Int J Clin Exp Pathol 2017;10(1):618-624
www.ijcep.com /ISSN:1936-2625/IJCEP0042188

Original Article
High expression of ADAM10 predicts
a poor prognosis for patients with glioblastoma
Kohei Kanaya1, Keiichi Sakai1,2, Kazuhiro Hongo1, Mana Fukushima3, Masatomo Kawakubo3, Jun
Nakayama3
Department of Neurosurgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan; 2Department of Neurosurgery, Shinshu Ueda Medical Center, 1-27-21 Midorigaoka, Ueda, Japan; 3Department of Molecular Pathology, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Japan
1

Received October 18, 2016; Accepted October 26, 2016; Epub January 1, 2017; Published January 15, 2017
Abstract: A disintegrin and metalloprotease 10 (ADAM10) is a member of the ADAM family of zinc proteases, which
are involved in the shedding of extracellular domains of various cell surface molecule. Several ADAM family members, including ADAM10, have been implicated in cancer growth and progression, however the clinical impact of
ADAM10 expression in glioblastoma remains unclear. ADAM10 has an essential role in Notch1 signaling, therefore,
we examined the expressions of ADAM10 and Notch1 by immunohistochemistry in 50 patients with IDH1 wild-type
glioblastoma. ADAM10 was highly expressed in the tumor specimen of 11 patients but ADAM10 was lowly expressed in 39 patients. No ADAM10 expression was found in normal brain tissue. ADAM10 expression was positively
correlated with Notch1 expression (P = 0.002). Low expression of ADAM10 had a tendency to be longer survival
in our study. In conclusion, the expression of ADAM10 had a correlation with that of Notch1 in glioblastoma and
ADAM10 expression might correlate with tumor growth and be a prognostic factor for patients with glioblastoma.
Keywords: ADAM10, Notch1, glioblastoma, immunohistochemistry, prognosis

Introduction
Glioblastoma is the most common and mostaggressive malignant primary brain tumor.
Despite advances in surgical techniques andconcurrent radiochemotherapy regimens, theprognosis remains poor, with a median survival
time of less than 2 years from diagnosis [1, 2].
For this reason, a great deal of research has
been devoted to identifying the molecularmechanisms driving malignant progression andinvasive growth of glioblastoma.
Invasion and migration of tumor cells are characteristics of aggressive malignancies. Disintegrin and metalloproteases (ADAMs) are afamily of trans-membrane multi-domain metalloproteases that are important regulators ofcell motility and migration, cell adhesion, angiogenesis, and cell signaling in both normalorgan development and tumorigenesis [3-5].
ADAM10 is a member of the ADAM family thathas been implicated in the shedding of a num-

ber of substrates that drive cancer progression[6]. Indeed, ADAM10 expression is associatedwith the pathogenesis and prognosis of several
types of malignancies [7-11]. In in vitro glioma
experiments, ADAM10 was necessary for the
shedding of Cadherin 2 to promote glioblastoma cell migration [12], and L1, an important
molecule for cell migration of neural and tumor
cells, to increase human glioma cell migrationand invasion [13]. Bulstrode et al demonstrated
that inhibition of ADAM10/17 function impairs
the growth of glioma tumor spheres [14]. Little
is known about the clinical significance of
ADAM10 expression in glioblastoma beyond asingle report correlating ADAM10 expression
with the grade of malignancy in human glioma[15].
Recently, Groot AJ et al reported that ADAM10
has an essential role in ligand dependent
Notch1 signaling [16]. Notch1 is a multi-functional receptor with a preeminent role in controlling cell fate specification and self-renewal

ADAM10 expression in glioblastoma
Table 1. Clinical characteristics of glioblastoma patients
Characteristics
Age (years)
Median (range)≥50 years<50 years
GenderMale
FemaleKPS
Median (range)≥70<70
Tumor size
≥5 cm
<5 cm
Surgical extent
BiopsyPartial resection
Subtotal resection
Gross total resection
ADAM10High
Low
Notch1High
Low

No. of patients (%)
59.5 (9-77)
40 (80.0%)
10 (20.0%)32 (64.0%)
18 (36.0%)
80 (20-100)
37 (74.0%)
13 (26.0%)
26 (52.0%)
24 (48.0%)
4 (8.0%)20 (40.0%)
12 (24.0%)
14 (28.0%)
11 (22.0%)
39 (78.0%)
12 (24.0%)
38 (76.0%)

processes in stem cell biology [17]. Importantly,
inhibition of the Notch1 pathway overcomes
apoptosis resistance and sensitizes glioblastoma cells to apoptosis induced by ionizing radiation [18]. The expression of Notch1 is positively
correlated with glioma progression, and highNotch1 protein expression is an independent
predictor of poor survival in glioma [19]. Notch1
also plays an important oncogenic role in thedevelopment and progression of astrocytic gliomas [20].
In the present study, we analyzed ADAM10 and
Notch1 expression levels in glioblastomas using immunohistochemical staining, and compared these data with the clinicopathologicalfeatures of the respective patients. We also
evaluated the prognostic significance of ADAM10 expression in the tumors of glioblastoma patients and assessed the correlation of
ADAM10 and Notch1 expression with clinicaloutcome. To our knowledge, the current study619

is the first to investigate the expression of
ADAM10 immunohistochemically in relation tosurvival in patients with glioblastoma.
Materials and methods
Patients
This study was approved by the Ethics Committee of Shinshu University School of Medicine (registration numbers 2604). Formalinfixed and paraffin-embedded (FFPE) tissue
samples from 50 patients with IDH1 wildtype glioblastoma. The negative expression of
IDH1 was determined by immunohistochemical evaluation. These data collected from consecutive patients with IDH1 wild-type glioblastoma initially treated at our institute from 1989
to 2012. Furthermore, neurologically normal
brain tissues from donor bodies from Shinshu
University Hospital were used as normal controls in this study.
Immunohistochemical analysis
FFPE glioblastoma samples were washed freeof fixative with Tris-buffered saline (TBS; pH
7.6), and exposed to 0.3% H2O2 in TBS for
10 min to inactivate endogenous peroxidase.
For Notch1 staining, samples were pretreatedwith EDTA for 30 min and microwaved. No antigen retrieval was used before ADAM10 immunostaining. For single labeling, FFPE sections
were incubated with ADAM10 antibodies (1:200, Merck Millipore, Darmstadt, Germany) or
Notch1 (1:100, Santa Cruz Biotechnology, Inc.,
Dallas, TX, USA) in a humidity chamber at 4°C
overnight. As the secondary antibody, polyclonal rabbit IgG antibody for ADAM10 and polyclonal goat IgG antibody for Notch1 wereapplied to the sections for 30 min. Staining
was developed with 0.02% 3,3’diaminobenzidine tetrahydrochloride and 0.006% H2O2 in
TBS. The slides were washed three times in
TBS and counterstained with Mayer’s hematoxylin. ADAM10 and Notch1 expression levels
were evaluated as both the proportion ofstained cells (PS) and the intensity of staining(IS). The PS was stratified into four grades:
undetectable, PS grade 0; detectable but≤33%, PS grade 1; 34-66%, PS grade 2; and≥67%, PS grade 3. Similarly, IS was also stratified into four grades: undetectable, IS grade
0; weak, IS grade 1; moderate, IS grade 2; andstrong, IS grade 3. The final score was obtained

Int J Clin Exp Pathol 2017;10(1):618-624

ADAM10 expression in glioblastoma

Figure 1. Immunohistochemical staining of ADAM10 and Notch1. In normal brain, (A) ADAM10 was not expressedand (B) Notch1 was slightly expressed in the cytoplasm of neurons. In glioblastoma, (C) ADAM10 was expressed in
the cytoplasm and nucleus of tumor cells and endothelial cells. (D) Notch1 was mainly expressed in the cytoplasmof tumor cells. Scale bars 50 µm.

by multiplying the IS and PS grades. Finalscores of ≥6 were defined as high, and thoseof <6 were defined as low.

Results

Statistical analysis

The characteristics of the 50 patients enrolled in the study are presented in Table 1. The
median age was 59.5 years (range 9-77 years).
Forty patients were 50 years or older, and 10
patients were under 50 years of age. There
were 32 male patients and 18 female patients.
The median KPS was 80 (range 20-100). Twenty-six tumors were ≥5 cm in diameter and 24
tumors were <5 cm. All patients underwent surgery. Fourteen patients were treated with grosstotal resection, 12 patients with subtotal resection, 20 patients with partial resection, andfour patients with biopsy. High expression of
ADAM10 was observed in 11 patients and low
expression of ADAM10 was observed in 39 patients. High expression of Notch1 was foundin 12 patients and low expression of Notch1
was observed in 38 patients.

The significance of correlations between ADAM10 expression levels and age, gender, Karnofsky Performance Status (KPS), tumor size
and Notch1 expression were assessed using
the Fisher’s exact test. The Kaplan-Meier method was used to estimate survival with comparison made between groups based on ADAM10
expression levels. Log-rank test was used totest differences in survival between the ADAM10 high and ADAM10 low groups. Univariate and multivariate analyses were performed using the Cox proportional hazards
model. Probability values of less than 0.05
(P<0.05) were considered significant. Xlstat®
software for Mac (Addinsoft SARL, Paris,
France) was used for the statistical analysis.
620

Clinical characteristics

Int J Clin Exp Pathol 2017;10(1):618-624

ADAM10 expression in glioblastoma
Table 2. Correlation between ADAM10 expression andclinicopathological factors
ClinicopathologicalfactorsnAge, Median (range) 59.5 (9-77)≥50 years
40<50 years
10
GenderMale
32
Female18
KPS, Median (range) 80 (20-100)
≥70
37
<70
13
Size
≥5 cm
26
<5 cm
24
Notch1 expression
High
12
Low
38
*

ADAM10 expression
p-value
High
Low
8
3

32
7

0.671

8
3

24
15

0.724

7
4

30
9

0.508

4
7

22
17

0.314

7
4

5
34

0.002*

Statisitical significance was determined with Fisher’s exact test.

ADAM10 low compared to ADAM10high by log-rank test (P = 0.033,
Figure 2A).
Kaplan-Meier survival curves andlog-rank tests for ADAM10 in patients
who underwent subtotal and grosstotal resection
We evaluated the prognosis for patients who underwent subtotal or
gross total resection. The median OS
was 319 and 725 days in ADAM10high and low patients, respectively.
Survival was significantly longer inthe patients with ADAM10 low compared to ADAM10 high by log-rank
test (P = 0.006, Figure 2B). However,there was no statistically significant
difference in OS between ADAM10high and ADAM10 low patients who
underwent partial resection and biopsy (data not shown).

Expression of ADAM10 and Notch1 in normal
brain and glioblastoma

Univariate and multivariate analyses of prognostic factors for overall survival

In normal brain, ADAM10 was not expressed,
and Notch1 was slightly detected in the cytoplasm of neurons (Figure 1A, 1B). In a case of
glioblastoma with high expression of ADAM10
and Notch1, ADAM10 was mainly expressed in
the cytoplasm and nucleus of tumor cells, andweak staining was observed in infiltrating endothelial cells (Figure 1C). Notch1 was mainly expressed in the cytoplasm of tumor cells(Figure 1D).

Univariate and multivariate analyses were performed for the survival rates of patients by age,
KPS, extent of resection, ADAM10 expression
and Notch1 expression. Younger age tended to
be associated with better survival with a hazard ratio of 0.434 by univariate analysis (P =0.067). The gross total resection patient grouptended to be better survival, although the difference was not statistically significant. The
ADAM10 low group was associated with significantly better survival with a hazard ratio of
0.432 (P = 0.038) and 0.298 (P = 0.048) by
univariate and multivariate analyses, respectively. However, KPS and Notch1 expression
was not associated with survival (Table 3).

Correlation between ADAM10 expression andclinicopathological factors
We found a significant positive correlation between the expression of ADAM10 and the expression of Notch1 (P = 0.002). No significant
correlations were detected between ADAM10
expression and age, gender, KPS score, or
tumor size (Table 2).
Kaplan-Meier survival curves and log-rank
tests for ADAM10
Kaplan-Meier survival curves were used tocompare patients with high or low ADAM10 expression levels. The median overall survival(OS) was 478 and 633 days in ADAM10 highand ADAM10 low patients, respectively. Survival was significantly longer in the patients with
621

Discussion
ADAM10 is a multipotent molecule involved inregulating ectodomain shedding, and is upregulated in various types of cancers, contributing
to cancer progression and metastasis [21-23].
In a previous study of glioma, Bulstrode et al
demonstrated that ADAM10 was overexpressedin human glioma tissue and was required for
growth of glioma tumor spheres [14]. In thisstudy, we used immunohistochemical staining
to examine ADAM10 expression. ADAM10 was
detected not only in the cytoplasm of glioblasInt J Clin Exp Pathol 2017;10(1):618-624

ADAM10 expression in glioblastoma

Figure 2. Kaplan-Meier survival analysis for overall survival based on ADAM10 expression in patients with glioblastoma. A. Survival was significantly longer in the patients with low ADAM10 expression compared to high ADAM10
expression in 50 patients with glioblastoma (P = 0.033, log-rank test). B. Survival was significantly longer in thepatients with low ADAM10 expression compared to high ADAM10 expression in 26 patients treated with subtotal
and gross total resection (P = 0.006, log-rank test).

Table 3. Univariate and multivariate analyses of factors predicting overall survival
Univariate
Multivariate
HazardHazard
95% CI
p-value
95% CI
p-valueratio
ratio
Age <50 years 0.434 0.177-1.061 0.067 0.565 0.202-1.584 0.278
KPS <70
1.212 0.550-2.671 0.633 1.355 0.569-3.231 0.493
Surgical extenta 2.055 0.948-4.453 0.068 2.063 0.895-4.753 0.089
ADAM10 low
0.432 0.196-0.955 0.038* 0.298 0.090-0.991 0.048*
Notch1 low
1.120 0.538-2.331 0.763 2.170 0.617-7.633 0.227

ADAM10 may be a valid
therapeutic target forglioblastoma.

Our immunohistochemical study revealed thatthe expression of ADAM10 was significantly positively correlatedwith Notch1 expression.
This result suggesteda: without vs. with gross total resection. *Statisitical significance was determined with Cox
that ADAM10 may be
proportional hazards model.
an endogenous Notch1
activator in glioblastotoma cells, but also in the nucleus of glioblasma, an observation that is consistent with studtoma cells and infiltrating endothelial cells.
ies of other cancers including non-small cell
Arima et al reported that in prostate cancer thelung cancer [26], and leukemia, breast cancer,
ADAM-10 protein showed a nuclear localization
lung cancer and glioma [16]. Notch1 plays a[9]. They found a positive correlation between
role in glioma cell migration and invasion [27]nuclear ADAM-10 staining intensity and proand activation of Notch is involved in the regugression of prostate cancer. The results suglation of vessel sprouting [28]. Li et al reported
gested that nuclear translocation of ADAM10that Notch1 expression is correlated with gliowas linked to the pathogenesis and progresma progression, and high Notch1 protein exsion of human prostate cancer [9]. In addition,pression is an independent predictor of poor
ADAM10 regulates endothelial permeability
survival in patients with glioma [29]. However,and T-cell transmigration by shedding of vascuin our study Notch1 was not correlated with alar endothelial VE-cadherin [24], suggesting
prognosis for patients with glioblastoma.
that the expression of ADAM10 in infiltrating
In conclusion, we found that high expression
endothelial cells may be involved in promotingof ADAM10 and Notch1 were observed in thetumor associated angiogenesis through regu22% and 24% patients in IDH1 wild-type gliolation of Vascular Endothelial Growth Factor
blastoma respectively, furthermore, ADAM10(VEGF)-induced endothelial cell function [25].
expression was positively correlated with NotOverall, these data together with confirmation
ch1 expression. However, there was no ADthat ADAM10 was expressed in glioblastoma
and not in normal brain tissue, suggest that
AM10 expression in normal brain tissue. In our
622

Int J Clin Exp Pathol 2017;10(1):618-624

ADAM10 expression in glioblastoma
small study, low ADAM10 expression in thepatients with IDH1 wild-type glioblastoma had
a tendency to be longer survival compared tohigh ADAM10 expression, especially in the patients who underwent subtotal or gross total
resection of the tumor. However, the patientnumber of this study was small and the patients’ background such as age, treatment was
not homogeneous. Although this study waspreliminary, our data suggest that therapeutic
ADAM10 inhibitors may potentiate anti-cancer
therapy for glioblastoma patients, more extensive studies on a larger cohort of patients are
required to definitively elucidate the function
and prognostic significance of ADAM10 expression in glioblastoma.

[3]

[4]
[5]

[6]

Acknowledgements
This study was supported in part by the Research Fund for Health Care Promotion Planin Jyosho Area, Nagano Prefecture, from the
Ministry of Health, Labour and Welfare ofJapan. We would like to thank Ms. Y. Satofor technical support of our laboratory experiments.

[7]

[8]

[9]

Disclosure of conflict of interest
None.
Address correspondence to: Dr. Keiichi Sakai,
Department of Neurosurgery, Shinshu University
School of Medicine, 3-1-1 Asahi, Matsumoto, 3908621, Japan. Tel: +81-263-37-2690; Fax: +81-26237-0480; E-mail: skeiichi@shinshu-u.ac.jp

[10]
[11]

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