Spontaneous colon cancer (CRC) is traditionally thought to arise from a series of genetic mutations to key tumor suppressors and oncogenes that drive its progression. Recently, however, the importance of the immune system and inflammation in exacerbating CRC development has been demonstrated, as seemingly non-inflammatory tumors have massive infiltration of immune cells. This phenomenon has been deemed “Tumor elicited inflammation” (TEI), whereby the tumor cells recruit immune cells to the tumor, promoting tumor development. Danger Associated Molecular Patterns (DAMPs), proteins that are released during cellular stress or oncogenic transformation, promote a robust immune response and are often up-regulated in cancer. Thus, DAMPs may serve as an initial cue to induce TEI. The precise mechanisms of these so-called “danger signals” in CRC development and TEI have not been fully elucidated.

Using a number of in vitro and in vivo models, we sought to uncover the major cellular producers of danger signals in the tumor microenvironment, how these danger signals recruit various immune cells to the tumor, and finally their effects on tumor progression. We found an up-regulation of three danger signals, S100A8, S100A9, and HMGB-1, in tumor tissue from mouse models of spontaneous CRC, at the RNA and protein levels. In addition, using FACS, the myeloid compartment of sorted immune cells demonstrated the highest expression levels of S100A8 and S100A9, as measured by qPCR. In order to further explore role of danger signals, lentiviral overexpression of S100A8, S100A9, and HMGB-1 was performed in MC38 colon cancer cells. Subsequently, these new cell lines were injected subcutaneously into C57BL/6 mice and tumor development was followed. S100A8 and S100A9 overexpressing tumors showed accelerated development and a greater influx of myeloid cells into the tumor when compared to GFP overexpressing control cells. Future work will focus on the crosstalk between cancer cells and immune cells, the key cellular pathways affected in cancer cells and immune cells, and finally if blockade of these signals has any therapeutic benefit in the treatment of CRC.

Citation Format: Ralph Francescone, Debora Vendramini-Costa, Oxana Dmitrieva, Vivi Hou, David Posocco, Sergei Grivennikov. Role of danger signals in tumor elicited inflammation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3183. doi:10.1158/1538-7445.AM2015-3183

©2015 American Association for Cancer Research.
2015