistochemical results were confirmed by a Western blot
study. Only the noninvasive 16HBE cell line expressed E-cadherin,
-catenin, and ß-catenin. In invasive cell lines, only ß-catenin
expression persisted in invasive cell lines (Figure 2)
.
|
Immunolocalization
These results are summarized in Table 1
.
|
-catenin,
and ß-catenin in nearly all tumor cells (Figure 3A and 3B)
, except at the periphery of
some poorly differentiated tumor clusters where positivities were
heterogeneous. Moreover, E-cadherin and -catenin were totally
missing in numerous infiltrating isolated tumor cells detached from the
primary tumor (Figure 3C and 3D)
, whereas ß-catenin expression was
globally more maintained (Figure 3E and 3F)
. However, the positive
samples showed different intensities and distribution patterns of the
adhesion complex even though labeling levels and patterns were similar
for the 3 antigens in each case. Indeed, 8 cases displayed strong
labeling, 28 cases moderate labeling, and 6 cases faint labeling. As
for the cellular distribution investigated by confocal microscopy, 10
samples displayed a thin continuous localization of adhesion molecules
along the tumor cell plasma membrane, a pattern similar to that of
normal bronchial epithelium which showed a strong membranous
cadherin-catenin labeling at the lateral cell borders (Figure 4, A, C, and E)
. On the other hand, 32
samples had a spotty and diffuse pattern corresponding to a clear
intracytoplasmic distribution of E-cadherin and catenins. This pattern
was observed in most invasive tumor nests infiltrating the stroma and
never found in preinvasive lesions in situ (Figure 4, B, D, and F)
. Statistically, the labeling intensity was not correlated to
the labeling pattern; a tumor with an internalized pattern did not
necessarily have faint labeling. On the other hand, labeling intensity
was not related to tumor histological type nor to tumor TNM stage,
whereas it was significantly correlated to the differentiation state.
Indeed, only 4% of moderately or poorly differentiated tumors
displayed a strong labeling versus 60% of
well-differentiated tumors (P = 0.0006). Moreover,
the cellular distribution pattern was correlated to the histological
type; 80% of adenocarcinomas including bronchioloalveolar carcinomas
showed a normal membranous E-cadherin and catenin distribution at the
cell membrane versus 8% of squamous cell carcinomas
(P = 0.0001). However, the cellular distribution
pattern was not related to the differentiation state of squamous cell
carcinomas or to the tumor TNM stage.
|
|
Because in vivo invasion of bronchopulmonary tumor cells was not related to a real loss of cadherin and catenin expression, but rather to a redistribution of the components of this complex, we performed an E-cadherin immunoprecipitation study to investigate the integrity of the cadherin-catenin complexes. This study was performed on 8 nontumoral lung parenchyma samples, 2 carcinomas with a membranous pattern (1 adenocarcinoma and 1 squamous cell carcinoma) and 5 carcinomas with a spotty cytoplasmic pattern (2 adenocarcinomas and 3 squamous cell carcinomas).
E-cadherin immunoprecipitation followed by Western blot analysis
indicated that E-cadherin was complexed to ß- and -catenins in all
samples tested (nontumoral parenchyma, carcinomas with a membranous
pattern, and carcinomas with a spotty cytoplasmic distribution) (Figure 5A)
. Then the tyrosine phosphorylation
state of the cadherin-catenin complex was analyzed. Whereas E-cadherin
was tyrosine-phosphorylated in the 2 nontumoral samples and in the 2
carcinomas showing a membranous pattern, its tyrosine phosphorylation
was down-regulated in the 5 carcinomas displaying a spotty cytoplasmic
pattern (Figure 5B)
. No - and ß-catenin tyrosine phosphorylation
was observed in either the carcinomas or the nontumoral samples.
Immunoprecipitation with antiphosphotyrosine PY20 antibody confirmed
that the tyrosine-phosphorylated band was E-cadherin in
nontumoral samples (Figure 5C)
.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-catenin in invasive cancer cell
lines.31-34
This is in agreement with our
results showing a total lack of E-cadherin and -catenin expression
in the invasive bronchial cell lines studied. In the same way, the loss
of adhesion molecules was confirmed in vivo in most isolated
infiltrating tumor cells detached from the primary tumor clusters,
underlining tumor heterogeneity. These E-cadherin and -catenin
negative cells in vivo may represent the most aggressive and
potentially metastatic tumor cell contingent that has been selected
in vitro in our cell lines. Thus, the total loss of
E-cadherin and/or -catenin may be a late event in bronchopulmonary
carcinomas. Concerning the tumor clusters, particularly those which
were well differentiated, E-cadherin, -catenin, and ß-catenin
remained globally highly expressed. In agreement with observations of
Böhm et al,26
we found a significant
correlation between decreased labeling intensity of adhesion molecules
and the loss of differentiation in tumor nests of bronchopulmonary
carcinomas. E-cadherin has already been considered as a cellular marker
of tumor dedifferentiation confirmed for
gastric,21,22
hepatocellular,23
bladder,24
prostate,25
and
esophageal carcinomas.35
However, we did not find
any correlation between decreased E-cadherin and catenin
immunoreactivity and tumor TNM stage. Depending on the type of cancers
studied and the detection methods used, such a correlation between
negative regulation of adhesion molecule expression and tumor
progression is not always found in
vivo.9,20,36
Numerous immunohistochemical
studies have been performed on formalin-fixed paraffin-embedded tissue
sections with a less sensitive detection than frozen
sections.8,22,24,25,35,37
In some tumor cells
located in clusters, we observed a redistribution of the E-cadherin
complex molecules from the cell surface to the cytoplasm. Similar
results for E-cadherin expression in lung carcinomas were also obtained
in two other studies.26,28
This redistribution
appears to be related to the histological type of carcinomas because
adenocarcinomas generally preserved a membranous pattern of expression,
whereas a spotty cytoplasmic pattern was observed in squamous cell
carcinomas. We could not establish any significant correlation between
cytoplasmic redistribution of the E-cadherin complex molecules and
tumor grade. Nevertheless, the cytoplasmic redistribution was observed
particularly in restricted invasive nests and never in in
situ lesions, suggesting that such a redistribution, altering
cell-cell contacts, could cause specific tumor cells to become
invasive. Considering that total loss of E-cadherin and catenins
expression contributes to the invasive behavior of isolated invasive
tumor cells, the present data suggest that another mechanism would be
used by tumor cells which have conserved the expression of these
molecules and which are located in cohesive tumor clusters. The three
different patterns of E-cadherin complex molecule expression (ie,
membranous, spotty patterns, and loss of expression) could represent
sequential stages toward the invasive phenotype. The mechanisms by which the molecules of the E-cadherin complex are redistributed remain elusive. We performed immunoprecipitation experiments to address this point and to reveal possible modifications in the interactions between E-cadherin and the catenins in the diverse patterns of expression described above. We found no difference between nontumoral and tumoral tissues as regards the link between catenins and E-cadherin. Indeed, we observed the preservation of adhesion complex integrity in all of the primary tumors tested. However, regarding phosphorylation state, we found a difference of phosphorylation on tyrosine residues of E-cadherin between nontumoral samples and tumors with different expression patterns. Whereas E-cadherin tyrosine phosphorylation was detected in nontumoral lung parenchyma and in carcinomas showing a well preserved membranous pattern, a down-regulated tyrosine phosphorylation was observed in primary tumors displaying a spotty cytoplasmic pattern. Thus, the adhesion complex redistribution may be related to E-cadherin dephosphorylation. A previous study performed on thyroid carcinomas also pointed to the absence of E-cadherin tyrosine phosphorylation in carcinomas as compared to nonmalignant tissues and this state was related to a pericellular redistribution of the complex with no synthesis variations for E-cadherin or catenins.38 The authors suggested that the cadherin-catenin complex was disconnected from the cytoskeleton.38 Other studies have also shown involvement of phosphorylation/dephosphorylation of the cadherin-catenin complex with respect to the regulation of its cellular adhesion function. The role of tyrosine phosphorylation of cadherin-catenin complex and in particular of ß-catenin is not clear because catenin-E-cadherin interaction is generally not affected. Instead of a disruption of the complex, modifications in tyrosine phosphorylation of adhesion molecules may induce the dissociation of E-cadherin and catenins from the cytoskeleton and thus dispersion of the complexes in the cell.6,12,13,36,39 Therefore we could speculate that, in the case of bronchopulmonary carcinomas, redistribution of the cadherin-catenin complex in association with a decreased tyrosine phosphorylation of E-cadherin may reflect a loss of adhesion functionality leading to the acquisition of an invasive phenotype.
In this study we have also observed that, in contrast with the other members of the complex, ß-catenin expression persisted in invasive bronchial cell lines and in most infiltrating tumor cells of bronchopulmonary carcinomas; its distribution pattern was, however, dramatically modified. The membranous pattern was replaced by a spotty and cytoplasmic pattern in invasive cancer cells. This observation emphasizes the multiple roles of this protein. Indeed, ß-catenin has been shown to possess a cellular signaling capacity as a participant in the developmental Wnt-signal transduction pathway. Indeed, cytoplasmic ß-catenin is involved in cell migration process via interaction with the product of adenomatous polyposis coli tumor suppressor gene and cytoskeleton.40-46 On the other hand, free cytoplasmic ß-catenin plays a role in activation of some genes, in particular cell proliferation-stimulating genes, or apoptosis-antagonizing genes and mesenchymal genes, by complexation with DNA-binding transcription factors such as lymphoid enhancer-binding factor (LEF)-1.40,42,47-49 Moreover, it has been shown that the LEF-1-ß-catenin complex binds in vitro to the E-cadherin promoter to regulate the transcription of this gene, suggesting that although adhesion function and intracellular signaling activity of ß-catenin are independent, they could be interrelated via negative regulation by E-cadherin.1,40,45,50 This is in agreement with our results showing that bronchial invasive cell lines and most in vivo isolated tumor cells displaying a spotty and cytoplasmic ß-catenin labeling were E-cadherin-negative. Globally, this observation suggests that the cytoplasmic distribution of ß-catenin may also reflect the invasive potential of cells.
In conclusion, our results show that the total loss of cadherin-catenin complex expression is a rare event in human bronchopulmonary carcinomas, restricted to highly infiltrative tumor cells. The most prominent observation is a cytoplasmic redistribution of the E-cadherin complex molecules associated with a decreased tyrosine phosphorylation of E-cadherin, suggesting that, at least in vivo, this characteristic may be a prerequisite for tumor cells to acquire an invasive pattern in lung tissue.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Supported in part by the Lions Club of Soissons, by a grant from La Ligue contre le cancer (département de la Marne), and by ASLK-VIVA (Belgium).
Accepted for publication July 22, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-catenin in human colon cancer cells. Cancer Res 1995, 55:4722-4728-catenin and restoration of E-cadherin function. Cancer Res 1995, 55:4813-4817-catenin. Histopathology 1996, 29:139-146[Medline]
-catenin in primary epithelial tumors of the liver. Gastroenterology 1996, 110:1137-1149[Medline]
-catenin cDNA and its aberrant mRNA in a human cancer cell line. Biochem Biophys Res Commun 1993, 193:897-904[Medline]
-catenin, ß-catenin and plakoglobin in esophageal carcinomas and its prognostic significance. Oncology 1997, 54:158-165[Medline]
This article has been cited by other articles:
 |
|
 |
|
  S. Hazgui, N. Bonnet, J. Cutrona, B. Nawrocki-Raby, M. Polette, L. Chouchane, P. Birembaut, and J.-M. Zahm 3D culture model and computer-assisted videomicroscopy to analyze migratory behavior of noninvasive and invasive bronchial epithelial cells Am J Physiol Cell Physiol, December 1, 2005; 289(6): C1547 - C1552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Faleiro-Rodrigues, I. Macedo-Pinto, D. Pereira, and C. S. Lopes Prognostic value of E-cadherin immunoexpression in patients with primary ovarian carcinomas Ann. Onc., October 1, 2004; 15(10): 1535 - 1542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. F. Calvisi, S. Ladu, V. M. Factor, and S. S. Thorgeirsson Activation of {beta}-catenin provides proliferative and invasive advantages in c-myc/TGF-{alpha} hepatocarcinogenesis promoted by phenobarbital Carcinogenesis, June 1, 2004; 25(6): 901 - 908. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Nawrocki-Raby, C. Gilles, M. Polette, C. Martinella-Catusse, N. Bonnet, E. Puchelle, J.-M. Foidart, F. van Roy, and P. Birembaut E-Cadherin Mediates MMP Down-Regulation in Highly Invasive Bronchial Tumor Cells Am. J. Pathol., August 1, 2003; 163(2): 653 - 661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Zhang, A. Ougolkov, K. Yamashita, Y. Takahashi, M. Mai, and T. Minamoto {beta}-Cateninand ras Oncogenes Detect Most Human Colorectal Cancer Clin. Cancer Res., August 1, 2003; 9(8): 3073 - 3079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kotsinas, K. Evangelou, P. Zacharatos, C. Kittas, and V. G. Gorgoulis Proliferation, but Not Apoptosis, Is Associated with Distinct {beta}-Catenin Expression Patterns in Non-Small-Cell Lung Carcinomas : Relationship with Adenomatous Polyposis Coli and G1-to S-Phase Cell-Cycle Regulators Am. J. Pathol., November 1, 2002; 161(5): 1619 - 1634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Bremnes, R. Veve, E. Gabrielson, F. R. Hirsch, A. Baron, L. Bemis, R. M. Gemmill, H. A. Drabkin, and W. A. Franklin High-Throughput Tissue Microarray Analysis Used to Evaluate Biology and Prognostic Significance of the E-Cadherin Pathway in Non-Small-Cell Lung Cancer J. Clin. Oncol., May 15, 2002; 20(10): 2417 - 2428. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Liu, C.-l. Huang, K. Kameyama, E. Hayashi, A. Yamauchi, S. Kobayashi, and H. Yokomise E-cadherin expression associated with differentiation and prognosis in patients with non-small cell lung cancer Ann. Thorac. Surg., March 1, 2001; 71(3): 949 - 954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Brambilla, B. Constantin, H. Drabkin, and J. Roche Semaphorin SEMA3F Localization in Malignant Human Lung and Cell Lines : A Suggested Role in Cell Adhesion and Cell Migration Am. J. Pathol., March 1, 2000; 156(3): 939 - 950. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
