ErbB-2 and COX-2 as Potential Molecular Targets in Cholangiocarcinoma
Alphonse E. Sirica
Virginia Commonwealth University
Supported by National Institutes of Health Grants R01 CA 39225 and
R01 CA 83650 to A.E.S.
Cholangiocarcinoma (ChC) is the collective term used to describe cancers arising within the intra- and
extrahepatic biliary tract. More than 90% of ChCs are adenocarcinomas, with different histological
variants being recognized. ChCs are further classified according to grade as being well, moderately, or
poorly differentiated, with the classic diagnosis being well to moderately differentiated ductal
adenocarcinoma. Desmoplastic reaction of variable degrees is also a common feature of ChC. While ChCs
can occur anywhere within the biliary tract, approximately 40 to 70% occur at the liver hilum at or in
close proximity to the bifurcation of the right and left hepatic ducts, whereas 5 to 20% of ChCs develop
within liver . The term peripheral ChC is used to describe ChC originating within liver, typically as a
solitary or multifocal mass, whereas those tumors originating at the liver hilum are known as hilar,
perihilar, or Klaskin tumors.
Macroscopically, intrahepatic ChCs have been further classified as being either:
with the most commonly encountered
types being the desmoplastic infiltrating nodular or diffusely infiltrating varieties
are typically observed as being sclerosing ductal adenocarcinomas]. The intraductal growth type is the
least common and characterized predominantly by intraductal growth with little or no extension beyond the
bile duct walls. In comparison, ChCs with a highly infiltrative growth pattern exhibit lymphatic and
intrahepatic metastases. Hilar-invasive-type ChCs have been observed to exhibit perineural invasion and
nodal involvement more frequently than do peripheral-type tumors. Intraductal papillary neoplasm of the
liver exhibiting frequent gastroenteric metaplasia, overproduction of mucin, and progression to
intrahepatic mucinous adenocarcinoma has also recently been characterized as forming a spectrum of
biliary neoplasms occasionally associated with hepatolithiasis, and which closely resemble intraductal
papillary mucinous neoplasm of the pancreas.
- mass-forming type
- periductal infiltrating type
- intraductal growth type
Currently, between two and three thousand new cases of ChC occur annually in the USA, and recent
epidemiological studies have called attention to the apparent fact that that devastatingly lethal cancer
has over the past two to three decades been increasing worldwide in both incidence and mortality ,
although the cause of these increases remains unclear. Furthermore, the challenges posed by ChC to
clinicians and researchers continue to be daunting, due in large part to high morbidity and mortality
rates, and the fact that early diagnosis of ChC is difficult, with the majority of patients presenting
with advanced disease.
Clinically, treatment options for ChC are limited, and conventional chemotherapy and radiation therapy
have to date been notably ineffective in improving long-term survival. Presently, the only hope for
long-term survival is complete resection of the tumor. Unfortunately, the vast majority of patients
(i.e., 70-90%) presenting with ChC are not good candidates for curative surgery, and in those that have
undergone complete surgical resection, the recurrence rate remains quite high . Patients with
unresectable ChC have a survival that is generally less than 12 months after diagnosis. In comparison,
the five year survival rates of patients in selected series that have undergone curative resection have
ranged from 0% to ~ 40%, with 5-year survival rates following resection for ChC complicating primary
sclerosing cholangitis (PSC) found to be less than 10%. Photodynamic therapy (PDT) has recently been
shown to have a promising effect on improving palliation and survival in patients with unresectable hilar
ChC. However, PDT is not curative and further trials are needed to fully assess its effectiveness in
combination with biliary stenting as a neoadjuvant therapy for ChC. Lastly, liver transplantation is not
generally indicated for ChC, due in large part to the high tumor recurrence rates, although a small
selected group of patients with early staged disease have benefited from this procedure.
Based on the fact that ChC remains for the most part a fatal disease with limited treatment options
for prolonged survival, together with the fact that this lethal cancer is being encountered more
frequently in clinical practice, there is now a real and urgent need to focus on developing novel
chemoprevention and therapeutic strategies aimed at exploiting select molecular targets aberrantly
expressed during cholangiocarcinogenesis that would hopefully impact in a significant way on clinical
ErbB-2 and COX-2 as Potential Molecular Therapeutic Targets in ChC
A strong positive correlation has recently been reported between increased plasma membrane ErbB-2
immunostaining intensity and COX-2 immunoreactivity in archival human surgical specimens of ChC of
Japanese, Thai, and USA origin and related risk conditions (hepatolithiasis and PSC) compared with normal
adult liver. Interestingly, ErbB-2 and COX-2 immunoreactivities were found to be highest in well
differentiated ChCs and in the large bile ducts of PSC and hepatolithiasis cases, consistent with the
view that ErbB-2 overexpression and COX-2 up-regulation may herald a critical early carcinogenic event in
the human hepatobiliary tract. The relationship between ErbB-2 and COX-2 in cholangiocarcinogenesis is
further highlighted by the fact that COX-2 mRNA and protein have been shown to be coordinately
up-regulated in furan-induced rat ChCs and in a furan tumor-derived ChC cell line (C611B ) constitutively
overexpressing tyrosine phosphorylated ErbB-2. In addition, constitutive ErbB-2 signaling has been
implicated in the up-regulation of COX-2 in gallbladder epithelium and tumors from transgenic mice
overexpressing wild type rat c-erbB-2 under the control of the bovine keratin 5 promoter. More recently, COX-2 was found to be induced in
malignant cell transformants of an adult rat cholangiocyte cell line, designated BDE1, following
retroviral infection of BDE1 cells in vitro with the rat erbB-2 oncogene.
The selective COX-2 inhibitor celecoxib has recently been reported to induce apoptosis in cultured
human and rat ChC cells by a mechanism involving suppression of serine/threonine kinase Akt/PKB (Akt)
phosphorylation. Celecoxib was also found to produce a modest but significant inhibition of the tumorous
growth of rat C611B ChC cells implanted subcutaneously into syngeneic rats. In addition, emodin, an
ErbB-2 inhibitor, has been shown to elicit significant dose-dependent growth inhibition correlated with
increased apoptosis in cultures of rat C611B ChC cells overexpressing ErbB-2. Moreover, of particular
emodin in combination with celecoxib acted synergistically to significantly suppress
anchorage-dependent and -independent growth of C611B ChC cells through a mechanism involving enhanced Akt
inactivation and increased activation of caspase-9/-3-mediated apoptosis . Similarly, a dual EGFR/ErbB-2
inhibitor acted synergistically with celecoxib to suppress the growth of cultured
HuCCT1 ChC cells.
Preclinical experimental animal experiments are now being conducted to test the effectiveness of
select molecular therapeutic and chemopreventive strategies aimed at targeting ErbB family receptor
tyrosine kinase receptors alone and in combination with select COX-2 inhibitors as potentially useful
adjuvant treatments for ChC. There is no doubt that selective molecular targeting, such as that which
may be obtained with select small drug inhibitors, antiisense vectors, small interfering RNA therapeutics
against animal models of ChC that recapitulate important cellular and molecular features of the human
disease will provide a challenging, but hopefully useful approach for realistically predicting if such
novel treatments can be translated into clinical therapies against a cancer for which there is currently
only limited treatment options.
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