Intra-tumoral interleukin-6 down-regulation system and genetic mutations of tumor suppressor genes in colorectal carcinoma

Abstract

BACKGROUND. The interleukin (IL)-I-IL-6 network, the most potent cascade of pro-inflammatory cytokines, plays an autocrine role in tumor growth. The IL-I-IL-6 network is down-regulated by a phased cytokine inhibitor IL-1 receptor antagonist (ra) and an anti-inflammatory cytokine IL-10. The current study evaluated this down-regulation system in colorectal carcinoma and its relation to the genetic alteration of tumor suppressor genes. METHODS. Seventy-four specimens of primary colorectal carcinoma and normal mucosa were collected to measure tissue concentrations of cytokines. Polymerase chain reaction amplification was performed to investigate the loss of heterozygosity of the microsatellite markers on chromosomes 17p and 18q. RESULTS. The IL-Ira/IL-6 ratio in the carcinoma specimens was lower than ratios in adenomas and normal mucosae and decreased with disease progression. The IL-Ira/IL-6 ratio in early cancers tended to be lower than that in adenomas and normal mucosae. However, the tissue concentrations of IL-1β and IL-10 were not associated with any clinicopathologic parameters. The tissue IL-1ra concentration correlated with that of IL-6 only in adenomas and early cancers. Immunohistochemically, IL-1ra and IL-6 were localized in the tumor cytoplasm. A reduced tissue IL-1ra/IL-6 ratio in the Carcinomas correlated with poor prognosis and was associated with the loss of heterozygosity of the microsatellite markers on chromosomes 18q. CONCLUSIONS. There is an IL-6-IL-1ra network system in colorectal tumors, but this system deteriorates with carcinogenesis and tumor growth. The deterioration of this network system was associated with the allelic loss of a portion of chromosome 18q, reflecting the genetic alteration of tumor suppressor genes. ©2002 American Cancer Society.