Colon Cancer as an Example of Inflammatory Induced Cancer

In earlier studies, we demonstrated the importance of the IL-6 trans-signaling pathway for the maintenance of chronic inflammatory bowl disease (Crohn disease) (Atreya et al. 2000).

Interestingly, our studies showed that in Crohn disease patients the T cells from gastric tissue are extremely resistant to apoptosis. Biochemical examinations showed that these T cells produced large amounts of IL-6 and that the intracellular JAK-STAT signal transduction pathway was activated. Surprisingly, treatment of these cells with a neutralizing monoclonal antibody to IL-6R induced apoptosis, although the cells lacked a membrane form of the IL-6R. As the treatment of the cells with sgp130 also induced apoptosis, this effect must have been mediated via the IL-6 trans-signaling pathway (Fig. 2). This finding showed that IL-6 trans-signaling is responsible for the surveillance of activated T cells within gastric tissue from Crohn disease patients by inhibiting apoptotic processes. The sIL-6R needed for IL-6 trans-signaling is most likely provided by shedding of the membrane IL-6R from lamina propria macrophages or infiltrating neutrophils (Atreya et al. 2000; Jostock et al. 2001). Interestingly, it was recently found that in addition to the levels of IL-6, the levels of sIL-6R and sgp130 are also elevated in chronic inflammatory bowel diseases, and that the IL-6 found in the circulation was preferentially complexed to sIL-6R and sgp130 (Mitsuyama et al. 2005).

Fig. 2 Apoptosis of lamina propria mononuclear cells (LPMC) of Crohn disease patients upon treatment with sgp130. LPMCs were isolated and cultured for 48 h in the presence or absence of 10 |ig/ml of a neutralizing mAB-specific for human IL-6R or 10 |ig/ml sgp130Fc. Cells were stained for annexin V and propidiumiodide and analyzed by FACS. The increase in apoptotic (annexin V-posi-tive and propidiumiodide-negative) cells is shown. The data presented are means of triplicate measurements with standard errors shown as vertical bars

Fig. 2 Apoptosis of lamina propria mononuclear cells (LPMC) of Crohn disease patients upon treatment with sgp130. LPMCs were isolated and cultured for 48 h in the presence or absence of 10 |ig/ml of a neutralizing mAB-specific for human IL-6R or 10 |ig/ml sgp130Fc. Cells were stained for annexin V and propidiumiodide and analyzed by FACS. The increase in apoptotic (annexin V-posi-tive and propidiumiodide-negative) cells is shown. The data presented are means of triplicate measurements with standard errors shown as vertical bars

Moreover, the production of sIL-6R as well as IL-6 trans-signaling processes play a dominant role in tumor cell growth. Interestingly, crosstalk between the TGFp and IL-6 pathway was demonstrated (Fig. 3). Inhibition of TGFp production resulted in an increased IL-6 production in mice. Surprisingly, the IL-6 overproduction is accompanied by a loss of membrane bound IL-6R from the cell surface of epithelial cells within tumor lesions. This loss of membrane bound IL-6R was most likely due to an increase of the cell surface expression of the protease ADAM17, which is responsible for cleavage of the IL-6R (Matthews et al. 2003). As the epithelial tumor growth could be inhibited either by a neutralizing antibody directed against the IL-6R or by sgp130Fc, we concluded that the growth of the tumor was promoted by IL-6 trans-signaling but not by the classic signaling via the membrane-bound IL-6R (Becker et al. 2004, 2005). The same observations of downregulation of the IL-6R on the surface of tumor epithelial cells and the upregulation of ADAM17 were made in human colon cancer patients, implying that a similar mechanism operates in human and mouse colon cancer development (Becker et al. 2005). These findings show that interrupting IL-6 trans-signaling with sgp130Fc in colon cancer patients will be a promising new therapeutical strategy.

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