Journal of Cancer Therapy, 2014, 5, 11-20
Published Online January 2014 (http://www.scirp.org/journal/jct)
http://dx.doi.org/10.4236/jct.2014.51002
OPEN ACCESS JCT
11
Clinical Significance of Platelet-Derived Growth Factor-C
Expression in Colorectal Cancer*
Shinichi Yamauchi1, Satoru Iida1#, Megumi Ishiguro1, Toshiaki Ishikawa2, Hiroyuki Uetake2,
Kenichi Sugihara1
1Department of Surgical Oncology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; 2Department of Transla-
tional Oncology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Received November 19th, 2013; revised December 11th, 2013; accepted December 18th, 2013
Copyright © 2014 Shinichi Yamauchi et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In
accordance of the Creative Commons Attribution License all Copyrights © 2014 are reserved for SCIRP and the owner of the intel-
lectual property Shinichi Yamauchi et al. All Copyright © 2014 are guarded by law and by SCIRP as a guardian.
ABSTRACT
Platelet-derived growth factors (PDGFs) are known to be associated with tumor growth and angiogenesis
through their activation of the receptor tyrosine kinases, PDGF receptors alpha and beta. Several studies re-
vealed the participation of the PDGF family in colorectal cancer (CRC). However, the role of platelet derived
growth factor-C (PDGFC) in CRC is less well studied. This study aimed to determine the correlation between
PDGFC expression and the prognosis of patients with CRCs. Tumor samples were obtained from patients with
CRC who underwent surgical resection between 2002 and 2006. The mRNA expression of PDGFC was investi-
gated by quantitative reverse transcription-polymerase chain reaction in 85 patients with stage I-IV CRC.
PDGFC protein expression was analyzed by immunohistochemistry, and the relationship between PDGFC pro-
tein expression and clinicopathologic features was investigated in 245 patients with stage I-III CRC. PDGFC
mRNA expression in cancer tissues was significantly higher in patients with distant metastases than in those
without metastases (P = 0.016). PDGFC protein overexpression was associated with significantly worse overall
and relapse-free survival (P < 0.0001 and P < 0.0001, respectively). Moreover, PDGFC protein overexpression
was an independent risk factor for CRC recurrence (relative risk = 3.395, 95% confidence interval = 1.895 -
6.081, P < 0.001). In the present study, PDGFC overexpression appeared to be predictive of recurrence and poor
prognosis in patients with CRC.
KEYWORDS
Platelet-Derived Growth Factor-C; Colorectal Cancer; Prognosis, mRNA Expression; Immunohistoch emistry
1. Introduction
Colorectal cancer (CRC) is one of the most prevalent
cancers in the world. It is the third most common cancer
and the second most common cause of cancer-related
mortality worldwide [1]. The mortality rate of this ma-
lignancy has changed little over the last 30 years despite
advances in the understanding of the pathogenesis of this
cancer at the molecular level. Approximately 20% - 40%
of patients with CRC who undergo curative surgery de-
velop local recurrence or distant metastases, resulting in
shorter survival [2]. The tumor node metastasis (TNM)
classification proposed by the International Union
Against Cancer remains an important indicator of prog-
nosis and provides the basis for therapeutic decision-
making [3]. However, the current TNM classification
system is limited in that it cannot predict prognosis for
individual patients. To improve the prognosis of CRC,
there is a crucial need to explore cancer-related genes
that can serve as predictive biomarkers for individualiza-
tion of the rapy [4].
Concerning treatment, the introduction of targeted
therapies, including the epidermal growth factor receptor
(EGFR)-targeting monoclonal antibodies cetuximab and
*No potential conflicts of interest were disclosed.
*Corresponding a uthor.

Clinical Significance of Platelet-Derived Growth Factor-C Expression in Colorectal Cancer
OPEN ACCESS JCT
12
panitumumab and the vascular epithelial growth factor
(VEGF)-targeting monoclonal antibody bevacizumab,
has improved the median survival of patients with me-
tastatic CRC to approximately 24 months. Several path-
ways for tumor growth and tumor angiogenesis, includ-
ing VEGF, fibroblast growth factor (FGF), and plate-
let-derived growth factor (PDGF) pathways that have
been identified recently, have attracted substantial inter-
est due to their potential clinical application [5,6].
The PDGF family is known to be associated with tu-
mor growth and angiogenesis through activation of the
receptor tyrosine kinases (RTKs) PDGF receptor (PDG-
FR) isoforms alpha and beta. A number of studies illu-
strated the importance of PDGFA and PDGFB in the
recruitment of tumor stroma in skin cancer, melanoma,
breast cancer, and lung cancer [7-10]. Conversely, PDG-
FC is a multi-domain protein with a C-terminal domain
capable of binding to and activating PDGFR [11,12]. It is
a potent mitogen for cells of mesenchymal origin, and its
function as an inductor of liver fibrosis has been estab-
lished [11-14]. A tumor growth-promoting function
through the recruitment of fibroblasts has occasionally
been described for PDGFC in a melanoma model and in
hepatocellular carcinoma [13,15,16]. Although several
reports revealed that the expression of PDGFs is related
to CRC, the role of PDGFC in cancer, especially CRC, is
less well studied. Few studies have revealed the rela-
tionship between PDGFC expression and clinical out-
come using samples from patients with CRC. Thus, this
study aimed to identify the correlation between PDGFC
expression and the prognosis of patients with CRC.
2. Methods
2.1. Patients
Primary tumors from 262 consecutive patients who un-
derwent surgical resection for CRC between 2002 and
2006 at Tokyo Medical and Dental University Hospital
were included in our study. All patients provided written
informed consent to participate in this study, and the In-
stitutional Review Board approved the study (approval
number: 831). Samples from 85 patients with stage I-IV
CRC were submitted for quantitative reverse transcrip-
tion-polymerase chain reaction (RT-PCR) analysis, in-
cluding samples from 9 patients with stage I CRC, 25
patients with stage II CRC, 34 patients with stage III
CRC, and 17 patients with stage IV CRC. The median
follow-up time was 48 months for these patients (range:
1 - 66 months). Fourteen patients with stage I-III CRC
experienced a relapse. We divided the 85 patients into
two groups: the non-metastatic (stage I-III without re-
currence, n = 54) and metastatic (stage I-III with recur-
rence and stage IV, n = 31) groups. An immunohisto-
chemical study was performed for 245 patients with
stage I-III CRC, including 68 patients who underwent
RT-PCR analysis, and for 17 patients with stage IV CRC
who underwent RT-PCR analysis. Of 245 patients ana-
lyzed by immunohistochemistry, 55 had stage I disease,
92 had stage II disease, and 98 had stage III disease. The
median follow-up time was 54 months for these patients
(range: 1 - 97 months). Six patients with stage II CRC
and 45 patients with stage III CRC received adjuvant
chemotherapy with 5-fluorouracil/leucovorin (5FU/LV)
or oral uracil and tegafur/leucovorin (UFT/LV) after
radical resection. Among 17 patients with stage IV, 6
patients received systemic chemotherapy and 6 received
hepatic arterial infusion (HAI) chemotherapy. Fifty-two
patients with relapse received the following treatment;
radical resection of metastatic lesions for 16 patients,
systemic chemotherapy for 15, systemic chemotherapy
with HAI chemotherapy for 5, chemo-radiation therapy
for 3, and supportive therapy or others for 13. The regi-
men of systemic chemotherapy included 5FU/LV, 5FU/
LV and oxaliplatin (FOLFOX), FOLFOX and bevacizu-
mab, oral UFT/LV, oral UFT/LV and irinotecan (TE-
GAFIRI), irinotecan alone, S-1 alone, and S-1/irinotecan
(IRIS).
2.2. Quantitative RT-PCR
Total RNA collected from bulk samples of cancer tis-
sues and adjacent non-neoplastic tissues was extracted
and purified using an RNeasy mini kit (QIAGEN) with
oncolumn DNase digestion according to the manufac-
turer instructions. For cDNA synthesis, 10 µg of total
RNA was reverse-transcribed into cDNA using a High
Capacity cDNA Reverse Transcription Kit (Applied
Biosystems, Foster City, CA) according to the manu-
facturer protocol. TaqMan gene expression assays (Ap-
plied Biosystems: PDGFC, Hs00211916_m1; β-actin,
Hs99999903_m1) were used to determine the expression
of PDGFC. β-Actin was used as an inter nal control. PCR
was performed using the TaqMan Universal PCR Master
Mix (Applied Biosystems) with 1 µL of cDNA in a 24-
µL final reaction volume. The thermal cycling conditions
were as follows: 50˚C for 2 min, 95˚C for 10 min, and 40
cycles of 15-s denaturation at 95˚C and 1-min annealing
at 60˚C. All calculated concentrations of target genes
were normalized to the amount of the endogenous refer-
ence by the comparative Ct method for relative quantifi-
cation (∆∆Ct method) using Relative Quantification
Study Software (7300 Sequence Detection System ver-
sion 1.2.1; Applied Biosystems). Each assay was per-
formed in duplicate.
2.3. Immunohistochemist ry
Immunohistochemical studies of PDGFC expression
were conducted using formalin-fixed, paraffin-embedded

Clinical Significance of Platelet-Derived Growth Factor-C Expression in Colorectal Cancer
OPEN ACCESS JCT
13
surgical sections. Following deparaffinization in xylene
and antigen retrieval by microwaving (Microwave-MI 77;
Azumaya Corporation, Tokyo, Japan), pretreatment at
98˚C was performed for 30 min in a high pH target re-
trieval solution (Dako, Carpentaria, CA). The endogen-
ous peroxidase activity was quenched by 15-min incuba-
tion in a mixture of 3% hydrogen peroxide solution in
100% methanol. After washing with phosphate-buffered
saline (PBS), nonspecific binding was blocked by treat-
ing slides with 10% normal rabbit serum IgG (Nichirei
Bioscience, Tokyo, Japan) for 10 min. Following wash-
ing with PBS, the specimens were incubated with a goat
polyclonal antibody against human PDGFC (sc-182280;
Santa Cruz Biotechnology, CA) at a 1:50 dilution over-
night at 4˚C after 60-min incubation at room temperature.
Sections were washed with 0.1% Tween 20/PBS thrice
and incubated with peroxidase-labeled anti-goat antibody
(Histofine Simple Stain Max PO(G); Nichirei Bioscience)
for 30 min at room temperature. Peroxidase activity was
detected via incubation with 0.02% 3,3’-diaminobenzi-
dine tetrahydrochlorid e (Nichirei Bioscience) for 30 min.
The sections were counterstained with hematoxylin.
PDGFC expression was graded by two independent ob-
servers. The semiquantitative assessment of PDGFC im-
munostaining included both the intensity (0, no staining;
1, weak staining; 2, moderate staining; and 3, strong stai-
ning, as compared with positive internal controls) and
extent of staining (1, <10%; 2, 10% - 40%; 3, 41% - 70%;
and 4, >71%). The scores were determined by the sum of
the intensity grade and the extent of staining grade (range
of scores, 1 - 7).
2.4. Statistical Analysis
Statistical analyses of PDGFC expression were con-
ducted using SPSS (version 17.0, SPSS Inc.) for Win-
dows software. Differences between groups were esti-
mated using the Mann-Whitney U test, the Wilcoxon
signed-rank test, and the
χ
2 test. Correlation was esti-
mated using Spearman’s rank correlation coefficient.
Survival curves were estimated using the Kaplan-Meier
method, and comparisons between curves were made
using the log-rank test. Prognostic factors were estimated
using univariate and multivariate analyses (Cox propor-
tional hazards model). P < 0.05 denoted statistical signi-
ficance.
3. Results
3.1. Expression of PDGFC mRNA in Cancer and
Normal Tissues
Quantitative RT-PCR analyses of 85 patients with stage
I-IV CRC revealed that PDGFC mRNA express ion levels
were significantly higher in cancer tissues than in adja-
cent noncancerous tissues (P < 0.001; Figure 1(a)). The
(a)
(b)
Figure 1. PDGFC mRNA expression by qRT-PCR analysis
in 85 patients with stage I-IV CRC. (a) Cancer tissues
showed higher PDGFC expression than normal epithelium
in 85 patients (P < 0.001). (b) PDGFC expression was high-
er in patients with distant metastases or recurrence (metas-
tatic group: n = 31) than in patients without distant metas-
tases (non-metastatic group: n = 54; P = 0.016).
mRNA expression of PDGFC in cancer tissues was sig-
nificantly higher in patients with distant metastases and
recurrence (n = 31) than those without metastases (n = 54,
P = 0.016; Figure 1(b)). Concerning other clinicopatho-
logic parameters, depth of tumor invasion (T1-T3 versus
T4), lymphatic invasion, lymph node metastasis, and
carcinoembryonic antigen (CEA) level before surgical
resection (<5 ng/ml versus >5 ng/ml) were significantly
associated with metastatic CRC (P = 0.00 2, P = 0.001, P
< 0.001, and P < 0.001, respectively).
3.2. PDGFC Protein Expressio n in Cancer and
Normal Tissues
The results obtained for PDGFC protein expression in

Clinical Significance of Platelet-Derived Growth Factor-C Expression in Colorectal Cancer
OPEN ACCESS JCT
14
CRC and normal colorectal epithelium are shown in
Figure 2. PDGFC expression was detected in the mem-
brane and cytoplasm of cancer cells. There was no sig-
nificant localization of staining in cancer tissues. In nor-
mal epithelial cells, 162 patients (74.3%) displayed no
staining or only weak staining and 56 patients (25.6%)
exhibited moderate to strong staining. A significant cor-
relation between the staining score in cancer cells and
staining in normal epithelium was observed in our study
(P = 0.041). PDGFC mRNA expression was correlated
with protein expression in the 85 patients who underwent
RT-PCR analysis (correlation coefficient r = 0.247, P =
0.022; Figure 3).
3.3. High PDGFC Protein Expression Correlates
with Clinicopathologic Variables and
Survival
The experimental samples from patients with out stage IV
CRC that were used for immunohistochemical analysis
were divided into two groups: the low expression (stain-
ing score ≤5, n = 144 [58.7%]) and high-expression
groups (staining score ≥6, n = 101 [41.2%]). There were
26 patients (10.6%) with no staining or almost no stain-
ing in cancer cells. Table 1 shows PDGFC protein ex-
pression in cancer samples and the clinicopathologic data
of 245 patients with stage I, II, or III CRC. The high ex-
pression group had significantly greater frequencies of
lymphatic invasion (P = 0.032), venous invasion (P =
Table 1. Correlation between clinicopathological features
and PDGFC expression in stage I-III CRCsa.
Variables PDGFC expression P
Low (n = 144) High (n = 101)
Age (median), y 31 -92 (66) 20 - 85 (64) 0.289
Gender Male 86 75 0.022
Female 57 26
Location Colon 96 66 0.772
Rectum 47 35
Histology Well 64 38 0.267
Moderate, poor
and others 79 63
Depth T1/T2/T3 104 65 0.164
T4 39 36
Lymphatic
invasion
Absent 49 22 0.032
Present 93 79
Venous
invasion
Absent 26 8 0.022
Present 116 93
Lymph node
metastasis
Absent 89 58 0.450
Present 54 43
CEA (ng/ml) <5 106 64 0.049
>5 34 36
aΧ2 test.
Figure 2. Representative of colorectal cancers and normal colorectal epithelium immunostaining for PDGFC: (a) 0 no stain-
ing; (b) 1+ weak staining; (c) 2+ moderate staining; (d) 3+ strong staining; (e) normal epithelium staining 1 (magnification
200×).

Clinical Significance of Platelet-Derived Growth Factor-C Expression in Colorectal Cancer
OPEN ACCESS JCT
15
Figure 3. PDGFC mRNA expression was correlated with
protein expression in the 85 patients who underwent RT-
PCR analysis and immunohistochemistry (correlation coef-
ficient r = 0.247, P = 0.022).
0.022), and elevated serum CEA levels (P = 0.049) than
the low expression group. In addition, the high expres-
sion group showed tended to have a higher number of
male patients (P = 0.022). There were no significant dif-
ferences in the factors of TNM staging (depth and lymph
node metastasis) between the low expression and high
expression groups among these patients. The relapse-free
survival (RFS) and overall survival (OS) rates were sig-
nificantly lower ( P < 0.0001 and P < 0.0001, respectively)
in patients with high PDGFC protein expression than in
those with low PDGFC protein expression (Figure 4).
Univariate analysis showed that the following factors
were significantly associated with wor se RFS: rectal can-
cer, moderately- or poorly-differentiated and other type
of cancer, T4 tumor, lymphatic invasion, venous invasion,
lymph node metastasis, an elevated CEA level, and high
PDGFC expression (Table 2). Multivariate analysis us-
ing the Cox proportional hazards model indicated that
lymph node metastasis and high PDGFC expression were
associated with worse RF S (relative risk [RR] = 2.184, P
= 0.012 and RR = 3.395, P < 0.001, respectively). Re-
garding OS, univariate analysis identified the following
factors as significantly associated with worse OS: male,
rectal cancer, moderately- or poorly-differentiated and
other type of cancer, T4 tumor, lymphatic invasion,
lymph node metastasis, an elevated CEA level, and high
PDGFC expression (Table 3). Multivariate analysis in-
dicated that gender (RR = 2.900; P = 0.05), location (RR
2.136; P = 0.041), and PDGFC protein overexpression
(RR = 3.374; P = 0.006) were independent risk factors
for the prognosis of patients with CRC.
4. Discussion
In this study, we investigated the correlation between
PDGFC expression and clinicopathologic features in
patients with CRC at both the mRNA and protein levels.
The expression of PDGFC in cancer tissues was signifi-
cantly higher in patients in the metastatic group than in
those in the non-metastatic group, suggesting that PDG-
FC might contribute to metastasis in CRC. To determine
whether PDGFC expression could predict the prognosis
of patients with CRC after curative surgery, we per-
formed immunohistochemical studies using samples
from patients with stage I, II, or III disease. We found
several significant correlations between PDGFC protein
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 20 40 60 80 100
0 20 40 60 80 100 120
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
(a) (b)
Figure 4. Kaplan-Meier curves for RFS (a) and OS (b) of 245 stage I to III CRC patients by PDGFC expression. The RFS and
OS rates were significantly lower (P < 0.0001 and P < 0.0001, respectively) in patients with high PDGFC protein expression
than in those with low PDGFC protein expression.

Clinical Significance of Platelet-Derived Growth Factor-C Expression in Colorectal Cancer
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16
Table 2. Univariate & multivariate analysis of clinicopathological features affecting RFS in stage I-III CRCs (Cox propor-
tional hazards model).
Variables No. patients Univariate analysis Multivariate analysis
P Relative risk (95% confidence interval) P
Age <65 122 0.829
>65 123
Gender Male 161 0.070
Female 84
Location Colon 163 0.028
0.054
Rectum 82
Histology Well 103 0.018
0.376
Moderate, poor and others 142
Depth T1/T2/T3 169 <0.001
0.325
T4 76
Lymphatic invasion Absent 71 0.003
0.438
Present 173
Venous invasion Absent 34 0.029
0.759
Present 210
Lymph node metastasis Absent 148 <0.001 2.184 0.012
Present 97 (1.190 - 4.008)
CEA (ng/ml) <5 170 <0.001
0.152
>5 71
PDGFC Low expression 144 <0.001 3.395 <0.001
High expression 101 (1.895 - 6.081)
expression and clinicopathologic factors. Moreover, mul-
tivariate analysis indicated that PDGFC protein overex-
pression was an independent and significant prognostic
factor for CRC recurrence after curative surgery.
PDGFC is a mitogenic factor for cells of mesenchymal
origin and appears to be involved in all three phases (in-
flammation, proliferation, and remodeling/maturation) of
wound healing [11,17-22]. Several studies identified
PDGFC as a potent antigenic factor, similar to VEGF
and the classical PDGFs [11,23-25]. Abnormalities in the
PDGF/PDGFR system such as constitutive activation of
PDGFR kinases, activating mutations of the PDGFR
kinases, and autocrine signaling due to overexpression of
PDGFs and the PDGFRs contribute to a number of hu-
man diseases, especially malignancies including osteo-
sarcomas, lung carcinomas, gliomas, malignant astrocy-
tomas, and medulloblastomas [26,27]. Oncogenic trans-
formation mediated by the autocrine PDGF loop occurs
through activation of the ras/MAPK pathway, which in-
creases cellular proliferation, and activation of the PI3K/
Akt pathway, which promotes cell survival [28]. The dis-
covery that PDGFB is a v-sis homolog made PDGFB one
of the earliest discovered oncogenes, connecting PDGF/
PDGFR to cellular transformation [29]. The finding that
PDGFC acts similarly as PDGF-AB, the most mitogenic
of all PDGFs [30], as it activates both PDGFR-AA and
PDGFR-AB, indicates a role for PDGFC as an oncogene
[11,31]. PDGFC induces tumor formation in nude mice,
activates anchorage-dependent growth, and is a potent
transforming growth factor in NIH/3T3 cells [32]. In v ivo
tumorigenesis may partially be explained by PDG-
FC-mediated VEGF expression, promoting indirect sti-
mulation of tumor angiogenesis. Moreover, it is known
that PDGFC behaves in a paracrine manner to recruit
cancer-associated fibroblasts (CAFs) and promotes an-
giogenesis and tumor growth. Anderberg et al. revealed
the functional sig nificance of par acrine PDGFC signaling
in the recruitment of CAFs into experimental mouse me-

Clinical Significance of Platelet-Derived Growth Factor-C Expression in Colorectal Cancer
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17
Table 3. Univariate & multivariate analysis of clinicopathological features affecting OS in stage I-III CRCs (Cox propor-
tional hazards model).
Variables No. patients Univariate analysis Multivariate analysis
P Relative risk (95% confidence interval) P
Age <65 122 0.129
>65 123
Gender Male 161 0.013 2.900 0.050
Female 84 (1.000 - 8.411)
Location Colon 163 0.037 2.136 0.041
Rectum 82 (1.030 - 4.430)
Histology Well 103 0.009
0.345
Moderate, poor and others 142
Depth T1/T2/T3 169 <0.001
0.064
T4 76
Lymphatic invasion Absent 71 0.029
0.703
Present 173
Venous invasion Absent 34 0.079
Present 210
Lymph node metastasis
Absent 148 0.004
0.279
Present 97
CEA (ng/ml) <5 170 0.003
0.257
>5 71
PDGFC Low expression 144 <0.001 3.374 0.006
High expression 101 (1.412 - 8.064)
lanoma, thereby augmenting both tumor growth and an-
giogenesis, and a paracrine signaling network involving
PDGFC that regulates the recruitment of CAFs into tu-
mors and their phenotype and is readily available for
therapeutic intervention [15]. Concerning its significance
in the treatment of cancer, some studies repor t the inhibi-
tion of tumor growth via the silencing of this gene. Li et
al. demonstrated that PDGFC overexpression in estab-
lished mouse tumor cell lines accelerates tumor growth
via both autocrine and paracrine modes of action. Ex-
pression of antisense PDGFC mRNA partially inhibits
tumor cell growth and tumor development in cells with
endogenous PDGFC expression [33]. Several tyrosine
kinase pathways are activated by overexpressed PDGFC
in cancer cells via autocrine pathways, thereby promot-
ing tumor growth and anti-apoptosis. It is possible that
tumors with PDGFC-mediated PDGF-receptor activation
are sensitive to tyrosine kinase inhibitors [34]. Thus, al-
though many studies suggest that PDGFC plays an im-
portant role in tumor growth, angiogenesis, and tumor
microenvironment both in vivo and in vitro, its precise
role in cancer and its impact on actual clinical outcomes
remain unknown. In the present study, we observed that
several clinical features were affected by the expression
of PDGFC. This is the first study to demonstrate the r el a-
tionship between PDGFC expression and prognosis in
patients with CRC.
Despite curative surgery for localized disease, approxi-
mately 40% of patients with CRC will eventually relapse
[35]. Recently, some adjuvant chemotherapies for pa-
tients with CRC were indicated to be associated with
improved cure rates after surgery [36]. Despite the effi-
cacy of these chemotherapies, they are costly and asso-
ciated with severe adverse effects. Therefore, there exists
a need to identify patients who would benefit from adju-
vant chemotherapy prior to treatment; molecular markers
may provide important insight concerning this challenge
[37,38], as these markers can be considered when select-

Clinical Significance of Platelet-Derived Growth Factor-C Expression in Colorectal Cancer
OPEN ACCESS JCT
18
ing the appropriate chemotherapy. Our study suggests
that high PDGFC protein expression is predictive of re-
currence after curative surgery for CRC. In the last dec-
ade, the development of novel therapies that target criti-
cal biological pathways has greatly expanded treatment
options for patients with CRC and resulted in substantial
improvements in survival [39]. PDGFC might be a useful
biomarker to decide whether to use strong adjuvant che-
motherapy in patients with CRC af ter curative surgery. In
this study, a subset analysis of patients with stage III
CRC revealed that patients with high PDGFC protein
expression had a poor clinical outcome irrespective of
the use of adjuvant chemotherapy after surgery (data not
shown). Intensive adjuvant chemotherapy may be appli-
cable for patients with CRC and high PDGFC expression
even if they lack other conventional risk factors for re-
currence. Multivariate analysis indicated that lymph node
metastasis and PDGFC protein expression are indepen-
dent prognostic factors for recurrence. Therefore, appli-
cation of PDGFC expression together with a prognostic
indicator such as TNM classification might improve the
prediction of prognosis in patients with CRC. Further-
more, although there is no evidence of synergy between
cytotoxic chemotherapy and molecular targeted drugs for
adjuvant therapy after curative surgery, multiple targeted
RTK inhibitors may have efficacy against PDGFC-over-
expressing CRC because PDGFC may play a role in the
activation of RTK pathways according to some reports.
Moreover, because PDGFC is overexpressed mainly in
cancer cells whereas it is not expressed or only weakly
expressed in normal cells, it may be a novel target for
cancer treatment without adverse effects on normal cells.
5. Conclusion
In conclusion, overexpression of PDGFC in CRCs was
correlated with recurrence and poor prognosis. PDGFC
may be a predictive biomarker of CRC recurrence and a
target for the treatment of this diseas e.
Acknowledgements
We thank Y. Takagi, S. Kishiro and J. Inoue for excellent
technical assistance.
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