HMGB1 as a marker of tumor development in mice with spontaneous hepatoma and implanted MC38 adenocarcinoma

4700

Background: HMGB1, is a DNA binding protein that has recently been described to have cytokine like function when released from cells dying necrotic death. It appears to serve as an endogenous danger signal to the host leading to endothelial cell activation, dendritic cell maturation, stem cell emigration and inflammation. Because most tumors have a component of necrotic cell death, we investigated serum levels of HMGB1 in two distinct murine tumor models. Methods: Serum levels of HMGB1 were measured by Western blot analysis on days 0, 3, 7, and 14 following inoculation of 3x10⁵ MC38 adenocarcinoma tumor cells into the flanks of C57BL/6 mice. In addition, levels of HMGB1 were determined at various time points in a transgenic MT-D2B6 SV40 murine model, which gives rise to spontaneous hepatomas at 12 to 14 weeks of life. Results: Serum levels of HMGB1 were elevated in tumor bearing animals in both the spontaneous and transplantable murine tumor models when compared to control mice. In the transplantable MC38 adenocarcinoma model, elevation in serum levels coincided with the onset of visible tumor after 3 days. Serum levels of HMGB1 were 4.4 times the control at 3 days ( control animals had only trace amounts of HMGB1 detected). HMGB1 levels remained elevated between 3.37 to 4.78 times control on days 7, 10 and 14 during tumor progression. In the spontaneous tumor model, levels of HMGB1 were undetectable before 3 months of age. Starting at 3 months of age HMGB1 was found in the serum of these mice at levels between 52.2 ng/ml to 67.8 ng/ml. HMGB1 levels peaked after 4 months, varying between 64 ng/ml and 130 ng/ml. In this tumor model three months is concurrent with conversion from hyperplasia/dysplasia to overt tumor.Conclusions: Our data demonstrate that the marker of necrotic cell death and cytokine, HMGB1, is elevated in the serum of mice with either spontaneous or implanted tumors. To the best of our knowledge this represents a novel and as yet unreported observation. These observations raise critically important questions regarding the role of HMGB1 in cancer biology that may to development of novel therapies.