Tumor Biol.
DOI 10.1007/s13277-015-3216-6
REVIEW
Hedgehog pathway aberrations and gastric cancer; evaluation
of prognostic impact and exploration of therapeutic potentials
Omar Abdel-Rahman
Received: 16 December 2014 / Accepted: 3 February 2015
# International Society of Oncology and BioMarkers (ISOBM) 2015
Abstract Gastric cancer is an important cause for mortality
and morbidity worldwide; it lies in the fourt rank as a cause of
cancer-related death in males and in the fifth rank of cancer-
related death in women. The prognosis of advanced/metastatic
gastric cancer cases looks poor with the majority of available
therapeutics. Thus, novel therapeutic strategies in this setting
have been considered a priority for leading cooperative oncol-
ogy groups. Hedgehog(Hh) pathway aberrations have sparked
particular interest as prognostic markers with data from mul-
tiple studies showing consistent evidence of a poor prognostic
value of Gli over expression in gastric cancer while on the
other hand the prognostic significance of Hh protein over
expression (particularly SHH) was not consistent among dif-
ferent studies. This review article revises the prognostic and
potential therapeutic opportunities in the targeting of hedge-
hog pathway in gastric cancer.
Keywords Gastric cancer . Hedghog . Vismodegib
Introduction
Gastric cancer (GC) is an important cause for mortality and
morbidity worldwide; it lies in the fourth rank as a cause of
cancer-related death in males and in the fifth rank of cancer-
related death in women [1]. A marked geographical variability
has been observed for gastric cancer incidence with almost
two thirds of cases reported in Eastern Europe, South
America, and Asia [2]. This has been attributed to difference
O. Abdel-Rahman (*)
Clinical Oncology Department, Faculty of Medicine,
Ain shams University, Cairo, Egypt
e-mail: omar.abdelrhman@med.asu.edu.eg
in environmental factors (e.g., Helicobacter pylori infection),
lifestyle/dietary factors as well as genetic predisposition
factors [3, 4].
The prognosis of advanced/metastatic gastric cancer cases
looks poor with the majority of available therapeutics [5].
Thus, novel therapeutic strategies in this setting have been
considered a priority for leading cooperative oncology groups.
The most commonly studied alternative therapies have fo-
cused on targeting novel molecular pathways like epidermal
growth factor receptor (EGFR), vascular endothelial growth
factor (VEGF), and mesenchymal epithelial transition (MET)
[6, 7]. In this review, we revised the prognostic significance of
hedgehog pathway aberrant expression in gastric cancer and
then explored the potential therapeutic opportunities for the
use of hedgehog pathway-targeted agents in this disease tak-
ing into consideration the previously published literature in
other solid tumors.
Basic biology of sonic hedgehog pathway
Hedgehog (Hh) was first identified as a secreted protein that
directs pattern formation in adjacent cells in Drosophila
melanogaster [8]; and shortly after its initial discovery three
mammalian counterparts were found including sonic hedge-
hog (SHH), Indian hedgehog (IHH), and desert hedgehog
(DHH), and an evolutionarily conserved role for these mole-
cules in body organization discovered [9, 10]. In the absence
of the ligand of HH receptor, Patched decreases Smo activity,
that is the driving factor for Hh signaling, and Gli2 and Gli3
are divided by ubiquitin ligases to form transcriptional repres-
sor isoforms [11]. In contrast, in the presence of Hh ligand,
release of inhibition of Smo by Patched occurs, leading to
activation of Smo, and transmission of Gli2 and Gli3 to the
nucleus as activators leading to the transcription of target
genes such as Patched and Gli1 (Fig. 1) [12].
 Tumor Biol.

Fig. 1 Hedgehog signaling (a)

pathway (a) in the absence of
hedgehog protein, with no
transmission of Gli 2 or Gli3 to
the nucleus; (b) in the presence of
hedgehog protein, transmission of
Gli2 and Gli3 to the nucleus as
activators occurs

(b)

Role of hedgehog pathway in gastric carcinogenesis
A number of studies have evaluated the prevalence of hedge-
hog pathway aberrations in gastric cancer and the potential
role played by these aberrations in the development of gastric
cancer. For example, Kim and coworkers investigated the im-
pact of H. pylori infection on the sonic Hedgehog (SHH)
signaling in gastric cancer. SHH, Patched (Ptch), and tran-
scription factor Gli1 were found to be over expressed in
H. pylori-infected gastric cancer cells and loss of SHH expres-
sion due to H. pylori has been hypothesized to be an early
change that occurs in the mucosa prior to neoplastic transfor-
mation. Moreover, CagA-positive H. pylori was found to cor-
relate with a higher SHH expression [13]. This may spot the
light on the potential role played by hedgehog pathway in
H. pylori-related gastric cancer. Moreover, Yang and co-
workers investigated the expression of hedgehog signaling
molecules in 30 specimens of gastric cancer and compared it
to the findings in gastritis specimens. They found that SMO
expression was detected in 18 gastric cancer specimens (60 %)
as well as in half of gastritis specimens (50 %). Moreover, Su
(Fu) was expressed in 15 gastric cancer specimens, HIP in 14
gastric cancer specimens, and PDGFRα in 6 gastric cancer
specimens [14]. Thus, the available evidence suggests a role
played by hedgehog pathway particularly in the pathogenesis
of H. pylori-related gastric cancer and this information may be
exploited further in the prevention and treatment of gastric
cancer particularly in regions with high prevalence of
H. pylori infection.
Prognostic impact of hedgehog pathway aberrations in gastric
cancer
Multiple studies have evaluated the prognostic value of aber-
rations at different levels in the hedgehog pathway including
Tumor Biol.
aberrations in the expression of HH protein and aberrations in
Gli expression.
Impact of Gli over expression
Data from multiple studies have shown a consistent evidence
of the poor prognostic indicator of Gli over expression in
gastric cancer.
& Yan and coworkers evaluated the role of HH pathway in
gastric cancer initiation and progression and found that
Gli1 overexpression and reduced SuFu expression are fre-
quent events in the tissues of gastric cancer. Additionally,
Gli1 overexpression was correlated with a more aggres-
sive phenotype including: poorly differentiated histology-
advanced TNM stage, serosal involvement and lymph
node spread [15].
& Lee and colleagues tried to identify a subgroup of GC
patients with HH activation and subsequently to assess
the impact of the use of an HH inhibitor in HH-activated
GC in vitro. GLI2 expression was correlated with lympho-
vascular invasion. Moreover, an advanced stage and neg-
ative PTCH1 staining were statistically significant unfa-
vorable independent risk factors for overall survival in
multivariate analysis (P < 0.001, 0.045, respectively).
When an HH inhibitor (GDC-0449) was used in vitro, it
had been found to have potent effects on GC cell lines
with SMO overexpression (which may be considered a
predictive marker for response to hedgehog-targeted
agents) [16].
Impact of SHH protein over expression
On the other hand, the prognostic significance of Hh protein
over expression (particularly SHH) was not clearly consistent
among different studies with some studies showing positive
prognostic impact of SHH over expression while other studies
showing the reverse (i.e., correlation between SHH over ex-
pression and more aggressive disease).
& Niu and coworkers evaluated 113 cases of gastric cancer
and 60 cases of normal gastric mucosa for over expression
of SHH. They found that 31.7 % cases of normal gastric
mucosa hadSHH protein overexpression, while 71.7 %
cases of gastric cancer had overexpression. SHH over ex-
pression was correlated with age (P=0.006), tumor differ-
entiation state (P<0.001), T staging (P=0.017), and N
stage (P=0.019). However, they found no significant im-
pact of SHH over expression on either overall or disease
free survival rates (P=0.168 and 0.071, respectively) [17].
& Kim and coworkers evaluated the prognostic role of sonic
hedgehog protein expression by immuno-histochemistry
in a clinically annotated tissue microarray comprising 319
human gastric cancer specimens. The sonic hedgehog
overexpression group included more patients with early
gastric cancer than the low sonic hedgehog expression
group (25.9 vs. 74.1 %, P=0.000). Sonic hedgehog ex-
pression was lower in patients with lymph node metastasis
than in patients without lymph node metastasis (31.4 vs.
68.4 %, P=0.02). Likewise, those patients with a lower
disease stage showed higher sonic hedgehog expression.
Moreover, the median survival of patients with sonic
hedgehog overexpression was significantly prolonged
compared with that of patients with low sonic hedgehog
expression (P=0.03) [18].
& Yoo and coworkers showed that in an analysis of 178
primary human gastric cancer tissues, SHH expression
was positively correlated with lymphatic metastasis and
poor prognosis. Moreover, in xenograft models of human
gastric cancer, enhanced expression of SHH significantly
increases the incidence of lung metastasis [19].
Hedgehog pathway and certain gastric cancer stem cells
A plenty of data has linked the hedgehog pathway aberrations
to gastric cancer stem cells subpopulation (CD44+ve) and
found that hedgehog pathway is essential for their mainte-
nance. Thus, providing a strong rationale for combining
hedgehog-targeted agents with traditional chemotherapy to
ensure complete eradication of the disease.
& Zhang and coworkers found that the expression of SHH,
PTCH1, and GLI3 is increased significantly in the CD44+
CD24 + subpopulation when compared with the CD44−
CD24− subpopulation. Meanwhile, when CD44+ CD24+
subpopulation was injected in mice, 50 % of the mice
developed gastric tumors, while tumors did not develop
in mice until at least 10,000 CD44− CD24− cells were
injected suggesting that this subpopulation represents gas-
tric cancer stem cells [20].
& Likewise, Song and coworkers found that SHH pathway
is essential for maintenance of cancer stem-like cells in
human gastric cancer. The expression levels of PTCH
and Gli1 (which are SHH pathway target genes) were
significantly higher in stem cells than in adherent cells
[21].
Additionally, Wang and coworkers tried to link mutations
in the hedgehog pathway genes SMO and PTCH1 to the dif-
ferent histological subtypes of gastric cancer but they found
that SMO and/or PTCH1 mutations are present in different
histological subtypes of gastric tumors and these do not appear
to be driver mutations in any of these subtypes [22]. These
results are in contrast to those of Fukaya et al. who found that

IHH, SHH, PTCH, and SMO were expressed more frequently
in the diffuse compared to the intestinal subtype of gastric
cancer. Moreover, in diffuse cancers, IHH was expressed in
cells with an epithelial phenotype and SHH in cells with a
mesenchymal phenotype [23].
Agents targeting hedgehog pathway at various stages
of development
Agents targeting the hedgehog pathway in different phases of
development include:
A. Agents targeting hedgehog protein: this includes the
agent Robotnikinin [24, 25].
B. Agents targeting Smo: this includes Vismodegib,
cyclopamine, in addition to the other Smo antagonists
in preclinical phases of development (IPI-927,
LDE225). These drugs inhibit Smo activity by binding
to the one portion of transmembrane segment [26, 27].
However, Smo is notably upstream in this pathway; thus
in case of resistance to one of the Smo antagonists it
seems reasonable to target other targets down in the path-
way. The most pertinent target in such case would be
GLi1.
C. Agents targeting Gli1: examples of Gli 1 inhibitors in-
clude GANT61 and physalin F [26, 27].
Preclinical data of hedgehog pathway inhibitors in gastric
cancer
A number of groups have conducted numerous preclinical
studies to evaluate the targeting of hedgehog pathway in gas-
tric cancer with encouraging results (Table 1). Examples are as
follows:
& Song and coworkers found that gene promoter methyla-
tion of PTCH and HHIP in gastric cancer alters their ex-
pression. Following treatment with 5-aza-dc (which is a
hypomethylating agent), AGS gastric cancer cell lines
showed reduced cell viability and increased apoptosis,
which is accompanied with upregulation of HHIP expres-
sion. These data suggested that loss of expression of
PTCH and HHIP may be caused by the methylation of
their gene promoters. These data indicates the possibility
of the targeting of HH pathway through the hypomethyla-
tion of its negative regulators (HHIP and PTCH) [28].
& Yan and coworkers showed that after treatment with
cyclopamine or GANT61, differentially expressed genes
in gastric cancer cell lines were enriched in the apoptosis.
Thus, inhibitors of the Hedgehog pathway may suppress
gastric cancer cell growth via apoptosis induction [29].
Tumor Biol.
& In an in vivo study using NOD/SCID mousexenografts,
Wan and coworkers have found thatcyclopamine signifi-
cantly prevented tumor growth and development; further
indicating that hindering ofSHH signaling pathway may
be a good therapeutic strategy in gastric cancer treatment
[30].
Thus, the above data clearly demonstrates the preclinical
activity of hedgehog pathway targeting for gastric cancer and
encourages further development of these agents in this
direction.
Clinical experience with hedgehog pathway targeting agents
in advanced solid tumors including gastric cancer (Table 2)
The clearest example of activity of hedgehog pathway
targeting in advanced solid tumors has been in the treatment
of basal cell carcinoma (BCC). Initially, in a multicenter
nonrandomized study, 96 patients with inoperable locally ad-
vanced or metastatic BCC were enrolled and treated with vis-
modegib as a monotherapy. In the 33 patients with metastatic
BCC, response rate was 30 % (P=0.001) while in the 63
patients with locally advanced BCC, response rate was 43 %
(P < 0.001), with complete responses in 13 patients
(21 %) [31].this concept has been further elaborated in
another randomized, placebo-controlled study enrolling
patients with the basal-cell nevus syndrome and compar-
ing vismodegib monotherapy versus placebo. Reduction
in the incidence of new surgically eligible BCC is the
primary end point. Vismodegib hinders the growth of
new BCC in patients with the basal-cell nevus syn-
drome. However, the adverse events associated with
treatment led to treatment discontinuation in more than
half of treated patients [32].
The initial success with BCC management has triggered
enthusiasm for use of vismodegib in other solid tumors with
reportedly high expression of hedgehog pathway. Kaye and
coworkers have presented a phase II, randomized study of
vismodegib versus placebo as a maintenance therapy for pa-
tients with ovarian cancer. However, median PFS was 7.5 and
5.8 months, respectively [HR 0.79; 95 % confidence interval,
0.46–1.35]. Thus, the sought magnitude of benefit was not
achieved for vismodegib maintenance [33].
Likewise, Berlin and coworkers presented a randomized
phase II trial of vismodegib versus placebo with FOLFOX
or FOLFIRI and bevacizumab in patients with untreated met-
astatic colorectal cancer (CRC). The median PFS hazard ratio
(HR) for vismodegib treatment compared to placebo was 1.25
(90 % CI, 0.89–1.76; P=0.28). Thus, vismodegib does not
appear to add to the efficacy of available standard therapy
for metastatic CRC [34].
Tumor Biol.

Both drugs were found to suppress gastric

Following treatment with 5-aza-dc, AGS

apoptosis, which is associated with up

For gastric cancer treatment, Cohen and coworkers con-

high CD44 expression was associated

in the chemotherapy plus VIS group,

associated with improved survival.

Cyclopamine significantly prevented

ducted a randomized phase II study which was reported in

reduced cell viability and induced

with decreased survival, whereas

cancer cell growth via apoptosis

tumor growth and development.

In the chemotherapy alone group,

regulation of HHIP expression.

an abstract form in ASCO GI meeting 2013. In this study,

high CD44 expression was

patients with untreated, metastatic or locally advanced gastric
adenocarcinoma were randomized to FOLFOX plus
Vismodegib or placebo. Median PFS was 11.5 months (vis-
modegib arm) versus 9.3 months (placebo arm) (p=0.34) and
median OS was 12.2 months (vismodegib arm) versus

induction.
13.9 months (placebo arm) (p=0.48) [35]. This indicates that
Results

addition of vismodegib to FOLFOX has no effect on PFS or

OS for unselected gastric cancer population. However, further
blood and tissue biomarker analyses to help determine if there
is a subset of patients who may derive an extra benefit from
Cell viability and apoptosis were
Migration, invasion and survival

Apoptosis and MAPK pathways

analyzed by MTT assay and

Cell cycle arrest and apoptosis

vismodegib are not yet published.
Thus, the negative results for the use of hedgehog targeting
Cell viability assessment

in advanced solid tumors (other than BCC) mandates a para-

digm shift in our approach to clinical trials design in this
flow cytometry

setting. Examples of innovative futuristic trial designs in the

setting of gastric cancer treatment are being described in the
next section.

Suggested futuristic trial design for hedgehog pathway

Cyclopamine/GANT61

Cyclopamine/GANT61
Chemotherapy with or
without vismodegib

targeting in gastric cancer

We propose here a number of approaches to improve the out-

Agents used

come of clinical trials of hedgehog pathway targeting in gas-

5-aza-dc

tric cancer; this includes co-targeting of hedgehog pathway

with other clinically/biologically relevant pathways in gastric
cancer, co targeting of multiple targets within the hedgehog
pathway itself e.g., co targeting Smo and Gli-1 to avoid the
grown as spheroids or sorted
AGS, MKN-45, and NCI-N87

development of resistance or the use of stem cell markers as a

molecular tailoring strategy for selecting patients for therapy
Gastric cancer cell lines

MKN-45 cell line

with hedgehog pathway-targeted agents.

Preclinical experience with hedgehog signaling in gastric cancer

GAM-016 and the

for CD44 (+)

AGS cell lines

A. combination with hedgehog pathway-targeted agents

Cell lines

with other agents

Kameda and coworkers evaluated the role of estrogen receptor

(ER)-α in the regulation of the hedgehog signaling pathway in
xenografts, and patient tumors
Gastric cancer cell lines, tumor

patients with ERα-positive gastric cancer. Their experiment

Cell lines-xenograft model

was based on the observation that ERα is highly expressed in

diffuse-type gastric cancer. They used 17-beta-oestradiol (E2)
as a stimulator forthe ERα pathway while the anti-estrogen
were examined
Type of the study

drug ICI 182 780 (ICI) and small interfering RNA against
ERα were used as inhibitors for ERα andcyclopamine was
Cell lines

Cell lines

used as the hedgehog pathway inhibitor. Activation of the

ERα pathway was found to increase cell proliferation by ac-
tivating the Hh pathway while cyclopamine decreased E2-
induced cell proliferation. This interesting study provides a
Yoon et al.

Song et al.

Wan et al.

hypothesis for a combination strategy targeting both ER path-

Yan et al.
Table 1

way and hedgehog pathway in ERα-positive gastric cancer

Study

[36].
Table 2 Clinical experience with the use of hedgehog pathway-targeting agents in advanced solid tumors including gastric cancer

Study Indication Number of patients ORR PFS/TTP OS G 3–4 Toxicities

1. Basal cell carcinoma

Sekulic et al. Vismodegib in locally advanced 63 patients with inoperable For metastatic disease, 30 % The median duration of
inoperable/metastatic
basal cell carcinoma
2. Ovarian carcinoma
Kaye et al. Vismodegib as a maintenance
therapy for ovarian carcinoma
in second or third complete
remission
3. Colon cancer
Berlin et al. vismodegib versus placebo with 199 patients
FOLFOX or FOLFIRI and
bevacizumab in metastatic
colon cancer
4. Gastric cancer
Cohen et al. FOLFOX with or without
vismodegib in advanced
gastric/gastroesophageal
adenocarcinoma
N/R Muscle spasms, alopecia,
locally advanced (95 % confidence interval response was 7.6 months dysgeusia (taste disturbance),
disease and 33 patients [CI], 16 to 48; P=0.001). in both cohorts. weight loss, and fatigue.
with metastatic disease For locally advanced
disease, 43 % (95 % CI,
31 to 56; P<0.001).
104 patients N/R 7.5 months (vismodegib) and N/R Dysgeusia/ageusia, muscle
5.8 months (placebo). spasms, and alopecia
51 % (placebo) and 46 % The median PFS hazard ratio N/R Fatigue, nausea, asthenia,
(vismodegib), (HR) for vismodegib mucositis, peripheral sensory
treatment compared with neuropathy, weight loss,
placebo was 1.25 (90 % CI, decreased appetite, and
0.89–1.76; P=0.28). dehydration
124 patients (60/64) N/R 11.5/9.3 months (95 % CI 8.5– 12.2/13.9 months Neutropenia 50.0/31.7 (p=0.07),
14.4/6.7–11.9; p=0.34) (95 % CI 10.2–14.3/ neuropathy 23.1/14.3
11.5–16.3; p=0.48). (p=0.33), fatigue 15.4/9.5
(p=0.50), thrombosis 13.5/
11.1 (p=0.92), anemia 9.6/9.5
(p=0.99), hypokalemia 9.6/
4.8 (p=0.52), nausea 7.7/9.5
(p=0.99).

ORR overall response rate, OS overall survival, PFS progression free survival
Tumor Biol.
Tumor Biol.
Other suggested pathways for co targeting in gastric cancer
include the EGFR/Her2 neu, VEGF, and c-MET pathways
due to the important role played by these pathways in the
progression of gastric cancer and the observed resistance with
the agents targeting these pathways which may be caused by
gastric stem cell subpopulations (previously suggested to be
dependent on hedgehog pathway for its maintenance as illus-
trated above). However, the lack of preclinical data in that
respect hinders the proper development of effective strategies
on that basis.
B. Targeting hedgehog pathway as a cancer stem cell
targeting strategy
As illustrated above, hedgehog pathway seems to be critically
important for the maintenance of gastric cancer stem cells,
thus this phenomenon can be exploited to decrease the recur-
rence with current systemic therapy strategies. For example,
Wan and coworkers analyzed tumor samples from a phase II
trial in patients with advanced gastric cancer for CD44 expres-
sion. High CD44 expression was associated with compro-
mised survival in the chemotherapy alone group, whereas in
the chemotherapy plus vismodegib group, high CD44 expres-
sion was associated with improved survival. This suggests that
CD44 expression can be used as a way to further personalize
administration of hedgehog-targeting agents [37].
Conclusions and future directions
Hedgehog pathway has been extensively studies in gastric
cancer. Initially, a role has been suggested to be played by
hedgehog pathway in the pathogenesis of H. pylori-related
gastric cancer. Moreover, an important role has been claimed
for hedgehog pathway-related molecules in determining the
prognosis of gastric cancer. For example, data from multiple
studies have shown a consistent evidence of the poor prog-
nostic indicator of Gli over expression in gastric cancer while
on the other hand the prognostic significance of Hh protein
over expression (particularly SHH) was not clearly consistent
among different studies with some studies showing positive
prognostic impact of SHH over expression while other studies
showing the reverse (i.e., correlation between SHH over ex-
pression and more aggressive disease). Additionally, a plenty
of data has linked the hedgehog pathway aberrations to gastric
cancer stem cells subpopulation (CD44+ve) and found that
hedgehog pathway is essential for their maintenance, thus,
providing a strong rationale for combining hedgehog-
targeted agents with traditional chemotherapy to ensure com-
plete eradication of the disease.
Accordingly, a number of groups have built up on the
above rationale and conducted numerous preclinical studies
to evaluate the targeting of hedgehog pathway in gastric
cancer with encouraging results. Clinically, hedgehog path-
way targeting agents have been evaluated in a number of solid
tumor indications and the most commonly clinically evaluated
agent of this group has been vismodegib. The greatest success
with vismodegib has been in the management of basal cell
carcinoma; in a phase III study, vismodegib reduces the
basal-cell carcinoma tumor burden and blocks growth of
new basal-cell carcinomas in patients with the basal-cell nevus
syndrome. However, the remarkable success achieved with
vismodegib in basal cell carcinoma was not duplicated when
used in other solid tumors like colon, ovary, or unselected
population with advanced gastric cancer. Thus, a paradigm
shift is required when planning for future clinical studies of
hedgehog pathway targeting agents in gastric cancer with ex-
ploitation of molecular tailoring strategies and co targeting
with other important pathways in gastric cancer. Moreover,
innovative designs for proper targeting of gastric cancer stem
cell subpopulation seem particularly attractive.
The fine tuning of gastric cancer systemic therapy and mo-
lecular targeting is a challenging job that requires in depth
knowledge of the preclinical and clinical aspects of develop-
ment and progression of gastric cancer.
Conflicts of interest None
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