Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis

Abstract

Ras is mutated to remain in the active oncogenic state in many cancers. As Ras has proven difficult to target therapeutically, we searched for secreted, druggable proteins induced by Ras that are required for tumorigenesis. We found that Ras induces the secretion of cytokine IL6 in different cell types, and that knockdown of IL6, genetic ablation of the IL6 gene, or treatment with a neutralizing IL6 antibody retard Ras-driven tumorigenesis. IL6 appears to act in a paracrine fashion to promote angiogenesis and tumor growth. Inhibiting IL6 may therefore have therapeutic utility for treatment of cancers characterized by oncogenic Ras mutations.Supplemental material is available at http://www.genesdev.org.

Eryngium foetidum Suppresses Inflammatory Mediators Produced by Macrophages

“…Elevated serum IL-6 in cancer patients or in tumor biopsy indicated that this cytokine plays role in cancer development (Chung et al, 2003;Kai et al, 2005). IL-6 induction by ras gene is a crucial factor for tumor growth in DMBA-TPA-induced skin carcinogenesis model (Ancrile et al, 2007). It also promotes proliferation and survival of pre-malignant intestinal epithelial cells and subsequently enhances the initiation and progression of colitisassociated cancer (Bollrath et al, 2009;Grivennikov et al, 2009).…”

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

“…Remarkably, the induction of interleukin-6 has been recently involved in the mechanisms of RAS-dependent tumorigenesis in vivo (Ancrile et al, 2007). Although this paper was submitted for publication, a paper reporting the AP-1-dependent regulation of miR-21 has been published.…”

Targeting oncogenic Ras: Figure 1.

“…Moreover, reducing IL6 levels through the use of short hairpin RNA (shRNA) knockdown technology markedly attenuated tumorigenesis in vivo. Interestingly, Ancrile et al (2007) present data that argue strongly against autocrine signaling as the reason that IL6 enhances tumor growth. Instead, the data support a paracrine mechanism through which tumor-produced IL6 acts on infiltrating cells in the tissue microenvironment (see Fig.…”

“…However, despite substantial effort, there are currently no agents that effectively counter the biochemical consequences of oncogenic Ras. A provocative paper by Ancrile et al (2007) in the July 15 issue of Genes and Development suggests that interfering with the ability of Ras-driven tumors to modulate the behaviors of other cells in the microenvironment could represent a viable therapeutic approach.…”

“…Ancrile et al (2007) harnessed a tractable system for transforming primary cells with a defined set of genes that includes SV40 T/t antigens, the telomerase catalytic subunit hTERT, the p110 isoform of phosphoinositide-3-OH (PI-3) kinase fused to a CAAX membrane localization sequence, and a regulatable HRAS G12V oncogene (Lim and Counter 2005). Inducing H-Ras G12V protein expression resulted in morphologic transformation and a tumorigenic phenotype, which was associated with dramatic up-regulation of IL6 production in multiple cell types.…”