Editors' ChoiceTumorigenesis

Oncogenic Ras-Induced Interleukin-6 Promotes Tumor Growth

Science's STKE  24 Jul 2007:
Vol. 2007, Issue 396, pp. tw258
DOI: 10.1126/stke.3962007tw258

Ras is a membrane-bound small guanosine triphosphatase (GTPase) that mediates signals from receptor tyrosine kinases to members of the mitogen-activated protein kinase (MAPK) family. Mutations in Ras that render it constitutively active are oncogenic, leading to the uncontrolled proliferation of cells and the growth of tumors. Many tumors are associated with such mutants of Ras (such as RasG12V) or with mutations in either upstream activators of Ras or its downstream effectors. However, Ras has not proved to be a very successful pharmacological target, so Ancrile et al. turned their attention to secreted factors associated with Ras-induced tumors. One such factor is the cytokine interleukin-6 (IL-6). IL-6 has both pro- and anti-inflammatory properties, and its abundance is increased in the sera of patients with pancreatic cancer, which is associated with oncogenic Ras mutations. The authors used enzyme-linked immunosorbent assays (ELISAs) to measure IL-6 secretion from a transformed human kidney cell line that expressed 4-hydroxytamoxifen (4-OHT)-inducible RasG12V. The abundance of IL-6 protein in 4-OHT-treated cultures was much higher than in noninduced cultures, and these results were confirmed at the level of IL-6 gene transcription by semiquantitative reverse transcription polymerase chain reaction (RT-PCR) assays. When RasG12V-expressing cells were placed under the skin of the flanks of mice, tumors developed. However, tumors that developed from cells treated with IL-6-specific short hairpin RNAs (shRNAs) were much smaller than those that developed from control shRNA-treated cells. Topical application of the carcinogen 7,12-dimethylbenzanthracene (DMBA) followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) produces papillomas with a high incidence of oncogenic Ras mutations. The authors performed DMBA and TPA treatments of both wild-type and IL-6–/– mice and found that IL-6–/– mice had fewer and smaller tumors than did treated wild-type mice and also developed these tumors later than did their wild-type counterparts. Flow cytometry revealed that RasG12V-induced tumor cells did not express IL-6 receptors, indicating that these cells did not need IL-6 for proliferation. However, immunohistochemical analysis revealed that tumors that developed from IL-6-specific shRNA-treated RasG12V-expressing cells contained far fewer endothelial cells than did tumors that developed from control shRNA-treated RasG12V-expressing cells, suggesting a role for RasG12V-induced IL-6 in stimulating angiogenesis, leading to tumor growth. Finally, using the same in vivo tumor model, the authors showed that treatment of mice with a neutralizing antibody against IL-6 led to smaller tumors (and a slower growth rate) than were observed in control antibody-treated mice. These data suggest that targeting IL-6 in Ras-related cancers might be of therapeutic benefit.

B. Ancrile, K.-H. Lim, C. M. Counter, Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev. 21, 1714-1719 (2007). [Abstract] [Full Text]