Interleukin 6 and C-reactive protein in esophageal cancer

doi:10.1016/j.cca.2012.05.009

Clinica Chimica Acta

Volume 413, Issues 19–20, 9 October 2012, Pages 1583-1590

https://doi.org/10.1016/j.cca.2012.05.009 Get rights and content

Abstract

Esophageal cancer (EC) is one of the most aggressive malignant tumors of the gastrointestinal tract. It is well known that cancer initiation and tumor development are closely linked with inflammation. C-reactive protein (CRP) and interleukin-6 (IL-6) are acute-phase proteins involved in cancer development. It was suggested that CRP and IL-6 play potential roles in the growth and progression of malignant tumors, including EC. The aim of the study was to describe the significance of IL-6 and CRP in the development of esophageal cancer and to assess the potential role of their serum levels as prognostic indicators of EC patient's survival.

Highlights

► The epidemiology and risk factors of esophageal cancer. ► Biochemical features of CRP and IL-6. ► The role of IL-6 and CRP in the development of maligncies. ► The role of IL-6 and CRP in esophageal cancer.

Section snippets

Epidemiology and risk factors of esophageal cancer

Esophageal cancer (EC) belongs to the most aggressive malignant tumors of the alimentary tract and the frequency of new cases of this neoplasm in the Western Europe and USA is still increasing [1], [2]. EC is the eighth most frequent tumor disease and sixth leading cause of cancer death worldwide [3]. The rates of mortality and incidence of EC are similar—the reason of this fact might be the relatively late stage of diagnosis and the rapid progression of tumor [4], [5]. The occurrence of this

C-reactive protein

C-reactive protein (CRP) was initially identified as a substance reacting with pneumococcal C-polysaccharide [19], [20]. This protein belongs to a family of pentraxins and is a pentameric protein, comprising five identical subunits with molecular mass of 110 kDa [21]. The pentameric CRP is the usual form found in plasma. The monomeric form of CRP is essentially expressed in tissues and at sites of inflammation [22], [23]. This form of CRP is characterized by the expression of neoantigenic

Interleukin-6

IL-6 is a protein of 185 amino acids (AA) glycosylated at positions 73 and 172. This cytokine is synthesized as a precursor protein of 212 AA [42]. Monocytes express at least five different molecular forms of IL-6 with molecular masses of 21.5–28 kDa, which differ mainly by post-translational alterations such as glycosylation and phosphorylation [43]. IL-6 isolated from various cell types shows some microheterogeneity in its N-terminus [44]. A 42–45 kDa form has been observed in plasma that is

The role of IL-6 and CRP in the development of malignant tumors

Persistent inflammatory state is the important factor in the development and progression of malignant tumors [57], [58], [59]. The tumor cells overexpress cyclooxygenase 2 and produce prostaglandins to facilitate tumor progression, in response to stimulation by cytokines. The inflammatory cells of tumor microenvironment, such as granulocytes, lymphocytes and macrophages, produce various inflammatory cytokines, particularly IL-6, in a response to tissue necrosis and the presence of tumor cells.

Tissue expression of IL-6 and CRP

It has been suggested that IL-6 and CRP play a potential role in the growth and progression of esophageal cancer. More than moderate levels of RNA for IL-6 and detectable levels of this cytokine in the culture supernatants were observed in human esophageal cancer cell lines using RT-PCR, although there was no correlation between cytokine mRNA expression and IL-6 concentration in supernatants [79].

Some studies showed the expression of IL-6 and its receptor in EC tissue [80], [81], [82]. Oka et

Conclusions

It was shown that IL-6 and CRP play a potential role in the pathogenesis and growth of various malignancies. Production of IL-6 as well as CRP in many malignant tumors, including esophageal cancer cells, has been reported. Esophageal cancer belongs to the most aggressive malignant tumors of the upper gastrointestinal tract. There are two distinct types of this tumor: adenocarcinoma of esophagus and esophageal squamous cell carcinoma, which differ in their etiology, risk factors and incidence.

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The C-reactive protein–albumin–lymphocyte (CALLY) index is a novel inflammatory nutritional biomarker. This study aimed to investigate the potential clinical significance and oncological prognostic role of the preoperative CALLY index in patients with esophageal cancer.
We analyzed the preoperative CALLY index in 146 patients with esophageal cancer. The CALLY index and clinicopathological variables were analyzed by the Mann–Whitney U test, and associations between the CALLY index and survival outcomes were analyzed by Kaplan–Meier analysis and log-rank tests. Univariate and multivariate analyses of prognostic variables were conducted using Cox proportional hazards regression.
A lower preoperative CALLY index was significantly correlated with patient age, advanced T stage, presence of lymph node metastasis, neoadjuvant therapy, lymphatic invasion, and advanced stage classification. The preoperative CALLY index decreased significantly in a stage-dependent manner. Patients with esophageal cancer with a low CALLY index had poorer overall survival, disease-free survival than those with a high CALLY index. Multivariate analysis showed that a low CALLY index was an independent prognostic factor for overall survival, disease-free survival and an independent predictor of postoperative surgical site infection.
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Citation Excerpt :
However, serum CRP is a well-established and commonly used inflammatory marker that reflects the prognosis of patients with various malignancies including esophageal cancer and gastric cancer [40–43]. Additionally, CRP itself has reported to be associated with tumor development and progression in various cancers [44–46]. Taking this evidence together with our novel findings from this study, measurement of LCR could satisfactorily reflect the immunological response, nutritional status, and systemic inflammation in patients with EGJ cancer.
There are still no useful predictive biomarkers for esophago-gastric junction (EGJ) cancer. We compared 15 candidate inflammation-based markers and investigated the clinical impact of the selected biomarker.
One hundred three patients with EGJ cancer between 2002 and 2020 were enrolled, and associations between clinicopathological data and inflammatory biomarkers were retrospectively analyzed. Area under the curve (AUC) values of 15 candidate biomarkers were compared in receiver operating characteristic (ROC) curves regarding overall survival (OS). Clinical impacts of the selected marker were further investigated regarding long-term prognosis, postoperative complications, and preoperative chemotherapy effects.
Lymphocyte/CRP ratio (LCR) demonstrated the highest AUC (0.68552) and was chosen as a candidate biomarker. The high LCR group (LCR >4610) demonstrated significantly better OS (p < 0.0001) and relapse-free survival (RFS) (p < 0.0001) compared with the low LCR group (LCR ≤4610), and preoperative LCR was an independent prognostic factor for both OS (HR 4.97, 95% CI:2.24–11.58; p < 0.0001) and RFS (HR 2.84, 95% CI:1.33–6.14, p = 0.007) in EGJ cancer patients. Another cut-off value was established for postoperative complications, and the incidence rates were significantly higher in the low LCR group (LCR ≤12000) than in the high LCR group (LCR >12000) for all postoperative complications, infectious complications, and surgical site infection (p = 0.013, p = 0.016, and p = 0.030, respectively). Furthermore, patients with decreased LCR after preoperative chemotherapy demonstrated significantly worse RFS compared with patients with increased LCR (p = 0.043).
LCR is a potential biomarker to predict long-term prognosis as well as occurrence of postoperative complications in patients with EGJ cancer.
Silencing of S-phase kinase-associated protein 2 enhances radiosensitivity of esophageal cancer cells through inhibition of PI3K/AKT signaling pathway
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Citation Excerpt :
Esophageal cancer (EC), one of the most aggressive malignant tumors, occurs in the gastrointestinal tract [1].
We investigated the effect of S-phase kinase-associated protein 2 (SKP2) on radiosensitivity of esophageal cancer (EC) cells. Expression of SKP2, PI3K, AKT, Bcl-2 and Bax were assayed in EC. EC cells were transfected with SKP2-siRNA/IGF-1 to detect expression of SKP2, PI3K, AKT, Bcl-2 and Bax. At last, the radiosensitivity of cells in different doses of X (0, 2, 4, 6, 8 Gy) irradiation and cell apoptosis were also detected. EC cells displayed a higher positive expression rate of SKP2, elevated mRNA and protein expression of SKP2, PI3K, AKT, Bcl-2 and Bax, as well as higher extent of PI3K and AKT phosphorylation. SKP2 silencing downregulated mRNA and protein expression of PI3K, AKT and Bcl-2 but increased p27 protein expression, and inhibited the cell survival rate while promoting cell apoptosis. Taken together, silencing SKP2 can inhibit the PI3K/AKT signaling pathway, thereby increasing the radiosensitivity of EC cells.
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As reported in literature, elevated CRP levels represent an inflammatory response secondary to tissue damage induced by infection, trauma and tumor necrosis.6,9 Increased CRP levels have shown to promote tumor growth, even in esophageal carcinoma.5,9,22 The principles concerning the complex relationship between CRP, the inflammatory system and tumor progression are described in detail elsewhere.6,9,22
Inflammation accelerates tumor growth followed by reduced survival in patients with cancer. The aim of this study was to evaluate the prognostic relevance of preoperatively increased levels of C-reactive protein (CRP) and the corresponding Glasgow Prognostic Score (GPS) on patients with esophageal carcinoma undergoing curative esophagectomy.
The data of 174 operated esophageal cancer patients were evaluated retrospectively. Patient's demographic and clinico-pathological data, tumor specific data, preoperative plasma levels of CRP and albumin, the corresponding GPS, overall survival (OS) and progression free survival (PFS) were assessed.
103 (59.2%) had adenocarcinoma and 71 (40.8%) had squamous cell carcinoma. 71 patients (43%) had elevated CRP concentrations. 118 patients (71%) had GPS 0, 41 (25%) GPS 1 and 8 (4%) GPS 2. Mean GPS was 0.3 (0–2). 5-year OS was higher in patients with normal CRP than in those with increased CRP (68% vs. 39%; p = 0.007). 5-year OS in patients with GPS 0 and GPS 1 and 2 were 65% and 31% (p = 0.001). 5-year OS for the whole cohort was 56% (1 year: 83%, 3 years: 64%). Recurrence rate was 16.1% closely associated with GPS (p = 0.002). Median follow-up was 23 months (0–118 months). In multivariate analysis GPS, lymph node involvement, T stage and tumor histology were the independent prognostic parameters (p = 0.004, <0.001, 0.035, 0.010).
Preoperatively increased GPS is significantly associated with reduced postoperative survival and tumor recurrence. The GPS as an independent prognosticator should be interpreted together with the TNM stage when the further postoperative treatment has to be scheduled.
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Invited critical reviewInterleukin 6 and C-reactive protein in esophageal cancer

Abstract

Highlights

Section snippets

Epidemiology and risk factors of esophageal cancer

C-reactive protein

Interleukin-6

The role of IL-6 and CRP in the development of malignant tumors

Tissue expression of IL-6 and CRP

Conclusions

Semin Oncol

Semin Radiat Oncol

J Nutr

Gastrointest Endosc

J Mol Biol

Am J Med Sci

Mol Immunol

J Biol Chem

Mol Immunol

Clin Immunol Immunopathol

Blood

Blood

Gynecol Oncol

Blood

Gynecol Oncol

Cancer Lett

Ann Thorac Surg

Am J Surg

The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence

J Natl Cancer Inst

Global cancer statistics, 2002

CA Cancer J Clin

Prognostic value of microvessel density, matrix metalloproteinase-9 and p53 protein expression in esophageal cancer

J Egypt Natl Cancer Inst

Predictive and prognostic molecular markers in outcome of esophageal cancer

Dis Esophagus

Etiology and risk factors for esophageal carcinoma

Dig Dis

Eurocare-3 summary: cancer survival in Europe at the end of the 20th century

Ann Oncol

Body mass, tobacco and alcohol and risk of esophageal, gastric cardia, and gastric non-cardia adenocarcinoma among men and women in a nested case–control study

Cancer Causes Control

Barrett's oesophagus: optimal strategies for prevention and treatment

Drugs

Evaluation of HPV, CMV, HSV and EBV in esophageal squamous cell carcinomas from a high-incidence area of China

Anticancer Res

Evaluation of the prevalence of human papillomavirus and Epstein-Barr virus in esophageal squamous cell carcinomas

Int J Biol Markers

Evidence of human papilloma virus infection and its epidemiology in esophageal squamous cell carcinoma

World J Gastroenterol

Cancer in cohort of HIV-infected population: prevalence and clinical characteristics

J Cancer Res Clin Oncol

CYFRA 21‐1 serum analysis in patients with esophageal cancer

Clin Cancer Res

Preoperative serum midkine concentration is a prognostic marker for esophageal squamous cell carcinoma

Cancer Sci

Serological reactions in pneumonia with a nonprotein somatic fraction of pneumococcus

J Exp Med

The occurrence during acute infections of a protein not normally present in the blood. I. Distribution of the reactive protein in patients' sera and the effect of calcium on the flocculation reaction with C polysaccharide of pneumococcus

J Exp Med

Identification and partial characterization of multiple native and neoantigenic epitopes of human C-reactive protein by using monoclonal antibodies

J Immunol

Biosynthesis of C-reactive protein

Ann NY Acad Sci

Interactions of C-reactive protein with the first component of human complement

J Immunol

Biosynthesis and postsynthetic processing of human C-reactive protein

J Immunol

Interleukin-6-dependent and independent regulation of the human C-reactive protein gene

Biochem J

C-reactive protein expression in Hep3B cells is exerted at the transcriptional level

Biochem J

Tumor necrosis factor induces acute phase protein in rats

J Biol Regul Homeost Agents

Transforming growth factor B1 regulates production of acute phase proteins

Proc Natl Acad Sci U S A

C-reactive protein is produced by a small number of normal human peripheral blood lymphocytes

J Exp Med

Membrane associated C-reactive protein on rat liver macrophages is synthesized within the macrophages, expressed as neo-C-reactive protein and bound through a C-reactive protein-specific membrane receptor

Hepatology

Invited critical review
Interleukin 6 and C-reactive protein in esophageal cancer