International Immunopharmacology 5 (2005) 1113 – 1130

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Mini review

The molecular mechanisms of oesophageal cancer

M.L. McCabe, Z. Dlamini*
School of Molecular and Cell Biology, Faculty of Science, University of the Witwatersrand, P/Bag 3, Johannesburg, 2050, South Africa
Received 27 September 2004; received in revised form 19 November 2004; accepted 29 November 2004

Abstract

Apoptosis is a process of programmed cell death, which is as essential as cell growth, for the maintenance of homeostasis.
When these processes loose integration such as cancer, then uncontrolled cell growth occurs. Cancer of the oesophagus ranks as
the ninth most common malignancy in the world, and recent evidence shows that its incidence is increasing. Prognosis of this
disease is poor, with an overall 5-year survival rate of less than 10%. Unraveling the mechanisms or developing animal models
for oesophageal carcinoma have thus far not been successful. It is believed that oesophageal cancer has an intricate molecular
mechanism of evading apoptosis by the down-regulation of Bax, up-regulation of Bcl-2, Bcl-xl and Survivin, mutation of p53
and alteration in Fas expression. A great deal of research has been performed in order to determine the key genes that initiate
and promote the growth of oesophageal cancer. This review focuses on apoptosis and candidate genes linked to the
development of oesophageal cancer, which it is hoped may provide diagnostic and therapeutic tools, and potential therapeutic
strategies for the management of this carcinoma.
D 2004 Published by Elsevier B.V.

Keywords: Human oesophageal cancer; Molecular genetics; Apoptosis signalling pathway; Genomics; Oesophageal cancer therapeutics

Abbreviations: AINs, Apoptosis inducing nucleosides; Apaf-1, Apoptosis activating factor 1; APC, Adenomatous polyposis coli; BAAC,
Barrets Oesophagus associated adenocarcinoma; BE, Barret’s Esophagus; Bcl-2, B-cell lymphoma mutant 2; Bcl-xl, B-cell lymphoma extra
long; CDDP, Cisplatin; CDK, Cyclin dependent kinase; COX-2, Cyclooxygenase 2; CSNK, Casein kinase; CTSB, Cathepsin B; DcR3, Decoy
receptor member 3; DISC, Death inducing signalling complex; DLC1, Deleted in lung cancer 1; EMR, Endoscopic mucosal resection; FasL, Fas
receptor ligand; GASC1, Gene amplified in squamous cell carcinoma 1; iNOS, Inducible nitric oxide synthase; Lef, Lymphoid enhancer binding
factor; LOH, Loss of heterozygosity; LOI, Loss of imprinting; MMP-7, Matrix metalloproteinase-7; MT, Metallothionein; MTX, Methotrextate;
ODC, Ornithine decarboxylase; OeAc, Adenocarcinoma; OeSc, Squamous carcinoma; p53, Protein with molecular weight ~53 kDa; p63,
Protein with molecular weight ~63 kDa; p73, Protein with molecular weight ~73 kDa; PARP, Poly-ADP-ribose polymerase; PCNA,
Proliferating cell nuclear antigen; PDT, Photodynamic therapy; pRb, Retinoblastoma protein; Rb, Restinoblastoma; Tcf, T cell specific
transcription factor; TNF-h, Tumour necrosis factor-h; TSGs, Tumour suppressor genes; WWOX, WW domain containing oxireductase.
T Corresponding author. Tel.: +27 11 7176366; fax: +27 11 7176351.
E-mail address: dlamini@gecko.biol.wits.ac.za (Z. Dlamini).

1567-5769/$ - see front matter D 2004 Published by Elsevier B.V.

doi:10.1016/j.intimp.2004.11.017
1114 M.L. McCabe, Z. Dlamini / International Immunopharmacology 5 (2005) 1113–1130
1. Oesophageal cancer
1.1. Prevalence
Cancer of the oesophagus ranks as the ninth most
common malignancy worldwide and recent evidence
shows that its incidence is rising [1]. Prognosis of this
disease is poor with an overall 5-year survival rate of
less than 10%. There are two major types of oesopha-
geal cancer: squamous carcinoma and adenocarci-
noma. The incidence of oesophageal adenocarcinoma
is increasing, and is most prevalent in the USA [2].
Universally, oesophageal cancer is more common
in men than in women, with decreasing sex ratios in
higher-risk areas and vice versa for lower-risk areas.
Incidence rate for oesophageal cancer increases with
age, with the lowest occurring at age 30 and the
highest at age 70. The highest mortality rates are
found in China accounting for 26.5% in males and
19.7% in females [3]. Oesophageal cancer in South
Africa is the second most common cancer among all
South African men combined and the most common
cancer in black males. Regions of South Africa, like
the Transkei, have recorded rise in incidence of
oesophageal cancer from 16 per 100,000 before
1970 to over 40 per 100,000 thereafter [4]. To date,
high incidence areas (expressed as crude incidence per
100,000) include: China (21 per 100,000), South
America (13 per 100,000), Western Europe (11 per
100,000), South Africa (10 per 100,000), Japan (9 per
100,000) and the former Soviet Union (8 per 100,000)
(Pearson et al., 2002) [5].
1.2. Etiology
Oesophageal cancer is a multifactorial disease; no
single agent has been identified thus far as the cause
of oesophageal cancer. Smoked food has a high
content of nitrosoamines and nitrites [6]. Methyl alkyl
nitrosamines appear to be specific inducers of
carcinoma of the oesophagus, regardless of its route
of administration. Smoking is also believed to play a
role in oesophageal carcinogenesis. Alcohol is also a
major etiological factor in oesophageal cancer. Fungal
toxins and spices are believed to have a positive
correlation with oesophageal cancer. It is suspected
that home brewed beers and other spirits prepared in
African countries cause oesophageal cancer due to
contamination with mycotoxins occurring during
preparation. The fungus, Fusarium moniliforme, is
believed to play a role in the toxicity of maize, and
when consumed, these mycotoxins are believed to
play a role in the development of cancer. Human
papilloma virus (HPV) serotypes 16 and 18 have also
been found to be associated with the development of
the disease. Barret’s Oesophagus (BE) has also been
found to be a risk factor for adenocarcinoma of the
oesophagus. BE a metaplastic change of the oesopha-
geal epithelium from squamous to columnar mucosa,
which is associated with repeated episodes of chronic
gastro-oesophageal reflux (GORD) [7]. It has been
shown that 86% of primary oesophageal adenocarci-
nomas originate from BE [8].
1.3. Molecular genetics of oesophageal cancer
As oesophageal carcinogenesis is poorly under-
stood, much research is being carried out to under-
stand the precise mechanisms causing the metaplasia–
dysplasia sequence of oesophageal carcinoma at a
molecular level [9]. It is known that tumour suppres-
sor genes, oncogenes, and apoptotic genes are
involved in the initiation and development of oeso-
phageal cancer, but to date no gene directly related to
oesophageal cancer has been identified [10].
Many candidate genes and their role in the
development of oesophageal cancer are still to be
revealed before a human oesophageal carcinogenesis
model can be developed. Key tumour related genes
and their specific role played in the development of
oesophageal cancer are discussed in more detail.
1.4. Apoptosis—genetic regulation of oesophageal
cancer
Each living cell undergoes cell cycle regulation
where an essential assessment mechanism occurs to
determine the status of the cell, whether it is healthy
enough to proceed to the next stage of cycle or
whether it should commit suicide.
Apoptosis is generally defined as a programmed
cell death that eliminates unwanted cells and is
essential for the homeostatic maintenance of an
organism. Like cell proliferation, cell death needs to
take place in order for normal development to take
place. It has been found that elevated levels of
 M.L. McCabe, Z. Dlamini / International Immunopharmacology 5 (2005) 1113–1130
apoptosis as well as low levels of apoptosis can have a
detrimental effect on the organism. This impaired
regulation of apoptosis leads to a variety of patho-
logical conditions, such as neurodegeneration, auto-
immunity, chronic inflammation, AIDS, and cancer.
In the eukaryotic cell cycle there are four stages, the
Gap-1 checkpoint (G-1), DNA Synthesis (S-phase),
Gap-2 checkpoint (G-2), and the Mitotic phase (M)
(view Fig. 1). Cyclin-cdks regulate the cell through
each phase. The G-1 and G-2 checkpoint phases are
where the cell assesses whether to proceed to the next
stage or commit suicide. The cell cycle results in either
of two processes, which is to proceed to the next stage
(cell division) or to induce apoptosis (cell suicide),
which is determined by the p53 protein [11].
There are two pathways by which a cell commits
suicide: (1) the intrinsic or mitochondrial pathway
and (2) the extrinsic or death receptor pathway. See
Figs. 2 and 3.
1.5. HPV and squamous oesophageal cancer cell
transformation
Human papilloma virus (HPV) has been found
to be the cause of many types of cancers. There
Fig. 1. Simple schematic diagram of normal cell cycle progression leading to Mitosis (M) or cell growth (if DNA is intact) or Apoptosis (if DNA
damage occurs).
1115
are more than 70 different HPV types that have
been identified and divided into two groups, high
and low risk HPVs. The high risk HPVs are the
cancer causing types (types 16 and 18), and the
low risk types that gives rise to warts and benign
lesions (examples include types 6, 11, and 33)
[12].
It has been shown that many HPV types
including the low risk types have been found in
oesophageal cancer tissues [13]. Particular studies
also show no HPV detection in oesophageal cancer
tissues, and the argument is that the detection
methods utilized are not sensitive enough. HPV
has been associated with oesophageal cancer and its
high frequency implicates the possibility of being an
etiological factor in this disease, but definite
evidence is still required [12].
A particular study carried out by Shen et al.
showed an immortal epithelial cell line from an
embryonic oesophagus, transformed to a malignant
cell type, by HPV-18 E6 and E7 oncoprotein
infection. This infection showed to induce chromo-
somal aberrations, telomeric shortening and telo-
merase activity, and expression of certain genes. It
was shown that a crucial event in the process of
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Fig. 2. Intrinsic apoptopic pathway, triggered by p53. When internal damage occurs in the cell, p53 signals Bax to induce apoptosis. Bax
then translocates into the mitochondrial membrane, displaces Apaf-1 and binds to the Bcl-2–Bcl-x complex. The mitochondrial
membrane then becomes permeable, and cytochrome c and Apaf-1 is allowed to translocate out of the mitochondria into the cytosol,
where it forms a complex with ATP and procaspase-9. This complex is known as the apoptosome. Procaspase-9 is cleaved and is
released from the complex and is now active. Active caspase-9 cleaves the effector caspase 7, 6 and 3, respectively, causing a cascade
of proteolytic events, whereby apoptosis is carried out. Degradation of structural proteins and DNA is the result, leading to phagocytosis
of the cell.

immortalization may be chromosomal instability vated (c-myc and ras) and tumour suppressor gene
and preneoplastic aneuploidy at an early stage, expression altered (p53 and Rb), resulting in loss
and in the progressive developmental stages, of cell growth control and apoptosis, causing
increased telomerase activity and amplification of cellular transformation [14].
some genes such as c-myc, ras, bcl-2, and p53.
HPV genome inserts and integrates with the
Early stage Metaplasia YChromosomal instability
chromosomes of host, causing confusing karyotypes (LOH and amplification)
and chromosomal changes and liabilities in genetic Progressive stage Dysplasia Y1. Increased telomerase activity
characteristics [13]. It has also been shown that 2. Oncogene activation
HPV E6 and E7 proteins are able to activate 3. Tumour suppressor
telomerase activity. Thereafter oncogenes are acti- gene alteration
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Fig. 3. Fas apoptotic signalling pathway. There are two pathways for Fas induced apoptosis, 1—activated by the Fadd/caspase-8/9/3 pathway
and 2—by the Daxx/JNK pathway.

1.6. Telomerase activity (metaplasia) stage showed a 60% telomerase activity

Repetitive telomere sequences are at the ends of
eukaryotic chromosomes to protect the ends from
damage and rearrangement. Progressive shortening
of telomeric sequences is associated with cell
division and DNA replication [15]. In a study carried
out by Li et al., it was shown that increased
telomerase activity was associated with the progres-
sion of squamous oesophageal carcinoma. Grade I
and Grades II (dysplasia) and III (high grade
dysplasia) showed 90% and 91% telomerase activity.
This result supported other reports of telomerase
activity being correlated with oesophageal squamous
carcinoma differentiation and lymphatic metastasis.
The poorer the differentiation, the higher the
telomerase activity occurred, and also patients with
lymphatic metastasis showed a higher telomerase
activity than those without.
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2. Oncogenes
The oncogenes most frequently activated in oeso-
phageal cancer are cyclin D1, c-erbB1 and 2, c-myc,
c-ras, Int-2/hst-1, and EGFR [16]. Frequent mecha-
nisms activating these oncogenes include point
mutations, amplification, rearrangement and over-
expression, with amplification and overexpression
being the most common [17].
2.1. Cyclin D1
Binds to and activates CDK4 and CDK6, which
can then phosphorylate the tumour suppressor protein,
retinoblastoma (pRb) [17].
It was shown that altered expression of the cyclin
D1 and Rb genes play a role in human oesophageal
cancer. Cyclin D1 gene amplification was found in
about 32% of oesophageal tumours analyzed, and
92% of these tumours showed cyclin D1 overexpres-
sion, as well as normal pRb expression levels [18]. In
contrast the tumours that did not show cyclin D1
amplification, did not appear to have pRb expression,
suggesting an inhibitory effect of pRb on cell cycle
progression can be abrogated during tumour develop-
ment either by loss of expression of the Rb gene or by
elevated expression of the Cyclin D1 gene [18]. View
Fig. 6.
2.2. Frat1
Is a proto-oncogene and it promotes carcinogenesis
through activation of the WNT–h-catenin–TCF sig-
nalling pathway [19]. It is known that overexpression
of Frat1 leads to the dissociation of GSK-3h from
Axin to inhibit h-catenin phosphorylation. Unphos-
phorylated h-catenin is not recognized by ubiquitin
ligase complex including hTRCP2, and is stabilized
and translocated to the nucleus. h-Catenin–TCF
complex activates transcription of WNT target genes,
such as c-Myc, WISP1, WISPf2, and cyclin D1. In
one study Frat1 expression was found to be relatively
high in human oesophageal cancer cell lines [19]. It is
therefore proposed that the up-regulation of Frat1
mRNA, not only in oesophageal cancer but several
other malignancies, might promote carcinogenesis
through the activation of the WNT–h-catenin–TCF
signalling pathway [19].
3. Tumour suppressor genes
Tumour suppressor genes are inactivated by
genetic or epigenetic changes such as point mutations,
deletions (LOH), promoter methylation, abnormal
splicing, deregulation of imprinting and haploinsuffi-
ciency [20].
LOH (loss of heterozygosity) causing inactivation
of most candidate tumour suppressor genes have been
found on the critical regions of chromosomes 1p, 3p,
4, 5q, 9, 11q, 13q, 17q, and 18q. Chromosome region
17q25.2–25.3 carries the autosomal dominant oeso-
phageal disorder, tylosis [2].
3.1. p53
p53 (a protein with molecular weight ~53 kDa) is a
tumour suppressor that halts progression in both the
G1 and G2 phase of the cell cycle to assess DNA
damage, view Fig. 4. If damage has occurred p53
determines whether damage can be repaired and if so,
triggers cell cycle arrest until the damage is repaired.
If damage is irreparable, they trigger apoptosis (see
Figs. 2 and 4). Cell cycle therefore results in either of
two processes, either to proceed to the next stage
(DNA synthesis or cell growth) or to induce apoptosis
(cell suicide). Mutations in these checkpoint genes
result in defective proteins and unsuccessful check-
points occur. Cells then complete mitosis but aberrant
daughter cells arise which leads to diseases where
uncontrolled cell growth occur, such as cancer.
Accumulation of p53 in the normal oesophagus,
suggested that the loss of suppressor function p53
might be an early event in carcinogenesis of the
oesophagus [2]. View Fig. 5.
Mutations in codons 175, 248, and 273 of p53 are
considered to have growth advantages to progress to
invasive squamous cell carcinoma and occur most
frequently [16], whereas codon 158, though consid-
ered as being highly sensitive to mutagenesis, does
not have the same carcinogenic transformation
properties [21].
Somatic alterations of p53 abolish its ability to
activate p21, Bax, and PIG3 reporter systems, thus
altering cell cycle control and apoptosis overall [22].
View Fig. 6.
It was determined that 85% of the p53 mutations in
oesophageal adenocarcinoma occurred as GCYAT
 M.L. McCabe, Z. Dlamini / International Immunopharmacology 5 (2005) 1113–1130 1119

Fig. 4. Role of p53 in cell cycle: mediator between cell growth and death. (i) During each checkpoint of the cell cycle, the cell cycle is arrested
for p53 (and other tumour suppressor genes) to check if DNA damage has occurred. If DNA damage has occurred p53 halts the cell cycle at the
checkpoint and signals appropriate proteins to repair damage. Once damage has been repaired, p53 signals cell to proceed to next phase of cell
cycle. (ii) If DNA damage is irreparable, p53 signals apoptotic inducing factors (AIF), like the Bcl-2 family, to induce apoptosis, rather than
proliferate and cause damage to the organism, e.g. cancer.

transitions, with 69% at the CpG dinucleotides [16].
GYA mutation pattern may have resulted from DNA
methylation induced by nitrosamine [23]. p53 mutated
oesophageal cancer is one of the malignancies that
have been recognized as a conventional chemo-
therapy-resistant disease [24].
3.2. Retinoblastoma (Rb)
Rb is a nuclear phosphoprotein that plays a role in
cell cycle regulation. Hypophosphorylated Rb in the
cell prevents cell progression when the cell is being
assessed, and upon phosphorylation the Rb protein
1120 M.L. McCabe, Z. Dlamini / International Immunopharmacology 5 (2005) 1113–1130
Fig. 5. Oesophageal cancer and mutant p53. Progression of oesophageal cancer is associated with an increase in mutant p53. It is believed that
mutation in p53 and Rb is the hallmark of oesophageal cancer, and these events are the initiation of an entire cascade of molecular events that
leads to the progression of this disease.
releases the E2F transcription factor that allows for the
expression of important cell-cycle control genes [25].
LOH of the Rb gene was found correlated with the
loss of pRb protein expression and associated with
p53 alterations in human oesophageal cancer [26]. It
is suggested that associated Rb and p53 inactivation
may be the major event in the development and
progression of oesophageal cancer, due to the greater
selective advantage of the affected cells. It is also
believed that other genes in the Rb and p53 pathways
contribute to the malignant transformation of the cells;
in the majority of cases an alteration of p16, p15, or
even both were shown to occur [26].
3.3. DLC1
DLC1 (deleted in lung cancer 1) is a putative
tumour suppressor gene identified by Daigo et al.
DCL1 is a commonly deleted region at 3p21.3 as
defined by LOH studies in lung cancer, and aberrant
splicing of this potential gene was found in a third of
oesophageal, lung, and renal cancers [27]. Normal
DCL1 cDNA was introduced into several cancer cell
lines and caused significant suppression of growth,
indicating that aberrant DCL1 transcripts may play a
critical role in the carcinogenesis of those tissues [27].
The encoding protein (M r 166) unfortunately has no
significant homology to known proteins and so
putative functional annotations could not be made. It
has been found though that DCL1 protein has 54
phosphorylation sites, 27 of which are casein kinase
(CSNK) II phosphorylation sites, and is localized in
the cytoplasm [27]. A ubiquitous, messenger-inde-
pendent serine/threonine kinase, CSNKII is localized
in both the cytoplasm and nucleus and functions as a
protease [28], and so it is supposed that DCL1 may
act as a downstream gene in the serine/threonine
kinase pathway [27].
3.4. p16INK4a and p15INK4b
These are tumour suppressor genes and are local-
ized to 9p21. This region has been shown to undergo
hemizygous or homozygous deletion in a variety of
tumour types [29]. These two genes encode two cyclin
dependent kinase (CDK) inhibitors which negatively
regulates the cell from G1-S phase in proliferating
cells, contributing to active pRb maintenance [30].
During the G1-S phase p16INK4a binds and inhibits
CDK4/6 activity [31], and p15INK4b binds to cyclin
D-dependent kinase and prevents p27 association. [32]
p27 then binds to E-CDK2 complex, blocking the cell
 M.L. McCabe, Z. Dlamini / International Immunopharmacology 5 (2005) 1113–1130 1121

Wild type p53 Mutant p53

in a normal oesophageal cell in a malignant oesophageal cell

wt
Mdm2 mt Mdm2

P
P21
P21
Survivin
Cyclin
D1 Cyclin
Cdk4 D1
Cdk4

P
pRb
E2F 1. 2. 3.

Survivin Cyclin D1 pRb

pRb Cdk4

E2F

G1 S
G1 S

M G2

M G2

Normal cell cycle progression Tumour development

Fig. 6. Wild type vs. mutant p53, and the effect it has on the cell cycle, GI/S phase. Wild type p53 activates p21 which in turn activates the
cyclin D1/cdk4 complex by hypophosphorylation. Activated cyclin D1/cdk4 then hypophosphorylates the pRb/E3F complex, causing the
release of E2F that translocates to the nucleus, leading to transcription of genes responsible for G1 progression the S phase and also progression
from G2 to M phase. Mutant p53 affects on cell cycle progression leads to abnormal cell growth, like cancer. Mutant p53 regulates p21 and
causes it to have negative regulatory affects on cyclins therefore resulting in negative affects on normal cell cycle progression. Once the mutant
p53 regulates p21, p21 interacts negatively with the cyclin/cdk4 complex. Overexpression of cyclin D1 is one result that occurs and has a
negative effect on the cell cycle, encouraging cell progression to S phase in oesophageal tumours. In contrast, the tumours that did not show
cyclin D1 amplification did not appear to have pRb expression, suggesting an inhibitory effect of pRb on cell cycle progression can be
abrogated during tumour development either by loss expression of the Rb gene or by elevated expression of the cyclin D1 gene. A protein found
to negatively regulate the cell cycle at the G2/M stage was Survivin, by interacting with CDK4 and displacing p21, and ultimately encouraging
tumour development. Furthermore, another protein found to negatively regulate the cell cycle, at the G2/M stage was Survivin. Survivin
interacts with CDK4 and displaces p21, and ultimately encourage tumour development.
1122 M.L. McCabe, Z. Dlamini / International Immunopharmacology 5 (2005) 1113–1130
cycle at the G1-S boundary, risking cells to abnormally
proliferate [32]. Aberrant methylation of p16INK4a
has been found to be a key feature in human carcino-
genesis and although aberrant methylation of
p15INK4b also occurs it is found to occur less fre-
quently in human oesophageal cancer in Lixian, China
[29]. A common feature of p15INK4b is homozygous
deletion, which also takes place in p16INK4a.
3.5. APC and MCC
APC is believed to be a tumour suppressor gene
[33], and like MCC it is located to chromosome 5q21
region. APC is mutated in adenomatous polyposis
(FAP) and like MCC again, it has been shown to play
a role in the pathogenesis of colorectal cancer and also
lung cancer [33,34]. It has been shown via linkage
analysis that LOH involving the APC and MCC
genetic loci occurs in the majority of human
oesophageal cancers and is involved in the develop-
ment and/or progression of the disease [35].
3.6. WWOX
The WWOX (WW domain containing oxireduc-
tase) gene was recently discovered as a candidate
tumour suppressor gene [36], at chromosomal region
16q23.3–24.1 [37]. It has been demonstrated in a
study carried out by Kuroki et al., that both alleles of
the WWOX gene are inactivated in squamous
carcinoma of the oesophagus, as a combination of
tumour-specific mutations and LOH of the WWOX
gene locus, which is also referred to as a two-hit
mechanism [38]. The WWOX enzymatic domain is
considered to be encoded mostly by the exon 6–8
regions of the gene and mutations in this region have
been found to occur in breast cancer [39], as well as in
oesophageal squamous carcinoma [40]. This data
suggests that WWOX could act as a tumour suppres-
sor in oesophageal squamous carcinoma.
4. Other apoptotic genes
4.1. Bcl-2 family
This family consists of at least 15 proteins with
either anti-apoptotic or pro-apoptotic function. Pro-
teins that have been found to be aberrantly expressed
within oesophageal cancer include the anti-apoptotic
proteins bcl-2 and bcl-xl (which are both up-regu-
lated) and pro-apoptotic protein bax (down-regulated)
[41]. View Fig. 7.
4.2. FAS
The non-functional Fas death receptor pathway is
believed to play a role in the development of
oesophageal cancer. A study showed increased Fas
protein expression during the progression of Barrett’s
metaplasia to adenocarcinoma [42], suggesting the
Fas receptor could be non-functional and therefore the
increase in the Fas ligand occurs. Aberrant Rb
proteins were also detected with the progression of
metaplasia to dysplasia, and since Rb plays a role in
the control of cell cycle regulation and Fas plays a role
in programmed cell death, another suggestion could
be an attempt by tumour cells to balance the
uncontrolled cell proliferation promoted by non-
functional Rb [42]. View Fig. 8.
4.3. Survivin
Survivin is a unique inhibitor of apoptotic proteins
(IAP), and is only expressed in foetal tissue and a
variety of human cancers, but almost undetectable in
most normal adult tissue [43]. Survivin inhibits
apoptosis by binding to microtubules of the mitotic
spindles [44] and ultimately inactivating caspase-3
and caspase-7 activity [45]. It has been shown that
increased expression of survivin can have a cancerous
effect on the cell as it surmounts the G2/M phase
checkpoint proceeding into mitosis and it has been
proposed that survivin is only present in the G2/M
phase [44]. Rodriguez et al also discovered that
survivin encouraged cell proliferation by interacting
with CDK4 and displacing p21 (view Fig. 6). The
nuclear survivin expression in Oesophageal squamous
carcinoma tissue was examined and found to correlate
with poor prognosis, but it seems that localization of
survivin expression is critical for activity in tumour
cells and its negative effect in dysregulating cell cycle
definitely plays a role in tumour progression [46]. It is
clear that survivin expression could be used as a
diagnostic tool, and possibly a therapeutic strategy, in
the near future.
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Fig. 7. Aberrant Bax, Bcl-2 and Bcl-xl expression in oesophageal cancer cells. Down regulation of Bax has been found to inhibit apoptosis and
lead to the development of tumours in oesophageal cancer. Bcl-2 and Bcl-xl overexpression has also been established to prevent the release of
cytochrome c from the mitochondria and therefore prevent apoptosis, leading to tumour development.

4.4. DcR3/M68 suggested that DcR3 overexpression precedes gene

A secreted decoy receptor (DcR3), member of the
tumour necrosis factor (TNF) receptor superfamily,
was found to be a negative regulator of Fas-mediated
apoptosis by binding to Fas ligand, FasL [47]. DcR3
shows overexpression in a variety of cancers includ-
ing gastrointestinal tract tumours, and it is believed
the blockade of FasL-induced cell death allows
tumour cell growth [48]. It seems that DcR3 over-
expression occurs without gene amplification, but it is
amplification in tumours [48].
4.5. E2F-1
Overexpression of E2F-1 has been shown to
induce apoptosis in several cancer cell types. Yang
et al. studied the effect of adenovirus-mediated E2F-1
overexpression on human oesophageal cancer cell
lines, Yes-4 and Yes-6. Overexpression of E2F-1
resulted in cell growth inhibition due to apoptosis
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Fig. 8. Fas expression in oesophageal cancer. Increased Fas expression is a characteristic of oesophageal cancer progression and is associated
with aberrant Rb expression. It is speculated that increased Fas expression in BAAC represents an attempt by tumour cells to balance the
uncontrolled cell proliferation promoted by non-functional Rb (Coppola et al., 1999).

induction in the Yes-4 cell lines, but the Yes-6 cells
were more resistant to E2F-1 overexpression. The
resistance of Yes-6 cells to E2F-1 is believed to be
caused by differential expression of cell death
inhibitory proteins of the Bcl-2 family. These proteins
include Bcl-2, Mcl-1, and Bcl-xl, which decreased
after 48 h in the Yes-4 cells, but remained unchanged
in Yes-6 cells. Restinoblastoma gene product (pRB)
also declined after 48 h in Yes-4 cells and remained
constant in theYes-6 cells. It is suggested that pRb
inhibits apoptosis, as it binds to E2F-1 and negatively
regulates its transactivation function [49]. The cas-
pases involved in the E2F-1 mediated pathway of
apoptosis in the Yes-4 cells were demonstrated by
caspase-3 and caspase-6, which cleaved caspase3/
CPP32 and poly-ADP-ribose polymerase (PARP), as
well as fragmentation of the caspase-6 substrate,
lamin B. p53 does not seem to play a role in this
E2F-1 apoptosis mediated pathway [50]. These
findings suggest E2F-1 mediated apoptosis may be
 M.L. McCabe, Z. Dlamini / International Immunopharmacology 5 (2005) 1113–1130
related to differential expression of Bcl-2 family
member proteins and suggest this therapy may be a
promising treatment strategy for the treatment of this
disease [50].
4.6. Metallothionein (MT)
Metallothionein is a thiol-rich protein that plays a
major role in detoxification of toxic metals and in
protection against oxidative damage [51].
Li et al. studied the relationship of MT and
apoptosis in the progression from metaplasia to
dysplasia to adenocarcinoma in subjects with BE. It
was found that tissue with high activity of apoptosis
had high expression of MT and vice versa. It is
believed that MT may contribute to cytoprotection,
thereby inhibiting apoptosis and increasing the like-
lihood of BE to progress toward adenocarcinomas. It
is hypothesised that MT might act as a zinc donor in
favour of tumour proliferation or it is induced by the
rapid growth of the tumour [52]. The exact mecha-
nism of MT in the metaplasia–dysplasia–adenocarci-
noma sequence has to be clarified.
4.7. Matrix metalloproteinase-7 (matrilysin/MMP-7)
Matrix metalloproteinase-7 has been implicated in
tumour initiation, growth [53], invasion [54], and
metastasis [55]. Matrilysin is a member of the MMP
family and it has wide variety substrate specificity, and
potency to start an activation cascade of MMPs [56].
MMP-7 was found overexpressed in a variety of cancer
tissues, including oesophageal cancer tissue. MMP-7
was also found to be susceptible to direct therapeutic
intervention. Administration of synthetic MMP in-
hibitor batimastat to Min mice suppressed tumour
multiplicity [57], and antisense technology also dem-
onstrated a suppression of invasive and metastatic
phenotype in in vitro and in vivo studies, respectively
[58]. MMP-7 was found to be up-regulated by the
organism Helicobacter pylori in epithelial cells in vivo
and in vitro, in a Cag dependent manner and considered
to contribute to carcinogenesis [59].
4.8. PCNA
Proliferating cell nuclear antigen (PCNA) expres-
sion increases gradually in cell nuclei with the
1125
progress of G1 phase and reach a peak when entering
the S phase [60]. In a study, foetal oesophageal
epithelia showed a much higher expression pattern
compared to normal adult oesophageal epithelia and
basal cell hyperplasia (BCH), and a much higher
expression pattern was observed in malignant adult
oesophageal tissue compared to foetal oesophageal
epithelia [60]. It was found that PCNA acts as a good
marker for cell proliferation [61].
Another study showed that p53 and PCNA are
already overexpressed to different extents in normal
epithelia and also precancerous lesions of the oeso-
phagus, but an increase in expression is observed with
progressive cancer stages [62].
It was suggested that since PCNA has been found
to play a role in DNA damage repair, it could combine
with hMSH6 and hMSH3, the subunits of hMutSul-
pha and hMutSbeta that act as cofactors in a DNA
mismatch repair system [60]. Malignant tissue is
characterized by high frequencies of DNA mismatch,
breakages, and mutations, and therefore the increase
in PCNA expression is thought to occur as a repair
response [60].
5. Other genes believed to play a role in the
development of oesophageal cancer
5.1. FEZ1
Fez1 was identified via genomic analysis of
chromosome 8p22 in oesophageal cancer, due to the
loss of this region in oesophageal cancer as well as
many other types of cancers [63]. It was found that
Fez1 encodes a leucine-zipper protein. Fez 1
expression was found almost ubiquitously expressed
in normal cells, but undetected in most of the
oesophageal cancer cells [64]. Three point muta-
tions were detected in Fez1 from oesophageal as
well as prostate cancer cell lines. E44 alteration
from TTCYCCC at codon 29, results in the
substitution of SerYPro, which is a predicted
cAMP-dependent kinase phosphorylation site [64].
Second mutation, an E50 alteration of AAG/
LysYGAG/Glu at codon 119 was found, resulting
in the allelic loss of the marker D8S261 [70]. The
third mutation change of CAG/GlnYTAG/Stop at
codon 501 in prostate cancer resulted in coding a
1126 M.L. McCabe, Z. Dlamini / International Immunopharmacology 5 (2005) 1113–1130
putative 166-aa protein lacking the C terminus [64].
This data suggests the major mechanism for Fez1
inactivation is a btwo-hitQ mechanism, allelic loss
and point mutations, and possibly, allele loss plus
failure in transcription [64].
5.2. FzE3
FzE3 is a frizzled gene that forms part of the
Frizzled family of seven-transmembrane proteins that
acts as receptors for Wnt signalling [65]. The protein
contains cystein-rich residues in its extracellular N
terminal region to which the Wnt proteins bind [66].
FzE3 was found specifically expressed in oesopha-
geal tumour tissue compared with normal mucosa
and is believed to alter the function of the tumour
suppressor gene, adenomatous polyposis coli (APC)
[67]. It has been shown that in normal cells, wild-
type adenomatous polyposis coli APC protein bound
to the serine–threonine glycogen synthase kinase
(GSK)-3h binds to h-catenin within the cytoplasm,
resulting in APC degradation [68]. In colon cancer
cells, mutated APC was found stabilizing h-catenin
to form a complex with transcription factors, Lef
(lymphoid enhancer binding factor) and Tcf (T cell
specific transcription factor), which then translocates
to the nucleus where up-regulation of cell prolifer-
ation genes occur.
In oesophageal tumour tissue wild-type APC was
found, so it has been suggested that the presence of
FzE3 acts as a negative regulator of APC function,
allowing h-catenin signal transmission to up-regulate
cell proliferation associated genes [67].
5.3. ODC
Ornithine decarboxylase (ODC) has been found to
play a critical role in the biosynthesis of polyamines
[69], which are important in cell proliferation [70].
Yoshida et al. and Mafune et al. demonstrated ODC
overexpression in oesophageal carcinomas. It has
been shown that overexpressed ODC cannot cause
tumour progression but increases the formation of
polyamines in premalignant cells [71]. It is believed
that the constant overexpression of ODC mRNA in
oesophageal tumours, especially in OeSc, may be
evidence that ODC play a critical role in the
tumourigenesis of the oesophagus [72].
5.4. Annexin 1
It has recently been discovered by Liu et al. that the
protein Annexin 1 translocated from the plasma
membrane in normal cells to the nuclear membrane
in malignant cells. It was found that Annexin 1
usually formed a consecutive typical trammel net on
the plasma membrane of normal oesophageal epithe-
lia, but in oesophageal cancer a great decrease was
found on the cellular membrane and was highly
expressed on the nuclear membrane, which was never
found on normal oesophageal epithelia [73]. This data
suggests that Annexin 1 translocation may correlate
with the tumourigenesis of oesophageal cancer [73].
5.5. Cathepsin B (CTSB)
Is a cysteine protease that also maps to chomosome
8p22 [74] and has been found overexpressed or
altered in certain tumours of the lung, breast, stomach,
colon and prostate [75]. CTSB was found amplified
and over expressed in oesophageal adenocarcinoma,
showing genomic alteration involving CTSB [76].
Extracellular expression of CTSB protein correlated
with the identification of higher M r forms in tumours
was also found [77]. It is therefore believed that
CTSB plays a critical role in tumour progression or
malignant transformation of oesophageal adenocarci-
noma, and even other types of malignancies [77].
5.6. GASC1
Gene amplified in squamous cell carcinoma 1
(GASC1) was found to be amplified and overex-
pressed in several OeSc cell lines. The GASC1 locus is
found on chromosome 9p23–24. It is found that GASC
contains one PX domain and two PHD fingers. PHD-
finger motifs are found in nuclear proteins that
participate in chromatin-mediated transcriptional reg-
ulation and are present in a number of proto-oncogenes
[77]. It is assumed that GASC1 may be involved in the
carcinogenesis or progression of multiple tumours,
even though its function is not clear [77].
5.7. ECRG4
Oesophageal cancer related gene 4 (ECRG4) is a
novel oesophageal cancer related gene and found to
 M.L. McCabe, Z. Dlamini / International Immunopharmacology 5 (2005) 1113–1130
be down-regulated in OeSc compared to normal
oesophageal tissues. It is located on chromosome
2q14.1–14.3 and it contains 4 exons. ECRG4 down-
regulation is believed to play a role in the develop-
ment of OeSc and the mechanism inactivating it has
been demonstrated to be aberrant methylation of CpG
islands in the core promoter of the ECRG4 gene [78].
6. Angiogenesis
Angiogenesis is the development of new blood
vessels, which provide blood and nutrient supply to
tumours to survive. Once the tumour is stable, it can
then invade neighbouring cells leading to metastasis.
In oesophageal cancer cells the increased expres-
sion of vascular endothelial growth factors (VEGFs)
stimulates endothelial proliferation and migration.
Increased expression of VEGFs and VEGFRs (recep-
tors) were detected in metaplastic tissues of the lower
oesophagus but not in normal oesophageal epithelium,
indicating sustained neovascular development early in
Barrett’s carcinogenesis [25].
7. Invasion and metastasis
Invasion and metastasis of oesophageal cancer is
poorly understood. The cell–cell adhesion molecules
(CAMs) hold cells together, and believed to play an
important role in metastasis of the cancer cell [25].
h-Catenin has been found to play a role in
squamous oesophageal cancer cells, by its cell–cell
adhesion function and interactions with the cytoske-
leton and cadherin junctions of cells. h-Catenin has
been implicated in the transcription of oncogenes such
as c-myc, c-jun and cyclin D1, which are oncogenes
frequently active in oesophageal cancer cells.
The APC gene product targets h-catenin for degra-
dation and prevents h-catenin dependent degradation.
Increased h-catenin dependent transcription due to h-
catenin binding to Fz receptors, mutations in h-catenin,
APC, and increased h-catenin expression due to Fz
receptor mutations, have all been found in adenocarci-
nomas and squamous oesophageal carcinomas [67].
It is therefore believed that down-regulation of h-
catenin expression by antisense technology could be
an effective treatment for oesophageal cancer [79].
1127
8. Potential therapeutic strategies in oesophageal
cancer
The management of oesophageal cancer manage-
ment to date remains an unsolved health problem. All
over the world diagnostic markers and therapeutic
analyses are carried out to generate a solution to this
problem. It is believed that the cure to cancer would
be a two directional method, one including chemo-
therapy or radiation, and a key drug that targets a
specific molecule present only in the cancer cells and
has a low or no toxicity effect on the normal
surrounding cells.
Apoptosis inducing nucleosides (AINs) from
CD57+HLA-DRbright-natural suppressor (57.DR-NS)
cell lines were used to induce apoptosis in human
oesophageal cancer cells. This study revealed that
AINs induce apoptosis in oesophageal cancer cells
through DNA strand breaks and caspase-3 activation
[80]. Further research is currently carried out to
develop an ideal anticancer agent, since apoptosis
generated in malignant cells lacked toxicity in normal
cells, suggesting a possible evasion from side effects
in clinical trials [81].
An antagonist to the anti-apoptotic gene, Survivin,
is a promising therapeutic strategy not only for
oesophageal cancer but various other types of cancers
where Survivin is highly expressed. It is believed that
antagonists to Survivin would increase the effective-
ness of chemotherapy by removing the protective role
of Survivin on the cancer cell [82].
Other drugs of interest would be those targeting
angiogenesis. Anti-angiogenesis drugs developed to
inhibit blood and nutrient supply to the tumour cells is
a potential therapeutic strategy as well. Researchers
are currently working on the development of antag-
onists to two angiogenesis molecules angiostatin and
endostatin, and there is great hope that these drugs in
combination with radiation or chemotherapy could be
the cure to cancer [83].
9. Concluding remarks
Oesophageal cancer is a disease that urgently
needs a consistent diagnostic tool for early
diagnosis, and also an effective therapeutic strategy
that ensures non-recurrence, best quality of life and
1128 M.L. McCabe, Z. Dlamini / International Immunopharmacology 5 (2005) 1113–1130
an increased lifespan. Many genes have been found
that are believed to play a role in the development
of oesophageal cancer but the underlying mecha-
nism by which this disease develops is still not
clear. A few genes with significant correlation to
this disease have been found, and are currently
being analyzed as potential candidates for deter-
mining prognosis and therapeutic strategies. A
human oesophageal tumour model would be of
interest, as it would help other researchers to focus
on the genes of interest, and diagnostic and
therapeutic tools could be developed at a much
quicker rate.
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