Establishment of a novel anti-tumour therapy by regulating the affinity of tumour growth cytokines for their receptors

点击翻译按钮获取中文摘要

To establish a new anti-tumor strategy, we investigated the intratumoural regulating mechanism of tumor growth factors through IL-1-IL-6 sequence cascade. Since intratumoural up-regulation of IL-1-IL-6 sequence cascade causes systemic inflammatory response in the host, systemic inflammatory response and tissue concentrations of cytokines in colorectal cancer patients were determined and an in vitro model was employed to determine the time course induction of interleukin(IL)-6 in Caco-2 cells. Preoperative systemic inflammatory response was associated with recurrent disease and shorter survival time. Surgical stress models showed that intense surgical stress and the presence of a systemic inflammatory response were independently associated with over-expression of IL-6 in the tumor. Enhanced IL-6 protein expression in Caco-2 cells induced by the initial treatment with IL-1 beta or lipopolysaccharide could be abrogated by additional pre-supplementation of IL-1ra. These findings suggest th … More at the presence of a systemic inflammatory response reflects uncontrolled up-regulation of the local IL-1-IL-6 network system in the tumor that may enhance the survival and proliferation of remnant cancer cells after tumor resection.Next, we investigated the expression of VEGF induced by IL-1β in five colon cancer cell lines and the possible involvement of IL-1ra. We found that IL-1β induced a 19-fold increase in Caco2 cells and IL-1ra inhibited IL-1β induced VEGF secretion by 87%. We also investigated intratumoural IL-1-IL-6 sequence cascade in gastric cancer tissue and cell lines. The tissue concentrations of IL-1ra in intestinal type cancers were significantly correlated with those of IL-1□ when they were early-staged. The IL-1ra/IL-1beta ratio in intestinal type cancer significantly decreased with the progression of the disease. With intestinal type cancer, an increased IL-6 Ca/N ratio was associated with liver metastasis and postoperative disease recurrence. Experimentally, both intestinal and diffuse type tumor cell lines produced IL-1beta and IL-6. However, additional pre-treatment of IL-1beta induced a significant decrease in intrinsic IL-1ra production followed by an exaggerated increase in IL-6 protein expression only in intestinal type cell lines. It is concluded from the above studies that an imbalanced synthesis of IL-1 and IL-1ra in gastrointestinal cancers may develop during tumor proliferation that may contribute to over-expression of tumor growth factors and unrestricted tumor growth. Based on these results, we transfected IL-1ra gene in colon cancer cell lines and found that tumor growth was suppressed in some cell lines. It is therefore conceivable that IL-1ra gene therapy is a new anti-tumor strategy which controls the IL-1-tumour growth factor cascade by regulating IL-1-IL-1 receptor binding affinity. Less