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of Pathology,
University
of Tennessee
Hospital, Memphis,
Tennessee,
USA
ABSTRACT
This review suggests that carcinogenesis
is linked to defects in linkages between
cellular differentiation
and regulation
of cell proliferation.
These linkages are discussed
in terms of
terminal and nonterminal
states of differentiation
and their relationship
to the control of proliferation.
The ability of differentiation to regulate proliferation potential proteins and cancer suppressor genes
is also discussed. because these mechanisms may be important for cancer prevention and therapy.
KEY WORDS:
diffl'l"I'ntiafif!ll,
and proliferation
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these states are quiescent. cells at the PGA state can either
differentiate or they can exit the PGA state and return to the cell
cycle and proliferate. The NTD state also serves to link the control
of proliferation and differentiation because at this state cells can
either undergo terminal differentiation, which is associated with the
irreversible loss of proliferative potential, or cells at the NTD state
can return to the cell cycle and proliferate in association with loss
of the differentiated
i.e.
phenotype,
dedifferentiation.
.-lhbrnJioliolll
111/'11 ill
t[itTcrentiati!)11
and
Illil
Imlwl:
C:\"s.
serum:
:\'TD. nonter11lillal
P~p. pn>lifcr:ttilfn
differellli;tlitll):
POIl'lllial
proteil1":
1'(',.\.
n'lil1oblaSI()!11;l
"~"H'Jl!:
..1l1)1)!1
l)'!CS.\.
I!l ;lcthity:
\\lX.
l11etl1\1 i...)IIlII\\
:-:':IIHhil1C;
)r ge!1t':
nm~:~ antiIIH'la..la..i..
suppn
1'1)(;1-". pl;lIt'lel
tlt'l i\[.t[ gl"l)lI'th Elt"ti>r;
aITe..t: Ph(:. prol('in
kin,,"!' (:: It-\. 1"t'lillUi.
pn'dittnclHi;niol1l-\"l'1\,'h
ttT111inal diJren'llliatinn:
Iran~f()n11illggrmnh
lit. IT!)\!..
cancer
IF:\". illtedt'ron:
al'iet; Rh-I,
(('nlra]
dedith'n'11Ii:tlitJ]1-indIHTt!
S\lpp['e~~or
~el1t'
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TD.
Avenue,
Memphis.
68
O,lIo,on'iollo,
"'"lIiotooP,.,...
Abbr..,,,,."
of 5..,.
Hig~l~
O'''.,o"liolo.
P~.n."p.
Prol,Io,.lion
Potooliol
E..mpIOl
01
h--'li>.JI
COY""'.""
Rog.no,.!ing
RG
PG'
NTD
TD
'opOl'<1\"
aui...."!
S'om Coil.
l,mp"oc,t..
Hop"..,'"
'"'
Houron..n.
",",.loC.II,
and differentiation
in
,. R.pidl1
Gro..lng,
Undlrr.r.nli.l.d
Can..rC.II.
G
;t
;
;
--
n.
Conc.r
C.lla ..i1~
". Inl.rmadlUa
G,o..111& D,II.r.nli.lion
ChtO.I.rI.1i.a
m Slo..G,owing.
Wall.Dil'.r.n,la1.d
Cane.,C.lla
it
8
Norm.1 Call,
I,
j f
db
~6,I
---
".
~~0
dlll.r.n! I1P. .rm... duignal. 1h. prob.blll11 01 on a..nl occuring Irom ~Igh10 low
-------~
69
InvClslon
Polential
biological
and molecular
can be experimentally
Differentiation
Control
linkages.
Scott and
TABLE 1
BIOLOGICAL
Aberrant
proliferation
control
CHARACTERISTICS
DF DIFFERENT
PHENOTVPES
Aberrant
differentiation
control
Invasion
potential
+
+
+
+
CEllULAR
Phenotypes
Nonmalignant:
inflammatory cells.
fibroblast, etc.
Nonmalignant:
hyperplastic cells
Nonmalignant:
metaplastic cells
Nonmalignant:
dysplastic cells
Malignant:
cancer cells
70
RE.
SCOff et a!.
TABLE 2
COMPARISON
Phenotype
NTO
I. Morphology
mature adlpocyte
..Mitogenic
TO
mature adipocyte
responsiveness
..
dedifferentiation
A. 30% FBS+50,ug/ml
B. TPA 1100 ng/mll
C. RA 110 pg/ml)
D. MIX (2xlO--: M)
insulin
+
+
+
~:
~:
..
NTD
I
..
Molecular Mechanisms:
Changes in multiple cytoplasmic
and nuclear proleins, especially the decreased
expression of P2Ps which represent a subset of
hnRNP proteins
Fig. 4. Characteristics
of the terminal
step in adipocyte
differentiation.
----
P2P expression
+
+
+
+
+
---------
71
Prollter.lIon
Conlrol
SUDDressor
Inv.slon
Potentl.,
--
activity in maintaining
72
.~
activity during
200
0-
:=
~u,
"
TABLE 4
~eN
OF CEllS
AND MOLECULAR
CHARACTHAT DO AND DO NOT EXPRESS D'CSA
D'CSA
positive
Morphology
Growth potential
Cell cycle characteristics
Oifferentlation
potential
Soft agar growth response to TGF~
DNA repair mechanisms
Cell-cell communication
characteristics
Interferon production
150
~~"'
vs
Same
Same
Same
Same
Same
Same
Same
Distinct
D'CSA
negative
o.
uu
-4i=
u"
E..:
e_0
.u"
"'-
t II0
50
O'
D2 CSA
Positive
Cell Clones
0 indicates
< 25 U based
correlates
D 2 CSA
Negative
Cell Clones
on the assay
sensitivity
of cancer
73
HOERL,B.J., WIER.
Conclusions
In summary, the data reviewed in this paper suggest that cellular
regulates the phenotype of normal cells and that
carcinogenesis is associated with the development of defects in the
differentiation
M.L and SCOTT, R.E. (1984). Blologici:ll mechanisms for the loss
of the differentiated phenotype bynon.terminallydifferentlaled
adipocytes. Exp. Cell
Res. 155: 422-434.
Proliferation
and differentIation
characteristics
of normal human squamous mucosal cens of the
upper aerodigestive tract. Ann. Oro. Rhinol. Laryn. 99: 29-37.
KITAVAMA,H., SUGIMOTO,V., MATSUZAK,T.,IKAWA, Y. and NODA, M. (1989). A rasrelated gene with transformation
suppressor
activity.
Gel/56:
77.84.
study of retinoblastoma.
Coupling of proadlpoq.te
growth
arrest
and
by heparin medium containing human plasma. J. Cell
Acknowledgments
Theauthors thank W.Patrick for typing this manuscript and our numerous
associates and technicians who have helped generate the results described
herein. We also acknowledge the fol/owing support that funded these
studies: NIH grants CA28240 and CA51715, CTR grant 2869 and the
Muirhead Endowed Chair to RES.
of fibroblast-like
178.
KURI.HARCUCH,W. and MARSCH.MORENO,M. (1983). DNAsynthesis and cell dl ision
related to adipose dIfferentiation
of 3T3 cells. J. Cell. PhysioJ. 114:39-44.
LASSAR, A.B., THAYER,MJ., OVERELL,R.W. and WEINTRAUB,H. (1989). Transfor.
matlon by acti...ated ras or fos pre...ents myogenesis by mhibiting expression of
myodD-1.
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