Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis
Open accessAbstract
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.
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IL-6 and IL-8 are known drivers of cancer proliferation.
“IL-6 and IL-8, two well- characterized and abundant SASP factors, are known drivers of cancer proliferation 163,164 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [163]
The Summary (page unavailable) reports that IL-6 promotes Ras-driven tumor growth and that inhibiting IL-8 reduced tumor growth in Ras-expressing HeLa cells. But the section ‘Ras-induced IL6 secretion acts in a paracrine fashion to promote tumor growth’ (page unavailable) reports no effect of IL-6 knockdown on proliferation in the tested kidney cells, so tumor growth cannot be equated with cancer-cell proliferation here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOncogenes such as RAS might exert cell-nonautonomous protumorigenic effects through nontransformed cells during the process of inducing senescence.
“Thus, oncogenes such as RAS, which are known to activate protumorigenic paracrine mechanisms during transformation [ 59 – 61 ], might also exert cell-nonautonomous protumorigenic effects through nontransformed cells during the process of inducing senescence ( Figure 7 D).”
From Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor (2008) · cites this paper as [59]
IL6 promotes tumour-supportive angiogenesis in a Ras-driven tumour model.
“In particular, IL6 has been reported to promote tumour-supportive angiogenesis in a Ras-driven tumour model.61”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [61]
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- Authors
- Ancrile, B., Lim, K.-H., & Counter, C. M.
- Affiliations
- Duke University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-07-15
- Volume
- 21
- Issue
- 14
- Pages
- 1714-1719
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1920165
- OpenAlex
- W2119444855
- Cited by
- 422
- References
- 32
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 17 · 2023: 24 · 2022: 19 · 2021: 23 · 2020: 27 · 2019: 15 · 2018: 21 · 2017: 24 · 2016: 20 · 2015: 15 · 2014: 26 · 2013: 30 · 2012: 32
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA94184, R01CA094184)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- oncogenic Ras, interleukin-6, carcinogenesis, paracrine signaling, angiogenesis, tumor growth
- MeSH terms
- Interleukin-6 Inhibitors, Animals, Base Sequence, Cell Line, Humans, Mice, Inbred C57BL, Neoplasms, Experimental, Genes, ras, RNA, Interleukin-6, Gene Expression Regulation, Neoplastic, Mice, SCID, Mice, Knockout, Cell Line, Tumor, Mice
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