*1.3. The Solid Component of ACP Also Demonstrates Elevated Levels of Several Inflammatory Markers*

Multiple studies have also identified high levels of cytokines and inflammatory markers in the solid component of ACPs, lending further support to the theory that inflammation plays a critical role in pathogenesis [18,31]. Gump et al. used micro-array data to demonstrate elevated levels of IL-6R in ACP relative to other pediatric brain tumors [11]. Subsequently, Donson et al. [31], utilized detailed transcriptomic analysis to demonstrate increased expression of pro-inflammatory mediators in ACP solid tumor tissue including IL-6, CXCL1, CLCL8, CXCR2, IL-10 and IDO-1. Separate

work by Martelli et al. [32] used advanced proteomics to investigate the protein signature in ACP. In addition to identifying beta-catenin and its related proteins in solid tumor tissue from seven patients, their analysis also identified the presence of increased levels of alpha-defensins 1–4. As previously stated, these proteins are neutrophil-derived proteins that play an important role in the innate immune response and in inflammation. Their detection in the solid portion of ACP again seems to confirm that the inflammatory response plays an important role in ACP tumorigenesis.

A recent paper by Apps et al. used transcriptome analysis of tumor tissue from 18 patients to identify a pattern of elevated expression of several immune cell markers and immune system genes in ACP [10]. Furthermore, their analysis used immunohistochemistry to reveal the presence of both myeloid-derived and lymphoid-derived cells infiltrating both the reactive glial and tumor epithelial compartments in the ACP samples. They also found that multiple cytokine encoding genes were highly upregulated in ACP and that the expression of such genes correlated with the immune infiltrate and inflammatory cell markers. This would suggest that this upregulated cytokine expression is mostly derived from the infiltrating immune cells rather than from the tumor cells that are over expressing beta-catenin. Finally, they also utilized multiplex ELISA to analyze protein lysates from eight patient ACP samples and this analysis revealed the expression of IL-1B, Il-6, IL-8, IL-10, IL-18, and TNF-alpha in all the samples.
