In mammals, protein zero (P0), a neural IgCAM, is expressed solely in the peripheral nervous system where it mediates self-adhesion of Schwann cell membranes as compact myelin is generated. We show that when P0 is expressed in HeLa, a cervical carcinoma cell line, cells regain adhesion-mediated growth control, including the acquisition of contact inhibition and loss of anchorage-independent growth. Additionally, P0-expressing HeLa cells lose the ability to invade an artificial matrix, which correlates with decreased secretion of matrix-degrading enzymes. Lastly, and of great interest, unlike the aggressively metastatic cell line from which they were derived, P0-HeLa cells are neither tumorigenic nor metastatic when injected into athymic nude mice. By all these criteria, P0 expression appears to efficiently suppress in the long term, the transformed state of this carcinoma cell line. N-cadherin and its intracellular partners plakoglobin, alpha- and beta-catenin were significantly upregulated in the P0-HeLa cells. It appears therefore that P0 induces epithelialization and suppression of tumorigenicity in HeLa through the activation of the cadherin/catenin signaling systems. We conclude that the forced expression of bona fide adhesion molecules, such as P0, may serve as ‘upstream’ inducers of an essentially dormant but undamaged adhesion program in carcinoma cells that ultimately triggers the re-acquisition of normal epithelial characteristics, thereby suppressing tumorigenicity. Therapeutically, it may be that intercellular adhesion, no matter how it is induced, may serve as a single master event that is able to induce reversion of the carcinomatous state.

REFERENCES

Aberle
H.
,
Schwartz
H.
,
Kemler
R.
(
1996
).
Cadherin-catenin complex: protein interactions and their implications for cadherin function.
J. Cell. Biochem
61
,
514
523
Albini
A.
,
Iwamoto
Y.
,
Kleinman
H. K.
,
Martin
G. R.
,
Aaronson
S. A.
,
Kozlowski
J. M.
,
McEwan
R. N.
(
1987
).
A rapid in vitro assay for quantitating the invasive potential of tumor cells.
Cancer Res
47
,
3239
3245
Amagai
M.
,
Fujimori
T.
,
Masunaga
T.
,
Shimizu
H.
,
Nishikawa
T.
,
Shimizu
N.
,
Takeichi
M.
,
Hashimoto
T.
(
1995
).
Delayed assembly of desmosomes in keratinocytes with disrupted classic-cadherin-mediated cell adhesion by a dominant negative mutant.
J. Invest. Dermatol
104
,
27
32
Andrews
N. A.
,
Jones
A. S.
,
Helliwell
T. R.
,
Kinsella
A. R.
(
1997
).
Expression of the E-cadherin-catenin cell adhesion complex in primary squamous cell carcinomas of the head and neck and their nodal metastases.
Br. J. Cancer
75
,
1474
1480
Arai
T.
,
Okamoto
K.
,
Ishiguro
K.
,
Terao
K.
(
1976
).
HeLa cell-tumor in nude mice and its response to antitumor agents.
Gann
67
,
493
503
Behrens
J.
,
Mareel
M. M.
,
van Roy
F. M.
,
Birchmeier
W.
(
1989
).
Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion.
J. Cell Biol
108
,
2435
2447
Birchmeier
W.
,
Behrens
J.
(
1994
).
Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness.
Biochim. Biophys. Acta
1198
,
11
26
Bracke
M. E.
,
van Roy
F. M.
,
Mareel
M. M.
(
1996
).
The E-cadherin/catenin complex in invasion and metastasis.
Curr. Top. Microbiol. Immunol
213
,
123
161
Bullions
L. C.
,
Notterman
D. A.
,
Chung
L. S.
,
Levine
A. J.
(
1997
).
Expression of wild-type alpha-catenin protein in cells with a mutant alpha-catenin gene restores both growth regulation and tumor suppressor activities.
Mol. Cell. Biol
17
,
4501
4508
Celis
J. E.
,
Small
J. V.
,
Andersen
P.
,
Celis
A.
(
1978
).
Microfilament bundles in cultured cells. Correlation with anchorage independence and tumorigenicity in nude mice.
Exp. Cell. Res
114
,
335
348
D'Urso
D.
,
Brophy
P. J.
,
Staugaitis
S. M.
,
Gillespie
C. S.
,
Frey
A. B.
,
Stempak
J. G.
,
Colman
D. R.
(
1990
).
Protein zero of peripheral nerve myelin: biosynthesis, membrane insertion, and evidence for homotypic interaction.
Neuron
4
,
449
460
Doyle
J. P.
,
Stempak
J. G.
,
Cowin
P.
,
Colman
D. R.
,
D'Urso
D.
(
1995
).
Protein zero, a nervous system adhesion molecule, triggers epithelial reversion in host carcinoma cells.
J. Cell Biol
131
,
465
482
Farquhar
M. G.
,
Palade
G. E.
(
1963
).
Junctional complexes in various epithelia.
J. Cell Biol
17
,
375
412
Filbin
M. T.
,
Walsh
F. S.
,
Trapp
B. D.
,
Pizzey
J. A.
,
Tennekoon
G. I.
(
1990
).
Role of myelin P0 protein as a homophilic adhesion molecule.
Nature
344
,
871
872
Freedman
V. H.
,
Shin
S. I.
(
1974
).
Cellular tumorigenicity in nude mice: correlation with cell growth in semi-solid medium.
Cell
3
,
355
359
Frixen
U. H.
,
Behrens
J.
,
Sachs
M.
,
Eberle
G.
,
Voss
B.
,
Warda
A.
,
Lochner
D.
,
Birchmeier
W.
(
1991
).
E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells.
J. Cell Biol
113
,
173
185
Geiger
B.
,
Ayalon
O.
(
1992
).
Cadherins.
Annu. Rev. Cell Biol
8
,
307
332
Gumbiner
B.
,
Stevenson
B.
,
Grimaldi
A.
(
1988
).
The role of the cell adhesion molecule uvomorulin in the formation and maintenance of the epithelial junctional complex.
J. Cell Biol
107
,
1575
1587
Gumbiner
B. M.
(
1993
).
Proteins associated with the cytoplasmic surface of adhesion molecules.
Neuron
11
,
551
564
Gumbiner
B. M.
(
1996
).
Cell adhesion: the molecular basis of tissue architecture and morphogenesis.
Cell
84
,
345
357
Gumbiner
B. M.
,
McCrea
P. D.
(
1993
).
Catenins as mediators of the cytoplasmic functions of cadherins.
J. Cell Sci
17
,
155
158
Hao
X. P.
,
Palazzo
J. P.
,
Ilyas
M.
,
Tomlinson
I.
,
Talbot
I. C.
(
1997
).
Reduced expression of molecules of the cadherin/catenin complex in the transition from colorectal adenoma to carcinoma.
Anticancer Res
17
,
2241
2247
Heussen
C.
,
Dowdle
E. B.
(
1980
).
Electrophoretic analysis of plasminogen activators in polyacrylamide gels containing sodium dodecyl sulfate and copolymerized substrates.
Anal. Biochem
102
,
196
202
Hiscox
S.
,
Jiang
W. G.
(
1997
).
Expression of E-cadherin, alpha, beta and gamma-catenin in human colorectal cancer.
Anticancer Res
17
,
1349
1354
Hoffman
A. G.
,
Burghardt
R. C.
,
Tilley
R.
,
Auersperg
N.
(
1993
).
An in vitro model of ovarian epithelial carcinogenesis: changes in cell-cell communication and adhesion occurring during neoplastic progression.
Int. J. Cancer
54
,
828
838
Jiang
W. G.
(
1996
).
E-cadherin and its associated protein catenins, cancer invasion and metastasis.
Br. J. Surg
83
,
437
446
Khokha
R.
,
Denhardt
D. T.
(
1989
).
Matrix metalloproteinases and tissue inhibitor of metalloproteinases: a review of their role in tumorigenesis and tissue invasion.
Invasion Metastasis
9
,
391
405
Krishnadath
K. K.
,
Tilanus
H. W.
,
vanBlankenstein
M.
,
Hop
W. C. J.
,
Kremers
E. D.
,
Dinjens
W. N. M.
,
Bosman
F. T.
(
1997
).
Reduced expression of the cadherin-catenin complex in oesophageal adenocarcinoma correlates with poor prognosis.
J. Pathol
182
,
331
338
Lai
C.
,
Brow
M. A.
,
Nave
K. A.
,
Noronha
A. B.
,
Quarles
R. H.
,
Bloom
F. E.
,
Milner
R. J.
,
Sutcliffe
J. G.
(
1987
).
Two forms of 1B236/myelin-associated glycoprotein, a cell adhesion molecule for postnatal neural development, are produced by alternative splicing.
Proc. Natl Acad. Sci. USA
84
,
4337
4341
Lemke
G.
,
Lamar
E.
,
Patterson
J.
(
1988
).
Isolation and analysis of the gene encoding peripheral myelin protein zero.
Neuron
1
,
73
83
Lewis
J. E.
,
Jensen
P. J.
,
Wheelock
M. J.
(
1994
).
Cadherin function is required for human keratinocytes to assemble desmosomes and stratify in response to calcium.
J. Invest. Dermatol
102
,
870
877
Lewis
J. E.
,
Wahl
J. K.
III
,
Sass
K. M.
,
Hensen
P. M.
,
Johnson
K. R.
,
Wheelock
M. J.
(
1997
).
Cross-talk between adherens junctions and desmosomes depends on plakoglobin.
J. Cell Biol
136
,
919
934
Mareel
M.
,
Berx
G.
,
van Roy
F.
,
Bracke
M.
(
1996
).
Cadherin/catenin complex: a target for antiinvasive therapy?.
J. Cell Biochem
61
,
524
530
Mareel
M.
,
Bracke
M.
,
Van Roy
F.
(
1995
).
Cancer metastasis: negative regulation by an invasion-suppressor complex.
Cancer Detect. Prev
19
,
451
464
McNeill
H.
,
Ryan
T. A.
,
Smith
S. J.
,
Nelson
W. J.
(
1993
).
Spatial and temporal dissection of immediate and early events following cadherin-mediated epithelial cell adhesion.
J. Cell Biol
120
,
1217
1226
Miyaki
M.
,
Tanaka
K.
,
Kikuchi Yanoshita
R.
,
Muraoka
M.
,
Konishi
M.
,
Takeichi
M.
(
1995
).
Increased cell-substratum adhesion, and decreased gelatinase secretion and cell growth, induced by E-cadherin transfection of human colon carcinoma cells.
Oncogene
11
,
2547
2552
Nagafuchi
A.
,
Takeichi
M.
(
1988
).
Cell binding function of E-cadherin is regulated by the cytoplasmic domain.
EMBO J
7
,
3679
3684
Oulad Abdelghani
M.
,
Bouillet
P.
,
Chazaud
C.
,
Dolle
P.
,
Chambon
P.
(
1996
).
AP-2.2: a novel AP-2-related transcription factor induced by retinoic acid during differentiation of P19 embryonal carcinoma cells.
Exp. Cell Res
225
,
338
347
Perl
A. K.
,
Wilgenbus
P.
,
Dahl
U.
,
Semb
H.
,
Christofori
G.
(
1998
).
A causal role for E-cadherin in the transition from adenoma to carcinoma.
Nature
392
,
190
193
Pignatelli
M.
,
Vessey
C. J.
(
1994
).
Adhesion molecules: novel molecular tools in tumor pathology.
Hum. Pathol
25
,
849
856
Ranscht
B.
(
1994
).
Cadherins and catenins: interactions and functions in embryonic development.
Curr. Opin. Cell Biol
6
,
740
746
Richmond
P. J. M.
,
Karayiannakis
A. J.
,
Nagafuchi
A.
,
Kaisary
A. V.
,
Pignatelli
M.
(
1997
).
Aberrant E-cadherin and alpha-catenin expression in prostate cancer: Correlation with patient survival.
Cancer Res
57
,
3189
3193
Rodriguez-Boulan
E.
,
Nelson
W. J.
(
1989
).
Morphogenesis of the polarized epithelial cell phenotype.
Science
245
,
718
725
Rodriguez-Fernandez
J. L.
,
Geiger
B.
,
Salomon
D.
,
Ben Ze'ev
A.
(
1993
).
Suppression of vinculin expression by antisense transfection confers changes in cell morphology, motility, and anchorage-dependent growth of 3T3 cells.
J. Cell Biol
122
,
1285
1294
Schmidt
A.
,
Heid
H. W.
,
Schafer
S.
,
Nuber
U. A.
,
Zimbelmann
R.
,
Franke
W. W.
(
1994
).
Desmosomes and cytoskeletal architecture in epithelial differentiation: cell type-specific plaque components and intermediate filament anchorage.
Eur. J. Cell Biol
65
,
229
245
Schneider-Schaulies
J.
,
von Brunn
A.
,
Schachner
M.
(
1990
).
Recombinant peripheral myelin protein P0 confers both adhesion and neurite outgrowth-promoting properties.
J. Neurosci. Res
27
,
286
297
Shapiro
L.
,
Doyle
J. P.
,
Hensley
P.
,
Colman
D. R.
,
Hendrickson
W. A.
(
1996
).
Crystal structure of the extracellular domain from P0, the major structural protein of peripheral nerve myelin.
Neuron
17
,
435
449
Shapiro
L.
,
Fannon
A. M.
,
Kwong
P. D.
,
Thompson
A.
,
Lehmann
M. S.
,
Grubel
G.
,
Legrand
J. F.
,
Als Nielsen
J.
,
Colman
D. R.
,
Hendrickson
W. A.
(
1995
).
Structural basis of cell-cell adhesion by cadherins [see comments].
Nature
374
,
327
337
Shiozaki
H.
,
Iihara
K.
,
Oka
H.
,
Kadowaki
T.
,
Matsui
S.
,
Gofuku
J.
,
Inoue
M.
,
Nagafuchi
A.
,
Tsukita
S.
,
Mori
T.
(
1994
).
Immunohistochemical detection of alpha-catenin expression in human cancers.
Am. J. Pathol
144
,
667
674
Shiozaki
H.
,
Oka
H.
,
Inoue
M.
,
Tamura
S.
,
Monden
M.
(
1996
).
E-cadherin mediated adhesion system in cancer cells.
Cancer
77
,
1605
1613
Simcha
I.
,
Geiger
B.
,
Yehuda Levenberg
S.
,
Salomon
D.
,
Ben Ze'ev
A.
(
1996
).
Suppression of tumorigenicity by plakoglobin: an augmenting effect of N-cadherin.
J. Cell Biol
133
,
199
209
Suzuki
T.
,
Kim
H. S.
,
Kurabayashi
M.
,
Hamada
H.
,
Fujii
H.
,
Aikawa
M.
,
Watanabe
M.
,
Watanabe
N.
,
Sakomura
Y.
,
Yazaki
Y.
, et al. 
(
1996
).
Preferential differentiation of P19 mouse embryonal carcinoma cells into smooth muscle cells. Use of retinoic acid and antisense against the central nervous system-specific POU transcription factor Brn-2.
Circ. Res
78
,
395
404
Umbas
R.
,
Isaacs
W. B.
,
Bringuier
P. P.
,
Xue
Y.
,
Debruyne
F. M. J.
,
Schalken
J. A.
(
1997
).
Relation between aberrant alpha-catenin expression and loss of E-cadherin function in prostate cancer.
Int. J. Cancer
74
,
374
377
vanderWurff
A. A. M.
,
Vermeulen
S. J. T.
,
vanderLinden
E. P. M.
,
Mareel
M. M.
,
Bosman
F. T.
,
Arends
J. W.
(
1997
).
Patterns of alpha-and beta-catenin and E-cadherin expression in colorectal adenomas and carcinomas.
J. Pathol
182
,
325
330
Vessey
C. J.
,
Wilding
J.
,
Folarin
N.
,
Hirano
S.
,
Takeichi
M.
,
Soutter
P.
,
Stamp
G. W.
,
Pignatelli
M.
(
1995
).
Altered expression and function of E-cadherin in cervical intraepithelial neoplasia and invasive squamous cell carcinoma.
J. Pathol
176
,
151
159
Vleminckx
K.
,
Vakaet
L.
Jr.
,
Mareel
M.
,
Fiers
W.
,
van Roy
F.
(
1991
).
Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role.
Cell
66
,
107
119
Watabe
M.
,
Nagafuchi
A.
,
Tsukita
S.
,
Takeichi
M.
(
1994
).
Induction of polarized cell-cell association and retardation of growth by activation of the E-cadherin-catenin adhesion system in a dispersed carcinoma line.
J. Cell Biol
127
,
247
256
Wong
M. H.
,
Filbin
M. T.
(
1994
).
The cytoplasmic domain of the myelin P0 protein influences the adhesive interactions of its extracellular domain.
J. Cell Biol
126
,
1089
1097
Wong
M. H.
,
Filbin
M. T.
(
1996
).
Dominant-negative effect on adhesion by myelin Po protein truncated in its cytoplasmic domain.
J. Cell Biol
134
,
1531
1541
This content is only available via PDF.