Both Cytokines, TNFá and IL-1 are Essential for the Tumorigenesis of Mouse Osteosarcoma

Ryotaro Iwasaki DDS, PhD, Department of Dentistry and Oral MaxillofacialSurgery, School of Medicine, Keio University, Tokyo, Japan
Takeshi Miyamoto MD, PhD, OrthopedicSurgery, The University of Keio University, Tokyo, Japan
Mayu Morita DDS, School of Medicine, Keio University, School of Medicine, Keio University, Tokyo, Japan
Tomoaki Mori MD, PhD, Department of Orthopedic Surgery, Keio Univesity,School of Medicine, Tokyo, Japan
Taneaki Nakagawa DDS, PhD, Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, School of Medicine,, Keio University, Tokyo, Japan
Hiromasa Kawana DDS, PhD, Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, School of Medicine, Keio University, Tokyo, Japan
Background and objectives

Chronic inflammation is frequently associated with tumorigenesis in elderly people. By contrast, young people without chronicinflammation often develop tumors considered independent of chronic inflammation but driven instead by mutations. Thus, whether inflammation has a significant role in tumor progression in tumors driven by mutations remains largely unknown.

Although osteosarcoma often causes local swelling and heat sensation in patients, the mechanisms that inflammation regulates tumorigenesis were not fully understood. We searched for the essential cytokines for tumorigenesis by using mouse osteosarcoma cell line AX, which was previously established. When AX cells were administered intraperitoneally into C57B6 mice, they generated bone nodules, metastasis and caused death within 3 weeks. Since serum IL-6 level was elevated in AX injected mice, and the IL-6 expression in AX cells was promoted by TNFα and IL-1, we analyzed AX cell injected IL-6-/-, TNFα-/- and IL-1α-/-IL-1β-/-mice to clarify the roles of inflammatory cytokines in regulating AX’s tumorigenesis as well as to identify a novel therapeutic target for osteosarcoma.

Methods

IL-6-/-, TNFα-/-, IL-1α-/-IL-1β-/-and wild type mice were administered AX cells intraperitoneally, and survival curve was created. Tumorigenesis in each mouse was also analyzed by immunohistochemistry, FACS and RT-PCR. Furthermore, AX injected wild type mice were administered Etanercept, a TNFR1 antagonist, and AZD6244, an ERK inhibitor, and survival curve was created.

Results

AX injected TNFα-/- mice and IL-1α-/-IL-1β-/- mice’s survival rate was almost 100%, however, AX injected IL-6-/-mice all died within 3 weeks and did not improve the survival curve compared with AX injected wild type mice. Both etanercept and AZD6244 treated mice demonstrated improved survival curve compared with control mice.

conclusions

We found that both TNFa and IL-1 maintained AX cells in an undifferentiated state via ERK activation. Thus, inflammatory cytokines are required to promote tumorigenesis.

Reference

c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis. Shimizu T et.al.,Oncogene. 2010 Oct 21;29(42):5687-99

See more of: Poster Session
See more of: Abstract/Poster Sessions
<< Previous Abstract | Next Abstract >>