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Inhibitory effect of locally produced and exogenous interleukin-6 on tumor growth in vivo
G J Dougherty1, J D Thacker, R S Lavey
1Terry Fox Laboratory, B.C. Cancer Research Centre, Vancouver, Canada.
Abstract:
In order to define the potential antitumor activity of the multifunctional cytokine interleukin-6 (IL-6), retrovirus-mediated gene transfer was used to introduce and express a cDNA encoding human IL-6 in the murine fibrosarcoma cell line Fsa-R. Although these genetically modified tumor cells appeared morphologically and phenotypically identical to control Fsa-R cells and had a similar plating efficiency in vitro, they were found to exhibit greatly reduced tumorigenicity in vivo following intravenous injection into syngeneic recipients. Exogenous IL-6 was shown to produce a similar inhibition of tumor growth in the lung if administered intraperitoneally. In contrast, tumor growth in subcutaneous sites was inhibited only if the tumor cells were engineered to express IL-6 locally, or if IL-6 was administered intratumorally. Intraperitoneal injection of IL-6 had no inhibitory effect. Tumors that did grow from IL-6-producing tumor cell inocula in subcutaneous sites were found to contain large numbers of macrophages. These results demonstrate that the antitumor activity of systemically administered IL-6 varies depending on the site of tumor growth and suggest an important role for IL-6 in the recruitment, proliferation and/or survival of tumor-associated macrophages.
Insights
Interleukin-6 (IL-6) gene transfer reduced tumor growth in mice, but its effectiveness depended on the tumor site. Systemic IL-6 showed antitumor activity, particularly in lung tumors, and influenced macrophages.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Interleukin-6 (IL-6) is a multifunctional cytokine with potential roles in cancer.
- Understanding IL-6's direct antitumor activity is crucial for therapeutic development.
Purpose of the Study:
- To investigate the antitumor potential of interleukin-6 (IL-6).
- To determine the impact of IL-6 expression and administration on tumor growth in vivo.
- To explore the role of IL-6 in the tumor microenvironment.
Main Methods:
- Retrovirus-mediated gene transfer to express human IL-6 in murine fibrosarcoma cells (Fsa-R).
- In vivo tumor implantation (intravenous, subcutaneous) in syngeneic mice.
- Intraperitoneal and intratumoral administration of IL-6.
Main Results:
- Engineered Fsa-R cells expressing IL-6 showed significantly reduced tumorigenicity in vivo.
- Intraperitoneal IL-6 administration inhibited lung tumor growth but not subcutaneous tumors.
- Local IL-6 expression or intratumoral administration was required to inhibit subcutaneous tumor growth.
- Subcutaneous tumors from IL-6-producing cells contained increased macrophages.
Conclusions:
- Systemic IL-6 exhibits site-dependent antitumor activity, with greater efficacy against lung metastases.
- Local IL-6 delivery or expression is necessary for inhibiting subcutaneous tumor growth.
- IL-6 plays a significant role in the recruitment, proliferation, and/or survival of tumor-associated macrophages.