BOSNlAN lOUlNAl Ol BASlC MlDlCAl SCllNClS 2010, 10 (3).

192-196

Abstract
Gallbladder carcinoma is the tth most common malinancv ot the astrointestinal
tract. Te absolute characteristics ot the disease are the hih mortalitv rate due to
the late discoverv ot a tumor and the lov therapeutic possibilities except bv surical
intervention. ln oncolov ve can predict the outcome ot the disease vith a com-
bination ot classical standard clinicopatholoical parameters (stae ot the tumors,
dierentiation) and the intrinsic enetic and biochemical properties ot the tumor.
Such intrinzic properties ot the tumors that are connected vith the outcome ot the
disease are the denominators (markers). Te author searched extensivelv tor the
expression and inuence ot markers included in chronic inammation and earlv
carcinoenesis, cell cvcle reulation and tissue hvpoxia. cvclooxvenase-. (COX-.),
p, ene and lucose transporter-+ protein (GlUT-+). Te author discusses their
possible role in the development as vell as htin this disease, it specic medica-
tions taretin them vere available.
llY WOlDS. allbladder carcinoma, cvclooxvenase-., p,, lucose transporter-+
CYCLOOXYGENASE-2,
P53 AND GLUCOSE
TRANSPORTER-1
AS PREDICTORS OF
MALIGNANCY IN
THE DEVELOPMENT
OF GALLBLADDER
CARCINOMAS
Mateja Legan*
lnstitute ot Histolov 8 lmbrvolov, lacultv ot Medicine, Universitv ot lublana,
lorvtkova ., Sl-+ooo lublana, Slovenia
Correspondin author
BOSNlAN lOUlNAl Ol BASlC MlDlCAl SCllNClS 2010, 10 (3). 193-196
MATllA llGAN. CYClOOXYGlNASl2, P33 AND GlUCOSl TlANSPOlTll1 AS PllDlCTOlS Ol
MAllGNANCY lN THl DlVllOPMlNT Ol GAllBlADDll CAlClNOMAS
Introduction
Mvsterious and hidden in the abdominal cavitv, all-
bladder malinancies have continued to be a puzzle
and an under-investiated disease. Hovever, allblad-
der carcinomas are the ,th most common malinancv
ot the astrointestinal tract. Histoloicallv, in ,, ot
cases there is an adenocarcinoma. lt is commonlv
detected late, atter a quiet period, manv times inci-
dentallv, so it is no surprise that this malinancv has a
poor overall survival ot ,-+ tor , vears (+). Because
next to surical resection there are no relevant uides
tor additional therapv, the situation calls tor investi-
ations ot earlv markers (andor triers) ot this dis-
ease and vith them - nev therapeutic possibilities.
larlv observations directed the attention tovards an
association vith cholelithiasis (.), in the lar last vith
an anomalous pancreatico-biliarv ductal unction
(APBDl) (), toether vith a common toether de-
nominator. lon-term inammation as a cause. Histo-
loical examinations revealed that epithelial chanes
and premalinant lesions vere tound adacent to the
tumor tissue (|). Novadavs, in contemporarv pathol-
ov, putative pathvavs ot allbladder carcinoenesis
are accepted. dvsplasia, adenoma and APBDl (|). Next
to these putative pathvavs, diseases vhich are prob-
ablv connected to allbladder carcinomas are. porce-
lain allbladder, ulcerative colitis, tamilial adenoma-
tous polvposis, Gardners and Peutz-lehers svndrome.
ln our part ot the vorld, the tirst pathvav ot all-
bladder tumorienesis, dvsplasia, is the most vide-
spread. The most important basis tor puttin dvs-
plasia in the position ot premalinancv is that the
detection rate ot dvsplasia adacent to a carcinoma is
|,-88, since solitarv dvsplasia is tound in o.|- ot
cases(|). Manv times in dvsplastic areas metaplasia
is detected, vith tvpical intestinal and pvloric lands.
Comin trom the assumption that the period required
to transtorm into an advanced carcinoma is +, vears (,),
novadavs ve knov hov important it is to nd tactors
that trier the carcinoenic process. Tese potential
earlv markers in the development ot allbladder can-
cer are mavbe at the same time also possible tarets tor
therapeutic intervention. loa has alreadv postulated
that in certain countries (such as Chile, vhere there is
a dierence in the lenth ot time ot the expression ot
allbladder carcinomas betveen tvo ethnic roups,
vhere the period ot time trom dvsplasia to carcinoma in
Mapuche lndians is halt as much as the other roup) an
eort should be made to determine the environmental
and nutritional risk tactors .o vears betore the appear-
ance ot advanced carcinomas, and that in these tactors
there miht be a clue tor ditterence in the ditterent
speed ot the carcinoma development. Nevertheless, in
contemporarv patholov the attention has been direct-
ed mostlv tovards the intrinsic enetic and biochemical
properties ot the tissue and so our research vas tocused
on COX-., the p, ene and the lucose transporter-+.
COX-
COX is a rate-limitin step in PGH. svnthesis. lt is
presented in . isotorms, trom vhich one is consti-
tutional. COX-+ is normallv present and obliatorv
tor maintenance ot astrointestinal mucosis, platelet
tunction and renal tunction. Hovever, COX-. is in-
duced bv inammatorv and carcinoenic stimuli. Once
COX-. is presented in the tissue, it has the pover to
promote tumorienesis bv enhancin anioenesis,
stimulation ot Bcl-. transcription, suppression ot the
cell-mediated anti-tumor immune response, induc-
tion ot matrix metalloproteinase, induction ot cell
proliteration and invasion and throuh the activa-
tion ot several classes ot chemical carcinoens (6-8).
COX-. overexpression vas detected in several mali-
nant and premalinant conditions (,), also in allbladder
carcinomas (+o-+.). Asano (+o) observed in advanced
allbladder carcinomas an enhanced expression ot
COX-. in the adacent stroma rather than in the cancer-
ous epithelia. Te stroma vas a potent source ot PG svn-
thesis. ln the studv bv lavamoto et al (+) the expres-
sion ot COX-. in the subserosal laver ot the allbladder
tumor stroma correlated vith the aressiveness ot the
disease. ln our studv (++) ve included surical speci-
mens (tissue samples) ot carcinomas, hih rade dvs-
plasias, lov rade dvsplasias, hvperplasias and normal
allbladders. A tvpical cvtoplasmatic pattern ot COX-.
stainin vas shovn either in tumor cells, sometimes in
stromal broblasts or smooth muscle cells, endothelial
or epithelial cells. lor evaluatin the deree ot COX-.
expression ve used an immunoreactive score, the prod-
uct ot the intesitv ot stainin and the quantitv ot posi-
tive cells. Te hihest llS vas tound in the hih-rade
dvsplasia and not in the carcinoma. Te hihest COX-.
expression that appeared in the premalinant condition
led us to the conclusion that COX-. overexpression is
an earlv occurrence in allbladder carcinoenesis (++).
Our observation vas in accordance vith tumor behav-
iour in astric cancer (+|), vhere enhanced COX-. ex-
pression vas also an earlv occurrence in tumorienesis.
Our studv is also supported bv the ndins ot lumino et
al (+.) vho detected enhanced an expression ot COX-.
BOSNlAN lOUlNAl Ol BASlC MlDlCAl SCllNClS 2010, 10 (3). 19+-196
MATllA llGAN. CYClOOXYGlNASl2, P33 AND GlUCOSl TlANSPOlTll1 AS PllDlCTOlS Ol
MAllGNANCY lN THl DlVllOPMlNT Ol GAllBlADDll CAlClNOMAS
in the mucosal hvperplasia ot the allbladder in patients
vith an anomalous arranement ot the pancreatico-
biliarv duct, suestin that COX-. miht plav a reu-
latorv role in the proliteration ot allbladder epithelia.
P
Te p, ene is knovn as the uardiane ot the enome.
Upon receivin a sinal ot DNA damae, the p, am-
plies and become active in the cell to induce transcrip-
tion, prolon the cell cvcle and repair the DNA or in-
duce apoptosis rather than repair, so that the damaed
cells are removed trom the tissue (+,). Wild-tvpe p, is
thus an oncosuppressor ene, knovn tor its instabilitv
and di cultv in immunohistochemical shovin in the
cell nucleus. Hovever, a mutant p, is a stable protein
vith a lon halt-lite, possible to reveal its presence in the
cells. An increased p, level in the cell can be used as an
indicator ot p, mutation. P, ene mutation or dele-
tion is observed in ,o ot cancers (+6). P, expression
vas tound to be neative in the normal allbladder epi-
thelium, hvperplasias and lov-rade dvsplasias, but posi-
tive in an important percentae ot hih-rade dvsplasia
ot allbladder epithelia(+,.) and in |8,+ ot allblad-
der carcinomas (++). Our results vere in accordance
vith previous studies vhere the incidence ot p, accu-
mulation in allbladder carcinoma vas 6-68 (+;-+,).
There are links betveen COX-. and p, expression.
COX-. miht be suppressed bv vild-tvpe p, (.o),
COX-. in turn inhibits the vild-tvpe p, dependant
transcription (.+). We vere the tirst to analvse the
relationship betveen COX-. and p, in various hvs-
toloical staes ot allbladder epithelial abnormalities
(++). Puttin on one side all p, neative cases and on
the other side p, positive cases, ve tound that amon
the p, positive cases there vere onlv . COX-. nea-
tive cases, all others vere positive too, and amon the
p, neative cases there vere 6o COX-. neative.
This vas statisticallv siniticant. The earlier appear-
ance ot COX-. expression has led us to presume that
COX-. overexpression miht be the tirst occurence
that in turn inhibits vild-tvpe dependant transcription.
We conclude that COX-. overexpression miht be
related to p, dvstunction (++). Tis has a reat thera-
peutic impact, because taretin COX-. miht be ben-
ecial, aectin . reulatorv molecules. COX-. and p,.
The use ot non-steroid anti-intlammatorv drus and
COX-. selective inhibitors in human cancers vere
tound promisin in the chemoprevention ot carci-
nomas. The use ot selective COX-. inhibitors (ce-
lecoxib) decreased the number and size ot colon
polvpees in tamilial adenomatous polvposis vithin 6
months ot treatment (..). The tollovin studies (.,
.|) shoved a sinicantlv hiher incidence ot cardio-
vascular occurrences in these patients, so the chemo-
prevention ot colorectal carcinomas vith them is not
ustitied. The complex role ot COX-. in the phvsi-
oloical and pathophvsioloical processes in humans
is hihlv suestive and merits turther investiations.
GLUT-
Accelerated lvcolvsis is one ot the biochemical char-
acteristics ot cancer cells (.,). GlUT-+ is a trans-
membrane lucose transport protein that allovs the
tacilitated transport ot lucose into cells. Next to its
normal expression in tissues vhich depend mainlv on
lucose metabolism, such as membranes ot ervthro-
cvtes, the endothelium ot brain capillaries, perineuri-
um, renal tubules, it is also tound also as an adaptation
mechanism ot tumor cells to ensure lucose transport
(.,, .6) and it is reconized as a successtul model that
leads to invasion and metastasis (.;, .8). lt has been
shovn that it is occasionallv present in reactive be-
nin epithelia in small quantities, but in increased ex-
pression in various malinoma. head and neck squa-
mous cell carcinomas, astric carcinomas, colorectal,
ovarian, endometrial, also in allbladder carcinomas
(.,-+). Novadavs ve knov that hvpoxic stimuli
accelerate GlUT-+ overexpression and increased
expression ot GlUT-+ is a marker ot hvpoxia (.).
Since lim et al. (o) shoved accelerated GlUT-+ ex-
pression in allbladder carcinomas, lean et al. (+)
proposed that the radual increase in GlUT-+ expres-
sion appears trom a lov rade dvsplasia tovards a
carcinoma. Since stron GlUT-+ expression appears
onlv in carcinoma cases, ve believe that our results
have compellin dianostic importance. This means
that the speciticitv ot stron GlUT-+ expression tor
detectin allbladder carcinomas is +oo (+). ln con-
temporarv patholov sometimes there is a puzzle to de-
cide betveen hih-rade dvsplasia and a carcinoma in
situ. ln such cases vhen the Asian school alvavs tends
tovards a carcinoma, ve nov have a complementarv
marker tor tacilitatin a decision. Hovever, the dia-
nostic puzzle remains in the GlUT-+ neativitv, vhich
vas the case in |8,. ot allbladder carcinomas (+).
Patients, vhose tumors stronlv expressed GlUT-+,
had siniticantlv shorter survival times than patients
vith absent, veak or moderate GlUT-+ expression
(). We conrmed that GlUT-+ is not onlv a marker
ot hvpoxia, but also an obvious denominator ot the
BOSNlAN lOUlNAl Ol BASlC MlDlCAl SCllNClS 2010, 10 (3). 193-196
MATllA llGAN. CYClOOXYGlNASl2, P33 AND GlUCOSl TlANSPOlTll1 AS PllDlCTOlS Ol
MAllGNANCY lN THl DlVllOPMlNT Ol GAllBlADDll CAlClNOMAS
Conclusion
A radual increase in the accumulation ot GlUT-+ (or p, andor COX-.) vas observed trom lov-rade dvsplasias to
carcinomas. Since COX-. and p, are involved in the carcinoenesis ot the allbladder itselt, GlUT-+ is a consequent
occurrence ot malinant or premalinant alterations. When once present it becomes more than ust a dianostic marker
in certain dubious cases but also a pronostic marker unmaskin hvpoxic conditions and throuh them the untavour-
able bioloical behaviour ot the tumor. larlv markers and denominators are important because thev ive the opportunitv
to detect earlv occurrences in the development ot allbladder carcinoma. Taretin them miht be benecial in patients
vith allbladder carcinomas and it is the subect ot present and tuture investiations.
List of Abbreviations
COX-. - cvclooxvenase-.
GlUT-+ - lucose transporter-+ protein
APBDl - anomalous pancreatico-biliarv ductal unction
llS - immunoreactive score
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