In this study, the serum levels of both IL-6 and CRP evidenced statistically significant differences in tumor size, tumor invasion depth, and LN metastasis. In the TNM stage, as the stage of the disease increased, serum IL-6 and CRP levels were significantly higher. Additionally, the median levels of IL-6 were significantly higher in the patients with peritoneal seeding than in those without peritoneal seeding, but in CRP, this was not proven. In terms of survival rate and time to cancer progression, the results of this study showed that IL-6 levels were associated with poor prognoses. As IL-6 and CRP levels were associated strongly with disease status, in our multivariate analysis, IL-6 and CRP were not identified as independent factors. In some papers, it has been reported that IL-6 was an effective prognostic indicator in stages II and III . In this study, we conducted multivariate analysis in stage II and III, but we were unable to detect any tendency that would point to IL-6 as an independent prognostic factor.
There have been a great many studies conducted concerning the values and functions of IL-6 in malignancy. The majority of these studies have shown that IL-6 levels were higher in malignancies than in non-malignancies, and increased with increasing tumor size and depth [17–19]. We detected a statistically significant relationship between IL-6 levels and existing LN metastasis. However, some studies have reported no relationship between IL-6 levels and LN metastasis . LN metastasis was shown to be affected by independent predictors in cases of advanced cancers. Many previous studies have also noted that IL-6 levels increased in cases of distant metastasis, especially hepatic metastasis [17, 18]. This result has been attributed to a host of mechanisms, including the autocrine and paracrine pathways. With regard to the autocrine pathway, IL-6 activated the production of IL-6 by tumor cells with the IL-6 receptor. With regard to the paracrine pathway, IL-6-stimulated stromal cells promoted the secretion of tumor growth and adhesion molecules containing VEGF and hepatocyte growth factor (HGF) [2, 17, 19, 21].
CRP has been identified in many previous studies as a poor prognostic factor in several diseases, including coronary artery disease, chronic obstructive pulmonary disease, diabetes mellitus, myeloma bone disease, and a variety of cancers [22–30]. In many studies of cancer patients, it has been noted that elevated CRP levels are associated with tumor size, cancer stage, cancer cachexia, and poor prognosis as independent prognostic indicators [19, 26, 28, 31]. In this paper, we described the relationship between CRP levels and tumor invasion depth, LN metastasis, and TNM stage. The operant mechanism in this regard remains unknown. However, elevations of CRP levels have been reported previously in patients with impaired T lymphocyte response, and thus this mechanism is considered to be related to the immunity system and poor survival rate .
CRP is generated by the liver and other organs in response to the release of IL-6 by monocytes and other immune cells . Thus, when IL-6 levels increased, CRP levels also increased. Although CRP was not found, in this study, to be related to TTP and OS in cancer patients, CRP has generally been connected with IL-6, and IL-6 is associated with cancer prognosis. This study was somewhat limited in that the patients' group was restricted in patients who underwent operations. Thus, this study included more patients who could undergo surgery at a lower stage than those who evidenced contraindications for curative operations, including those patients in stage IV. In particular, as compared with another study concerning the relationship between CRP levels and cancer prognosis, a small number of advanced-stage patients were enrolled in this study .
Elevated serum IL-6 levels have been implicated in many different conditions characterized by chronic inflammation, including viral and bacterial infections, autoimmune disease, ischemia, diabetes mellitus, severe exercise, and malignancy [6, 32]. Actually, when the IL-6 cutoff value was established at 6.77 pg/ml, the TTP and OS differed significantly between patients with IL-6 levels in excess of 6.77 pg/ml, and those with lower IL-6 levels. When the IL-6 cutoff value was established at 6.77 pg/ml, the sensitivity was 80.0% in TTP and 85.7% in OS; the specificity was 55.3% and 50.1%. Although there were many disturbance factors that complicated the elevation of IL-6 levels, the sensitivity of IL-6 in association with TTP and OS was found, in this study, to be sufficiently high. Thus, we surmise that the prognoses in gastric cancer patients with high IL-6 levels would be generally poor.
However, high IL-6 and CRP levels were related to advanced stage, including distant metastasis, in this study, and elevated IL-6 levels were associated with poor outcomes in cases of gastric cancer.