Connective Tissue Growth Factor
Immunohistochemical Expression Is Associated
With Gallbladder Cancer Progression
Patricia Garcia, MSc, PhD; Pamela Leal, DSc; Hector Alvarez, MD, PhD; Priscilla Brebi, DSc; Carmen Ili, MSc, PhD;
Oscar Tapia, MD; Juan C. Roa, MD
? Context.—Gallbladder cancer (GBC) is an aggressive
neoplasia associated with late diagnosis, unsatisfactory
treatment, and poor prognosis. Molecular mechanisms
involved in GBC pathogenesis remain poorly understood.
Connective tissue growth factor (CTGF) is thought to play
a role in the pathologic processes and is overexpressed in
several human cancers, including GBC. No information is
available about CTGF expression in early stages of
Objective.—To evaluate the expression level of CTGF in
benign and malignant lesions of gallbladder and its
correlation with clinicopathologic features and GBC
Design.—Connective tissue growth factor protein was
examined by immunohistochemistry on tissue microarrays
containing tissue samples of chronic cholecystitis (n = 51),
dysplasia (n = 15), and GBC (n = 169). The samples were
scored according to intensity of staining as low/absent and
high CTGF expressers. Statistical analysis was performed
using the v2test or Fisher exact probability test with a
significance level of P , .05. Survival analysis was assessed
by the Kaplan-Meier method and the log-rank test.
Results.—Connective tissue growth factor expression
showed a progressive increase from chronic cholecystitis
to dysplasia and then to early and advanced carcinoma.
Immunohistochemical expression (score ?2) was signifi-
cantly higher in advanced tumors, in comparison with
chronic cholecystitis (P , .001) and dysplasia (P = .03).
High levels of CTGF expression correlated with better
survival (P = .04).
Conclusions.—Our results suggest a role for CTGF in
GBC progression and a positive association with better
prognosis. In addition, they underscore the importance of
considering the involvement of inflammation on GBC
(Arch Pathol Lab Med. 2013;137:245–250; doi: 10.5858/
ment, and poor prognosis.1It is characterized by a wide
geographic distribution, and Chile is one of the countries
with the highest GBC mortality rates in the world.2
Gallbladder cancer is often discovered incidentally during
or after a cholecystectomy, when tumors are unfortunately
at an advanced stage. At present, early stage tumors are
often curable with a proper resection, whereas advanced
GBC requires additional treatment with adjuvant therapy;
however, only surgery offers any benefit in terms of survival
allbladder cancer (GBC) is an aggressive neoplasia
associated with late diagnosis, unsatisfactory treat-
Among the traditional prognostic factors in GBC, the
stage of the disease at diagnosis is the most important,
followed by histologic grade, depth of wall infiltration, and
lymph node metastases.6In addition, a large number of
molecular alterations with clinical significance have been
proposed as potential prognostic markers, including aber-
rant expression of proteins associated with tumor progres-
sion, invasion, and metastases.7–9The screening of these
alterations in normal epithelium and in benign and
malignant gallbladder lesions could help to understand
the molecular mechanisms involved in gallbladder carcino-
genesis and to identify potential markers for early detection
of the neoplastic process.
Connective tissue growth factor (CTGF), also known as
CCN2, is a member of the CCN family. All CCN family
members are secreted proteins associated with the extra-
cellular matrix, and they are involved in normal processes
such as implantation, placentation, embryogenesis, differ-
entiation, and development, as well as in pathologic
processes including wound healing, fibrotic disorders, and
tumorigenesis.10Connective tissue growth factor plays an
important role in tumor development and cancer progres-
sion, and it is found to be expressed in different types of
cancer.11The functional implications of CTGF overexpres-
sion in the biological behavior of cancer cells depend on the
Accepted for publication April 19, 2012.
From the Department of Pathology, School of Medicine, CEGIN-
BIOREN, Universidad de La Frontera, Temuco, Chile (Drs Garcia,
Leal, Brebi, Ili, Tapia, and Roa); the Department of Pathology, Johns
Hopkins University School of Medicine, Baltimore, Maryland (Dr
Alvarez); and the Department of Pathology, School of Medicine,
Pontificia Universidad Catolica de Chile (Drs Garcia and Roa).
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Juan C. Roa, MD, Department of Pathology, School of
Medicine, Universidad de La Frontera, PO Box 54-D, Temuco,
Araucania 4781186, Chile (e-mail: firstname.lastname@example.org).
Arch Pathol Lab Med—Vol. 137, February 2013CTGF Expression and Gallbladder Cancer Progression––Garcia et al 245
tumor origin. For example, high CTGF levels have been
associated with tumor growth and adverse prognosis in
pancreatic cancer12and gastric cancer.13,14Conversely,
CTGF overexpression is associated with metastasis inhibi-
tion and is a favorable prognostic marker in colorectal
cancers15and lung cancers.16,17
In GBC, immunohistochemical expression of CTGF in
surgical specimens has shown that advanced cancers with
high CTGF expression have a favorable prognosis.18A better
understanding of the role of CTGF in GBC pathogenesis
starts by studying the expression of this protein in early
stages, including inflammatory and precursor lesions
(chronic cholecystitis and dysplasia). Therefore, in the
present study we examined by immunohistochemistry the
expression of CTGF in benign and malignant gallbladder
lesions in order to analyze its possible involvement in
malignant progression. Additionally, we evaluated whether
CTGF expression is associated with clinicopathologic
parameters and prognosis in GBC.
MATERIALS AND METHODS
Patients and Tissue Samples
A total of 235 gallbladder lesions from patients who underwent
cholecystectomy between 1987 and 2006 were selected. The
formalin-fixed, paraffin-embedded tissues were retrieved from
the surgical pathology archives at Herna ´n Henr´ ıquez Aravena
Hospital, Temuco, Chile. These samples included 51 chronic
cholecystitis samples, 15 dysplasias (10 low-grade and 5 high-
grade dysplasias) and 169 adenocarcinomas grouped into 32 early
cancers and 137 advanced carcinoma according to T stage
(infiltration level): mucosal (pT1a), muscular (pT1b), subserous
(pT2) and serous (pT3). According to the TNM staging system for
GBC (AJCC Cancer Staging Manual, 7th edition),19the adenocar-
cinomas were grouped as stage I (32 cases), stage II (81 cases),
stage IIIA and IIIB (24 cases), and stage IVA and IVB (32 cases). The
clinicopathologic features were obtained from medical records.
Complete postoperative follow-up was available for 121 of 137
patients with advanced GBC. This study was approved by the ethics
committee of the Universidad de La Frontera, Temuco, Chile.
Tissue microarrays were constructed with 2-mm cores of 3
different representative areas of each case. Unstained 4-lm-thick
sections were cut from each tissue microarray and then dewaxed in
xylene, rehydrated through graded concentrations of ethanol, and
placed in an antigen retrieval solution (citrate buffer, pH 6.0) for 15
minutes at 958C. After cooling for 30 minutes, the tissue sections
were quenched with 3% hydrogen peroxide for 10 minutes to block
endogenous peroxidase activity. The slides were then washed
thoroughly with phosphate-buffered saline and stained for 120
minutes at room temperature with goat polyclonal anti-CTGF
antibody using a 1:100 dilution (clone L-20; Santa Cruz Biotech-
nology Inc, Santa Cruz, California). Labeling was detected with the
Liquid DAB Substrate-Chromogen System (Dako North America
Inc, Carpinteria, California) according to the manufacturer’s
protocol. Sections were counterstained with hematoxylin, then
dehydrated, cleared, and mounted. Negative control was prepared
by replacing the primary antibody with phosphate-buffered saline.
Evaluation of CTGF Immunostaining
Connective tissue growth factor is expressed in the cytoplasmic
compartment with membranous accentuation. Based on intensity
advanced gallbladder cancer (pT2). C, Strong staining in dysplasia. D, Strong staining in advanced gallbladder cancer (pT3) (immunohistochemistry,
original magnifications ·100 [B] and ·400 [A, C, D]).
Immunostaining of connective tissue growth factor in gallbladder tissues. A, Weak staining in early cancer (pT1a). B, Moderate staining in
246Arch Pathol Lab Med—Vol 137, February 2013CTGF Expression and Gallbladder Cancer Progression––Garcia et al
of labeling, a semiquantitative scale of 0–3 was used to score the
reactivity of the samples (0, absent; 1, weak; 2, moderate; 3, strong),
using a method that had been validated earlier.18Subsequently, the
235 samples were arbitrarily classified as absent/low CTGF
expressers (score 0 and 1) or high CTGF expressers (score 2 and
3). The evaluation of the immunohistochemical staining was
independently performed by 2 pathologists without knowledge of
The analyses were performed using the statistical package SPSS
version 17.0 (SPSS Inc, Chicago, Illinois). A comparison of the
background data was made between the low-CTGF and the high-
CTGF groups. The correlation of CTGF expression with the clinical
and pathologic variables was assessed using the v2test or Fisher
exact probability test (2-sided). Kaplan-Meier survival curves were
plotted for patients with high versus low CTGF expression and
compared using a stratified log-rank test. The stratification factor
was the infiltration level, because this covariate has been
recognized as a strong predictor of survival in patients with
advanced GBC.6,20The level of significance was set at P , .05.
showed a distinctive labeling in the cytoplasm and
membrane of nonneoplastic and neoplastic epithelial cells.
Examples of staining intensity are illustrated in Figure 1, A
through D. In only 16 of 235 cases (1 early cancer and 15
advanced carcinomas) did the tumor cells show complete
absence of staining; these were classified as CTGF low
expressers. Of the 51 chronic cholecystitis analyzed, 49
(96%) had low CTGF expression, whereas only 2 (4%)
showed high CTGF levels. In dysplasia, low and high
expression levels of CTGF were 73% (11 of 15) and 27% (4
of 15), respectively. According to the degree of dysplasia, a
high CTGF expression was observed in 30% (3 of 10) of the
cases with low-grade dysplasia and in 20% (1 of 5) of the
cases with high-grade dysplasia.
The incidence of high CTGF expression among the
adenocarcinomas was 44% (14 of 32) in early cancers, and
56% (76 of 137) in advanced carcinomas (Figure 2). As
shown in Table 1, the level of CTGF was significantly higher
in gallbladder adenocarcinomas than in either dysplasia
tissues (P = .03) or chronic cholecystitis (P , .001). No
statistically significant differences were found in CTGF
levels between sequential lesions (chronic cholecystitis to
dysplasia; dysplasia to early cancer).
The relationship between CTGF expression and each
clinicopathologic factor was analyzed for each gallbladder
lesion. Consistent with previous study,18no significant
correlation was found between the level of CTGF and
patients’ age, sex, ethnic group, or tumor differentiation
Clinical outcome was analyzed in 121 patients with
advanced GBC (excluding 16 patients who died before 30
days postsurgery). The observation time ranged from 1 to
243 months, with a median time of 13 months. The
relationship between CTGF expression and patient survival
at 5 years postsurgery was examined by Kaplan-Meier
analysis. The entire group (n = 121) had an estimated 5-year
survival rate of 31% with a median survival of 17.1 months.
Patients with absent/low CTGF labeling (n = 50) had a 5-
year survival rate of 22% with a median survival of 14.8
months, whereas patients with high CTGF labeling (n = 71)
had a 5-year survival rate of 37% with a median survival of
18.1 months. According to a predetermined criterion
(stratified log-rank test), survival distributions were statis-
tically significant between groups and high CTGF expres-
sion was associated with better patient outcomes (P = .04)
factor expression in sequential gallbladder lesions. Ad-GBC, advanced
cancer; CC, chronic cholecystitis; DYS, dysplasia; E-GBC, early cancer.
Frequency distribution for high connective tissue growth
advanced gallbladder carcinoma. The solid line indicates patients
whose tumors express high levels of connective tissue growth factor
(CTGF) and the dotted line indicates patients with low CTGF expression
(P =.04; stratified log-rank test).
Five-year survival curves (Kaplan-Meier) for patients with
Expression in Benign and Malignant Lesions
Connective Tissue Growth Factor (TGF)
Abbreviation: GBC, gallbladder cancer.
aCompared with advanced GBC.
Arch Pathol Lab Med—Vol. 137, February 2013CTGF Expression and Gallbladder Cancer Progression––Garcia et al247
The relevance of 5-year survival and other clinicopatho-
logic characteristics were also assessed by Kaplan-Meier
analysis, which showed that serosal infiltration (pT3) was
significantly associated with poorer survival of patients with
advanced GBC (P , .001), whereas age, sex, ethnicity,
tumor differentiation grade, and TNM staging did not
account for poor prognosis (Table 3).
In the present study we evaluated the expression of CTGF
in the epithelial component of benign (chronic cholecysti-
tis), premalignant (dysplasia), and malignant gallbladder
lesions (early and advanced carcinoma). We found that
CTGF is overexpressed with significantly higher frequency
in advanced tumors, showing a progressive increase from
chronic cholecystitis to dysplasia and then to early and
advanced carcinoma. Furthermore, in accordance with the
work of Alvarez et al,18Kaplan-Meier analysis showed that
overexpression of CTGF was significantly associated with
better survival of patients with advanced GBC.
Several lines of evidence support a role for CTGF in
fibrotic disorders and tumorigenic processes. In fact, it has
been documented that CTGF and the other members of the
CCN family are aberrantly expressed in cancer and that they
are linked with either promotion or inhibition of the
pathologic processes.21,22This seemingly contradictory role
Table 2. Association Between CTGF Expression (Low/High) and Clinicopathologic Parameters
Chronic Cholecystitis (n = 51) Dysplasia (n = 15) Early Cancer (n = 32)Advanced Cancer (n = 137)
. . .
. . ..47b
Abbreviation: CTGF, connective tissue growth factor.
aFisher exact test.
Table 3. Five-Year Survival Analysis According to Clinicopathologic Factors
VariableCases (n = 121)Events (n = 83) 5-y Survival Rate, %Median Survival, mo
III þ IV
Abbreviation: CTGF, connective tissue growth factor.
248Arch Pathol Lab Med—Vol 137, February 2013CTGF Expression and Gallbladder Cancer Progression––Garcia et al
of CTGF in human malignancies appears to depend on the
tissue involved. It has been reported that high CTGF
expression is associated with a worse overall survival in
gastric cancer14and esophageal squamous cell carcinoma,23
whereas a reduced expression of CTGF correlates with
advanced stage of disease, lymph-node metastases, and/or
shorter survival in breast cancer,24lung cancer,16,25intrahe-
molecular mechanisms involved in CTGF-mediated modu-
lation of tumor cell behavior have been studied in some of
these neoplasms. They have been found to be related to the
expression of some important cancer progression/suppres-
sion-related molecules or pathways, such as TGF-b, HIF-1a,
b-catenin/Tcf/MMP-7, and PI3K/AKT.11
Collectively, our findings suggest that CTGF is involved in
gallbladder carcinogenesis. Our results showed that CTGF is
expressed at low levels in chronic cholecystitis, suggesting a
role for this protein in the inflammatory process of the
gallbladder. Several lines of evidence have demonstrated the
participation of CCN proteins in inflammation. Interesting-
ly, CCN expression is regulated by several factors that act as
mediators of the inflammatory process (eg, nitric oxide,
interleukins, TNF-a, TGF-b) and, conversely, these also
participate in the regulation of the expression of cytokines,
chemokines, and matrix metalloproteinases.27
It is now accepted that several cancers are linked to
chronic inflammatory states, and that GBC usually emerges
from a background of gallstones and chronic inflammation
of the gallbladder mucosa.28In the dysplasia-carcinoma
sequence the initial lesions on the mucosal epithelium are
attributable to inflammation.29The inflammatory process
could be activated by the irritation caused by gallstones,
which creates a propitious condition for the development of
a persistent local inflammatory state. The chronically
inflamed mucosa undergoes adaptive changes such as
metaplasia that could progress to dysplasia, the most widely
accepted precursor lesion for GBC.30Several cytokines,
growth factors, and small molecules, such as TGF-b, TNF-a,
and COX2, that are actively involved in the inflammatory
response are deregulated in GBC and have been associated
with malignant transformation of gallbladder epithelium.31–
35As mentioned in the literature, CTGF may be differentially
regulated by some components of the inflammatory process,
contributing to pathogenesis in highly inflamed tissues.27,36
We found that CTGF levels increase progressively from CC
to advanced GBC, and, in a cancer-related inflammation
context, it might be possible that complex interactions
between crucial inflammatory mediators and CTGF in early
stages of gallbladder carcinogenesis—in association with
other carcinogenic stimuli—may contribute to the develop-
ment of sequential histologic changes of the mucosal
epithelium favoring the appearance of precursor lesions
that ultimately lead to invasive carcinoma.
We found that CTGF protein levels in infiltrating
gallbladder carcinoma were significantly higher than in
chronic cholecystitis and dysplasia. Furthermore, Kaplan-
Meier curves revealed that high CTGF expression was
significantly associated with improved survival of patients
with advanced GBC (stratified log-rank test, P = .04). These
results suggest that overexpression of CTGF could interfere
with the invasive process in later stages of gallbladder
carcinogenesis. As a key downstream modulator of TGF-b
signaling, CTGF influences the composition of tumor
microenvironment by stimulating the synthesis of extracel-
lular matrix proteins, promoting a desmoplastic reaction and
epithelial-mesenchymal transition through autocrine/para-
crine signaling.37Furthermore, it is noteworthy that CTGF
has been found to be expressed either in neoplastic cells
and/or in the surrounding stromal cells. In some cancers,
such as pancreatic and prostate carcinoma, the expression of
CTGF in stromal cells modulates the tumor behavior.38–40
Advanced GBCs usually show an invasive growth with
desmoplastic reaction. It is possible that an enhanced CTGF
expression in GBC cells may regulate the stromal compo-
sition by means of paracrine action, which could reduce the
tumor growth and spread.
In conclusion, our results suggest that CTGF might be
playing a dual role in the malignant transformation of the
gallbladder. Tumor progression from premalignant to
advanced disease would be accompanied by increased
levels of CTGF expression with an inflammatory back-
ground. This intricate and complex network of inflammatory
components may contribute to carcinogenesis by induction
of genetic and epigenetic changes, causing alterations in
critical pathways and promoting several protumor functions,
including enhanced proliferation, resistance to apoptosis,
tumor neovascularization, and matrix remodeling. In later
stages of gallbladder carcinogenesis, a high expression of
CTGF in tumor cells may affect the spectrum of biological
responses associated to this protein. The mechanisms
involved in this response are unknown, but they are likely
related to important modifications in the tumor microenvi-
ronment. Functional studies in cell lines and animal models
will be necessary to determine whether CTGF acts in an
autocrine or paracrine manner on gallbladder tumor
initiation and progression.
Supported by FONDECYT project 1090171, DIUFRO project
DI09-0082, and grant for support of doctoral thesis CONICYT-
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250Arch Pathol Lab Med—Vol 137, February 2013CTGF Expression and Gallbladder Cancer Progression––Garcia et al