309

ORIGINAL
SDF-1 expression after preoperative chemoradiotherapy is
associated with prognosis in patients with advanced lower
rectal cancer
Shohei Okikawa, Jun Higashijima, Masaaki Nishi, Toshiaki Yoshimoto, Shohei Eto, Chie Takasu, Hideya Kashihara,
Takuya Tokunaga, Kozo Yoshikawa, and Mitsuo Shimada
Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, Tokushima University, Tokushima, Japan

Abstract : Stromal cell-derived factor-1 (SDF-1) expression is associated with cancer progression, as a biomarker
of prognosis. We clarified the significance of SDF-1 expression on chemoradiotherapy (CRT) resistance and prognosis in advanced lower rectal cancer patients. We evaluated 98 patients with advanced lower rectal cancer who
underwent preoperative CRT. All patients received 40 Gy of radiation therapy, with concurrent chemotherapy
containing fluorinated pyrimidines, followed by surgical resection. SDF-1 expression in surgical specimens was
examined by immunohistochemistry. We divided the patients into SDF-1-positive- (n = 52) and SDF-1-negative
groups (n = 46) and compared the clinicopathological factors and survival rates. The SDF-1-positive group was
more resistant to CRT than the SDF-1-negative group (non-responder rate, 63.5% vs. 47.8%, respectively ; p = 0.12).
Overall survival (OS) in the SDF-1 positive group was significantly poorer vs. the SDF-1-negative group (5-year
OS, 73.4% vs. 88.0%, respectively ; p = 0.02), and disease-free survival (DFS) was worse (5-year DFS, 61.0% vs. 74.1%,
respectively ; p = 0.07). Multivariate analysis confirmed that SDF-1 expression was a significant independent
prognostic predictor of OS (p = 0.04). SDF-1 expression after preoperative CRT is significantly associated with apoor prognosis in advanced lower rectal cancer patients and is a promising biomarker. J. Med. Invest. 68 : 309314, August, 2021
Keywords : Rectal cancer, Stromal derived factor-1, Radiation resistance, Preoperative chemoradiotherapy

INTRODUCTION
Preoperative chemoradiotherapy (CRT) is widely used as amajor treatment modality in advanced lower rectal cancer patients to control local tumor progression, allow sphincter-sparing
surgery, and improve survival (1, 2). However, the rate of distantmetastasis after CRT followed by radical operation in advanced
lower rectal cancer patients remains high at 15%–20% (2-4).
New biomarkers are necessary to select patients with a high riskof recurrence and allow for personalized therapy.
Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine andis also known as CXC motif chemokine ligand-12 (CXCL12).
SDF-1 is ubiquitously expressed in almost all organs, and is essential for hematopoiesis, vascular development, cardiogenesis,
and neurogenesis (5-7). CXC chemokine receptor-4 (CXCR4),
which is an SDF-1 receptor, expresses on the cell surface ofhematopoietic stem cells and T and B lymphocytes, and SDF-1
is implicated in the homing of these cells (8, 9). CXCR4 also
express on the surfaces of malignant cells ; the SDF-1 / CXCR4axis enhances cancer cell survival, proliferation, angiogenesis,
and metastasis (10, 11). In addition, high expression of SDF-1 incancer cells attracts CXCR4-positive cells, such as cancer-associated fibroblasts (CAF) or immune cells, including myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg) andtumor-associated macrophages (TAM), to the tumor sites andconverts the tumor microenvironment (TME) to immune tolReceived for publication May 19, 2021 ; accepted June 2, 2021.
Address correspondence and reprint requests to Masaaki Nishi,
MD, PhD, Institute of Health Biosciences, Department of Digestive and Pediatric Surgery, The University of Tokushima Graduate School 3-18-15 Kuramoto, Tokushima 770-8503 Japan andFax : +81-88-631-9698.

erance (12-14). Therefore, SDF-1 might have potential as a new
therapeutic target, and could be a useful biomarker for patientswith malignant tumors.
SDF-1 expression in cancer cells promotes the progression ofbreast cancer, lung cancer, and lymphoma, and could be a biomarker for a poor prognosis (15-17). The significance of SDF-1
expression remains unclear, and few reports have focused on
SDF-1 expression in advanced lower rectal cancer (18, 19). Recently, several reports described that SDF-1 was a factor related
to resistance to radiotherapy for glioblastoma, and head andneck cancer (20, 21). In this study, we evaluated whether SDF-1
expression in cancer cells could induce radiation resistance andlead to a poor prognosis in advanced lower rectal cancer patients
undergoing preoperative CRT.
The aim of this study was to investigate the significance of
SDF-1 expression in advanced lower rectal cancer patients undergoing preoperative CRT.

PATIENTS AND METHODSPatients

We evaluated 98 surgically-resected specimens from advanced
lower rectal cancer patients who underwent preoperative CRT
followed by radical resection from April 2006 to July 2018 at
Tokushima University Hospital. The indications for preoperative
CRT at our institution were previously reported (22). Briefly,
preoperative CRT was offered to advanced lower rectal cancer
patients who were diagnosed with locally advanced (≥ T3 and / or
≥ N1) cancer or to those who were estimated to have T2 cancer
close to or involving the anal sphincter. Preoperative pelvic
irradiation constituted a total dose of 4000 cGy at 200 cGy per
fraction daily, five times weekly. The radiation field included

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S. Okikawa, et al. SDF-1 expression in rectal cancer

the lateral pelvic lymph nodes, and radiation therapy was administered concomitantly with chemotherapy that included
fluorinated pyrimidines. The regimen constituted tegafur-uracil(UFT) or S-1 orally, only (n = 18, n = 45, respectively) ; S-1 andoxaliplatin ; bevacizumab (SOX + Bev, n = 33) ; or S-1 and CPT11 (IRIS, n = 2).
This study was approved by the Institutional Review Board ofTokushima University (Tocms2901-1). This study was conducted according to the principles expressed in the Declaration of
Helsinki. All tissue samples included in this investigation wereobtained with the patients’ informed consent.

Immunohistochemical staining
The immunohistochemical method was reported previously(22). Briefly, paraffin sections were cut at 4-μm thicknesses fromarchival formalin-fixed paraffin-embedded tissue blocks. The
sections were deparaffinized using xylene and dehydrated using
a series of graded ethanol solutions. Endogenous peroxidase
activity was blocked by administering 0.3% hydrogen peroxidase
and methanol. After washing three times for 5 minutes (eachwash) with phosphate-buffered saline (PBS), the sections were
processed in 10 mM EDTA buffer (pH : 9) in a microwave for antigen retrieval. After cooling at room temperature, the sections
were incubated with primary mouse monoclonal antibody forSDF-1 (MAB350, dilution 1 : 50 ; R&D Systems, Minneapolis,
MN, USA) at 4℃, overnight, followed by three washes. The
sections were then incubated with a Dako REAL EnVision / HRP
detection system (Dako, Tokyo, Japan) for 1 hour. After threewashes, 3,3′-diaminobenzidine tetrahydrochloride (DAB) wasused to develop the peroxidase reaction. Nuclei were counterstained with Mayer’s hematoxylin solution to complete theprocedure.
SDF-1 expression in cancer cells was scored by staining
intensity (SI), as follows : no staining = 0 ; weak = 1 ; moderate = 2 ; and strong = 3 (23). We then categorized SDF-1 values
into negative and positive groups (0, 1 : SDF-1-negative ; 2,
3 : SDF-1-positive).

(Japanese Classification of Colorectal, Appendiceal, and Anal
Carcinoma). All specimens with SDF-1-positive grade 2 or 3 wereclassified as responders, and specimens with grade 0 or 1 wereclassified as non-responders.

Statistical analyses
All statistical analyses were performed using JMP statisticalsoftware (version 8.0.1 ; SAS Institute Inc., Cary, NC, USA).
The χ2-test and Mann–Whitney U test were used to compare
the clinicopathological variables between the two groups. Survival curves were created using the Kaplan–Meier method, andthe curves were compared using the log-rank test. p < 0.05 wasconsidered statistically significant.

RESULTS
Typical immunohistochemistry images of SDF-1-positive
cells in lower rectal cancer tissues are shown in Figure 1. All
patients were divided into an SDF-1-positive group (n = 52) or-negative group (n = 46). The clinicopathological characteristics
of each group are shown in Table 1. SDF-1 expression correlated

Pathological evaluation
Evaluation of patients’ therapeutic responses to preoperative
CRT was described previously (24). Briefly, the evaluation ofsurgical specimens was performed according to the histopathological response criteria of the general rules for clinical andpathological studies on cancer of the colon, rectum, and anus

Figure 1. Representative immunohistochemical staining of stromalcell-derived factor-1 (SDF-1).
SDF-1 expression was assessed in the cytoplasm of cancer cells.

Table 1. Comparison of the clinicopathological characteristics between the SDF-1-positive and -negative groups
Variable

SDF-1-negative (n=46)

SDF-1-positive (n=52)

p-valueAge (years)

63 ± 1066 ± 90.11

Sex (M / F)

30 / 1635 / 17

0.82

Location (Ra / Rb / P)

8 / 37 / 1

7 / 42 / 3

0.58

Depth of invasion (T1–2 / T3–4)

24 / 2221 / 31

0.24

Lymph node metastasis (−/ +)38 / 834 / 18

0.05

Lymphatic invasion (−/ +)30 / 929 / 18

0.12

Venous invasion (−/ +)20 / 1924 / 24

0.90

Differentiation (tub1 / tub2 / others)

22 / 22 / 2

20 / 29 / 3

0.47

Stage (0 / I / II / IIIa / IIIb / IV)

6 / 18 / 11 / 5 / 4 / 2

5 / 12 / 16 / 6 / 9 / 4

0.46

Neoadjuvant chemotherapy(UFT / S-1 / IRIS / SOX+Bev)

10 / 26 / 0 / 10

8 / 19 / 2 / 23

0.02

Adjuvant chemotherapy (−/ +)40 / 639 / 13

0.13

SDF-1, stromal cell-derived factor-1 ; y, years ; M, male ; F, female ; Ra, rectum above the peritoneal reflection ; Rb, rectum
below the peritoneal reflection ; P, proctos ; tub1, well differentiated adenocarcinoma ; tub2, moderately differentiated adenocarcinoma ; UFT, uracil / tegafur ; IRIS, irinotecan plus S-1 ; SOX, S-1 combined with oxaliplatin ; Bev, bevacizumab

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The Journal of Medical Investigation Vol. 68 August 2021
with lymph node metastasis and neoadjuvant chemotherapy
regimens. We investigated whether there was a correlation
between SDF-1 expression and the effect of radiation therapy.
Approximately 63.5% of the patients in the SDF-1-positive groupand 47.8% in the SDF-1-negative were non-responders to preoperative CRT (p = 0.12, Fig. 2).
Overall survival (OS) in the SDF-1-positive group was significantly poorer than that in the SDF-1-negative group (5year OS, 74.3% vs. 88.0%, respectively ; p < 0.05 ; Fig. 3A),and disease-free survival (DFS) was also poorer (5-year DFS,
61.0% vs. 74.1%, respectively ; p = 0.07 ; Fig. 3B). Univariate
analysis showed that sex, pT, pN, lymphatic invasion, serum
CEA concentration, and SDF-1-positive expression were significant prognostic factors for OS, and pT, pN, lymphatic invasion, and high expression of SDF-1 were prognostic factors for
DFS (Table 2 and Table 3). Multivariate analysis showed thatSDF-1 was a significant independent risk factor for both OS(relative risk, 2.85 ; p = 0.04 ; Table 2) and DFS (relative risk,
2.07 ; p = 0.06 ; Table 3).

A

Figure 2. Pathological response to preoperative CRT after surgicalresection
The Stromal cell-derived factor-1 (SDF-1)-positive group had more
non-responders compared with the SDF-1-negative group.

B

Figure 3. Kaplan–Meier analysis of overall survival (A) and disease-free survival (B) for stromal cell-derived factor-1(SDF-1) expression.

Table 2. Univariate and multivariate analysis of the prognostic factors for overall survival (OS)Variable

5-year OS (%)

Age (< 60 / ≥ 60 years)

Univariate

Multivariate

p-valueHR (95% CI)

p-value

87.5 / 78.7

0.51

0.84 (0.25–2.82)

0.77

Sex (M / F)81.4 / 79.1

0.70

1.15 (0.40–3.24)

0.78

Tumor differentiation (tub1, tub2 / others)

80.9 / 80.0

0.92

0.79 (0.09–6.82)

0.83

T stage (T1–2 / T3–4)

87.0 / 75.5

0.02

1.40 (0.45–4.32)

0.55

Lymph node metastasis (−/ +)88.1 / 58.8

< 0.012.09 (0.54–8.09)

0.28

Lymphatic invasion (−/ +)88.6 / 57.3

< 0.013.04 (0.94–9.81)

0.06

Venous invasion (−/ +)84.1 / 71.6

0.17

2.41 (0.84–6.91)

0.10

CEA (< 5 ng / ml / ≥ 5 ng / ml )81.3 / 71.4

0.01

4.53 (1.14–17.93)

0.03

Adjuvant chemotherapy (−/ +)83.0 / 71.2

0.19

3.27 (0.81–1.14)

0.08

SDF-1 (negative / positive)

88.0 / 74.3

0.02

2.85 (1.00–8.11)

0.04

HR, hazard ratio ; CI, confidence interval ; y, years ; M, male ; F, female ; tub1, well differentiated adenocarcinoma ; tub2,
moderately differentiated adenocarcinoma ; CEA, carcinoembryonic antigen ; SDF-1, stromal cell-derived factor-1

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S. Okikawa, et al. SDF-1 expression in rectal cancer

Table 3. Univariate and multivariate analysis of the prognostic factors for disease-free survival (DFS)
Variable

5-year DFS (%)

Age (< 60 y / ≥ 60 y)

Univariate

Multivariate

p-valueHR (95% CI)

p-value

79.1 / 63.7

0.31

1.34 (0.51–3.54)

0.54

Sex (M / F)67.9 / 66.3

0.79

0.58 (0.26–1.27)

0.17

Tumor differentiation (tub1, tub2 / others)

67.8 / 60.0

0.73

0.76 (0.16–3.65)

0.73

T stage (T1–2 / T3–4)

84.1 / 53.5

< 0.011.61 (0.59–4.34)

0.34

Lymph node metastasis (−/ +)76.9 / 42.3

< 0.01

3.02 (1.03–8.40)

0.04

Lymphatic invasion (−/ +)74.8 / 36.6

< 0.01

3.11 (1.34–7.19)< 0.01

Venous invasion (−/ +)70.3 / 55.1

0.11

1.61 (0.70–3.71)

0.25

CEA (< 5 ng / ml / ≥ 5 ng / ml )69.0 / 42.8

0.09

2.87 (0.82–10.06)

0.09

Adjuvant chemotherapy (−/ +)71.2 / 52.6

0.06

2.63 (0.13–1.05)

0.06

SDF-1 (negative / positive)

74.1 / 61.0

0.07

2.07 (0.94–4.55)

0.06

HR, hazard ratio ; CI, confidence interval ; y, years ; M, male ; F, female ; tub1, well differentiated adenocarcinoma ; tub2,
moderately differentiated adenocarcinoma ; CEA, carcinoembryonic antigen ; SDF-1, stromal cell-derived factor-1

DISCUSSION
In the current study, we identified the significance of SDF-1
expression as a biomarker for predicting the prognosis of advanced lower rectal cancer patients undergoing preoperative
CRT, using immunohistochemical staining.
SDF-1 activates the downstream signal pathways, such as
PI3K / AKT / mTOR and ERK1 / 2, and enhances cancer cell survival, proliferation, and chemotaxis by binding to CXCR4 (25).
High SDF-1 expression was associated with a poor prognosis inesophagogastric, pancreatic, and lung cancer patients in two meta-analyses (26, 27). In CRC patients, the significance of SDF-1
expression in cancer cells remains controversial because SDF-1
is reported to be both tumor promoting (28) and tumor suppressive (29). There are only a few reports of the significance of SDF-1
expression in cancer cells regarding prognosis in advanced lower
rectal cancer patients (18, 19). In cancer cells, the SDF-1 / CXCR4axis activates intracellular signaling through the MEK / ERK
and PI3K / AKT pathways and promotes cell survival and proliferation, and metastasis (30, 31). In addition, SDF-1 can attract
CXCR4-positive cells, such as CAF, MDSC, Treg, or TAM, tothe tumor sites and assist tumor progression in the TME (10,14). Our data showed that SDF-1 expression in cancer cells after
preoperative CRT was an independent prognostic factor for OS
in advanced lower rectal cancer patients. Our data also showedthat SDF-1 expression correlated with higher recurrence rates.
Our results were compatible with previous reports, and indicate
the significance of SDF-1 in advanced lower rectal cancer patients undergoing preoperative CRT.
Several researchers reported that SDF-1 expression induced
resistance to radiation therapy in glioblastoma, and head andneck cancer (20, 21). Kim et al. reported that upregulation of
SDF-1 before and after preoperative CRT was associated withradiation resistance (18). In our study, SDF-1 expression in cancer cells correlated with response to radiotherapy. To the best of
our knowledge, no previous reports identified the mechanism ofacquiring radiation resistance via upregulation of SDF-1 expression in advanced lower rectal cancer. Recently, converting the
TME has been shown to be an important factor inducing radiation resistance in cancer cells (32-34), and several studies showedthat MDSC and Treg recruitment to the TME was a major factor
in radiation resistance (35, 36). As the SDF-1 / CXCR4 axis plays

a crucial role in recruiting MDSCs and Tregs to the TME (37,38), we speculate that upregulation of SDF-1 expression may induce tumor radiation resistance via infiltration of these immune
cells. In a future study, we will investigate the relationship between SDF-1 expression in tumors and immune cell infiltration.
Increasing experimental evidence suggests using the
SDF-1 / CXCR4 axis as a therapeutic target. Some researchers
showed that inhibiting the SDF-1 / CXCR4 axis improved tumor
malignancy and survival. For example, AMD3100, an anti-CXCR4 drug, was associated with reduced proliferation andmetastasis of cancer cells in ovarian cancer (39), and NOX-A12,
an anti-SDF-1 aptamer, improved the survival of irradiated rats
with glioblastoma (40). Other researchers have also suggested
that modulating the SDF-1 / CXCR4 axis could revert the tolerogenic polarization of the TME, and modulate immunotherapy
with anti-CTLA-4 or anti–PD-1 antibody (13, 41).
There are limitations in our study. While almost 100 tissue
specimens were included in the analysis, sample sizes were relatively small. However, SDF-1 expression correlated with CRT response. To further investigate the relationship between radiation
resistance and SDF-1 expression, it will be necessary to evaluate
not only the SDF-1 expression level after surgical resection, butalso the SDF-1 expression level prior to preoperative CRT.
In conclusion, in advanced lower rectal cancer, cancer cells
expressing SDF-1 were less sensitive to radiation therapy andmore frequently associated with postoperative recurrence. Additionally, SDF-1 expression was an independent prognostic factor
for OS. SDF-1 expression in cancer cells is a useful biomarker
and has the potential to become a new therapeutic target.

CONFLICTS OF INTEREST
The authors declare that they have no conflicts of interest.

ACKNOWLEDGEMENTS
We thank Jane Charbonneau, DVM, from Edanz Group(https://en-author-services.edanz.com/ac) for editing a draft ofthis manuscript.

The Journal of Medical Investigation Vol. 68 August 2021
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