Elevated tumour interleukin-1beta is associated with systemic inflammation: A marker of reduced survival in gastro-oesophageal cancer

Abstract

Systemic inflammation is associated with adverse prognosis cancer but its aetiology remains unclear. We investigated the expression of proinflammatory cytokines within normal mucosa from healthy controls and tumour tissue in cancer patients and related these levels with markers of systemic inflammation and with the presence of a tumour inflammatory infiltrate. Tissue was collected from 56 patients with gastro-oesophageal cancer and from 12 healthy controls. Tissue cytokine mRNA concentrations were measured by real-time PCR and tissue protein concentrations by cytometric bead array. The degree of chronic inflammatory cell infiltrate was recorded. Serum cytokine and acute phase protein concentrations (including C-reactive protein (CRP)) were measured by enzyme-linked immunosorbent assay. Proinflammatory cytokines were significantly overexpressed (interleukin (IL)-1beta, IL-6, IL-8 and tumour necrosis factor-alpha) both at mRNA and protein levels in the cancer specimens compared with mucosa from controls. Interleukin-1beta was expressed in greatest (10-100-fold) concentration and protein levels correlated significantly with systemic inflammation (CRP) (P = 0.05, r = 0.31). A chronic inflammatory infiltrate was observed in 75% of the cancer specimens and was associated with systemic inflammation (CRP: P = 0.01). However, the presence of chronic inflammation per se was not associated with altered cytokine expression within the tumour. Both a chronic inflammatory infiltrate and systemic inflammation (CRP) were associated with reduced survival (P = 0.05 and P = 0.03, respectively). Tumour chronic inflammatory infiltrate and tumour tissue IL-1beta overexpression are potential independent factors influencing systemic inflammation in oesophagogastric cancer patients.

Figure 1

Representative photomicrographs taken from three patients with poorly differentiated adenocarcinoma of the oesophagus. Patient (A) demonstrates minimal/no inflammatory cell reaction. Patient (B) has a patchy chronic inflammatory cell infiltrate. Patient (C) shows a diffuse chronic inflammatory cellular infiltrate present throughout the tumour. Sections of tumour tissue were fixed with formalin and stained with haematoxylin and eosin (magnification × 100).

Figure 2

Kaplan–Meier survival plot presented by serum CRP concentration. Heavy line CRP >10 mg l⁻¹ (median survival 509 days) vs light line CRP <10 mg l⁻¹ (median survival >900 days); P=0.031, log-rank test.

Figure 3

Comparison of cytokine levels of (A) mRNA and (B) protein between tissue from healthy controls and tumour tissue from patients with gastro-oesophageal cancer. The lines represent the median value, bars=interquartile range, error bars=extreme values. IL-1β=interleukin-1β, TNF-α=tumour necrosis factor-α. ^*P<0.05, ^**P<0.01, ^***P<0.001 (Mann–Whitney U-test).

Figure 4

A scatter plot illustrating the relationship between serum CRP concentrations and tumour tissue IL-1β protein concentrations (P=0.05, r=0.31; linear regression).

Figure 5

A diffuse or patchy inflammatory cellular infiltrate was associated with elevated serum CRP concentrations (P=0.01, Mann–Whitney U-test). Thick bar represents median, the box represents quartiles, and lines represent extreme values.

Figure 6

Kaplan–Meier survival plot presented by the presence or absence of a chronic inflammatory cellular infiltrate within the tumour. The heavy line represents the presence of a chronic inflammatory infiltrate vs focal lymphoid aggregates alone, light line (P=0.05; log-rank test).