CXCR2 expression and postoperative complications affect long-term survival in patients with esophageal cancer

Esophageal cancer is the eighth most common cancer worldwide, with an estimated 482,000
new cases (3.8 % of the total) diagnosed in 2008, and the sixth most common cause
of cancer-related death, with 407,000 deaths (5.4 % of the total) in 2008 1]. The prognosis of esophageal cancer is generally poor because of its biological aggressiveness
and anatomical characteristics. According to the American Joint Committee on Cancer
(AJCC), the postoperative 5-year survival rate is approximately 90 % for stage I esophageal
cancer, and it decreases to 45 % for stage II, 20 % for stage III, and only 10 % for
stage IV 2].

Esophagectomy with radical lymphadenectomy represents the standard treatment for patients
with clinically resectable esophageal cancer 3]. Recently, it was reported that preoperative chemotherapy or preoperative chemoradiotherapy
followed by surgery improves prognosis compared with surgery alone 4]; however, the overall survival (OS) rate remains unsatisfactory. Therefore, there
remains an urgent need to identify novel promising markers that can be used to predict
the survival outcome as well as a new groundbreaking therapy for esophageal cancer.

Radical esophagectomy is one of the most invasive surgical treatments for digestive
tract cancer, and the blood levels of inflammatory cytokines such as interleukin (IL)-1,
IL-6, and IL-8 are increased for several hours after surgery. In addition, compared
with other surgeries, esophagectomy is associated with a higher rate of complications,
such as postoperative pneumonia and anastomotic leakage 5], 6]. Such postoperative complications are known to cause a cytokine storm 7].

Chemokines are small chemotactic cytokines that mediate communication among different
cell types 8]. CXCR2, an IL-8 receptor, is a member of the G-protein–coupled receptor superfamily
and the receptor of Glu–Leu–Arg (ELRþ) CXC chemokines. CXCL1, CXCL2, CXCL3, CXCL5,
and CXCL7 bind specifically to CXCR2, while CXCL6 and CXCL8 (IL-8) are shared ligands
of CXCR1 and CXCR2 9]. CXCR2 expression has been demonstrated in neutrophils, monocytes, eosinophils, mast
cells, basophils, lymphocytes, epithelial cells, and endothelial cells. In addition,
CXCR2 is expressed on several carcinomas, and IL-8 signaling promotes proliferation,
survival, and invasion of cancer cells as well as angiogenesis within tumors 9]–12]. Previously, we reported that the expression of both IL-8 and CXCR2 in esophageal
squamous cell carcinoma (ESCC) was an independent predictor of prognosis 13].

Some reports on a variety of malignancies demonstrated that postoperative complications
may have either a positive or negative impact on long-term oncological survival 14]–18]. The same thing goes for esophageal cancer. Some studies have shown that postoperative
complications are negative predictors of the long-term survival after esophagectomy
19]–21]. However, other studies reported that postoperative complications are not associated
with long-term survival after esophagectomy 22]–24].

It has been reported that serum and plasma levels of IL-8 are enhanced in patients
with sepsis, acute lung injury (ALI), and pneumonia 25]–27].

In our present study, we hypothesized that CXCR2 expression could stratify prognosis
in ESCC patients with postoperative complications. To clarify the prognostic significance
of CXCR2 expression and its relationship with common clinicopathological factors,
particularly postoperative complications, in ESCC, we retrospectively examined 82
primary thoracic esophageal carcinomas using immunohistochemical staining.